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Recent Developments in
Medicine and Medical Research
Vol. 7
Recent Developments in
Medicine and Medical Research
Vol. 7
India . United Kingdom
Editor(s)
Dr. Barkat Ali Khan
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, D.I. Khan KPK,
Pakistan.
Email: barki.gold@gmail.com, Barkat.khan@gu.edu.pk;
FIRST EDITION 2021
ISBN 978-93-5547-030-0 (Print)
ISBN 978-93-5547-052-2 (eBook)
DOI: 10.9734/bpi/rdmmr/v7
_________________________________________________________________________________
© Copyright (2021): Authors. The licensee is the publisher (B P International).
Contents
Preface
i
Chapter 1
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
Mohamed Rahouma, Massimo Baudo, Shon Shmushkevich, Ayah Hassan, Mostafa
Rahouma, Maha Yahia and Abdelrahman Mohamed
1-16
Chapter 2
Experience with Burn Prevention Program in North Eastern India: A Recent Study
Bhupendra Prasad Sarma, Kabita S. Choudhury and Dipak Sarma
17-34
Chapter 3
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT
(Japanese Version of CWPT): A Recent Study
Takaki Shimura, Eriko Okuyama and Hironori Ohsugi
35-41
Chapter 4
Study about Empowering Clinicians with Lifestyle Changes for Management of
Diabetes
Dalia Biswas and P. A. Nikose
42-49
Chapter 5
A Comparative Clinical Study on Healing Potential of Different Scaffolds
Sangeeta Nawal, Rajesh Nawal, Pallavi Kumbhare and Mousumi Sarkar
50-57
Chapter 6
Counselling for Down Syndrome, are We Doing it Right?
Osama Hafiz El Shazali and Hala Abdullahi
58-63
Chapter 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with
Twin-occlusion Prosthesis
Cora A. Coutinho, Ivy F. Coutinho, Divya Hegde, Chottakyatanahalli R. Vijayalakshmi,
Ruchika Iyer and Akansha Priya
64-73
Chapter 8
The Evolution of Obesity: An Approach for Evolutionary Advantage to a Disease
Keneilwe Malomo and Ontefetse Ntlholang
74-81
Chapter 9
Anastomotic Pseudoaneurysm in Post Renal Transplantation
Kajal N. Patel and Shruti Mehta
82-92
Chapter 10
Assessing the Effects of Thermal Stimulation on Skeletal Muscle-Derived Cell
Density
Masayo Nagai and Hidesuke Kaji
93-99
Chapter 11
α-tocopherol: A Ticket to Prevent Antitubercular Drugs Induced Hepatotoxicity
Rajiv Nehra, Pinki Vishwakarma, Manju Nehra and Shashank Tyagi
100-107
Chapter 12
Determination of Intravenous L- Carnitine in HD Patients and Some of Its Benefits
Abir Farouk Megahed, Ghassoub Mustafa Hles, Amany S. Elbahnasawy and Nagy
Sayed-Ahmed
108-112
Chapter 13
Case Report of Odontoma – Mixed Odontogenic Tumor
S. Vidyalakshmi
113-118
Chapter 14
Determination of a Possible Benefit of 4-Aminoquinoline Drugs to Reset Post-Acute
Inflammation in Old Age
Stephen Allen and Divya Tiwari
119-126
Chapter 15
Study on Nocardia in Psoas Abscess: A Rare Case Presentation
Maninder Kaur and Aruna Aggarwal
127-132
Chapter 16
Determination of Foetal cases of Sirenomelia Sequence with Their Embryological
Correlations
Usha Rani Vanagondi, S. Saritha, Jwalaram Kumar Chaluvadi, Gayathri Pandurangam
and D. Nagajyothi
133-146
Chapter 17
Functional Improvement in β-Islet Cells, Hepatocytes and Cardiomyocytes with
Decreasing Deuterium from Low Carbohydrate Intake in a Type-II Diabetic
Edwin C. Jones and Cortney L. Jardet
147-162
Chapter 18
Determination of Tramadol as an Adjuvant to Ropivacaine in Utrasound Guided
Erector Spinae Plane Block for Postoperative Analgesia after Sternotomy
Sofia Jaswal, Rashi Sarna, Richa Saroa and Sanjeev Palta
163-169
i
Preface
This book covers key areas of Medicine and Medical Research. The contributions by the authors include
Immunotherapy, pneumonitis, cardiotoxicity, pembrolizumab, survival, Burn prevention, first aid, public
awareness, school education, Color words pick-out test, neuropsychological test, Preclinical Stage of
Dementia, Mild Cognitive Impairment, slight disorder, Neurobics, sanskar remodelling, diabetes,
Periapical lesion, Mineral Trioxide Aggregate , Bone Graft , Platelet Rich Fibrin , β- Tricalcium Phosphate,
Platelet Rich Plasma , Children with down syndrome, Counselling, Hemimandibulectomy, mandibular
deviation, paired occlusion, twin occlusion, Obesity, Pseudoaneurysm, Renal transplantation, Ultrasound,
Multislice CT scan, Imaging, Colour Doppler, Thermal stimulation, heat, fomentation, cell growth, cell
division, apoptosis, skeletal muscle-derived cells, Transcriptome, Antitubercular drugs, Hepatotoxicity, α-
tocopherol, antioxidant property, L- Carnitine Administration, Hemodialysis Patients, muscle fatigue,
intradialytic hypotension, Odontoma, compound odontoma, mixed odontogenic tumor, hamartomatous
lesion, Systemic inflammation, frailty, sarcopenia, immune modulation, theophylline, chloroquine,
Immunocompetent, modified acid fast staining, psoas abscess, Nocardia, Sirenomelia, Caudal
Regression Syndrome , vascular steal theory and Teratogenesis, ATP, ATPase nanomotor, β-islet cell,
deuterium-depletion, deuterium-depleted water, glucose tolerance, HBa1c, type-II diabetes, Ultrasound
guided, Erector spinae plane , and block Tramadol. This book contains various materials suitable for
students, researchers and academicians in the field of Medicine and Medical Research.
ii
_____________________________________________________________________________________________________
1Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
2Cardiothoracic Surgery Departments, Weill Cornell Medicine, New York 14853, NY, USA.
3Cardiac Surgery Department, Spedali Civili di Brescia, Brescia, Italy.
4Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.
5Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Egypt.
6Information Technology Department, National Cancer Institute, Cairo University, Egypt.
7Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
*Corresponding author: E-mail: mhmdrahouma@gmail.com;
Chapter 1
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Cardiothoracic Related Complications of Anti-
PD/PD-L1 Immunotherapy
Mohamed Rahouma1,2*, Massimo Baudo3, Shon Shmushkevich2,4,
Ayah Hassan5, Mostafa Rahouma6, Maha Yahia7 and Abdelrahman Mohamed1
DOI: 10.9734/bpi/rdmmr/v7/8497D
ABSTRACT
Background: Despite their high prevalence of cutaneous, gastrointestinal, and endocrine adverse
effects, anti-PD/PD-L1-targeted immunotherapy is associated with astonishingly high rates of
persistent clinical responses in patients across a range of tumour types. Pneumonitis and
cardiotoxicity risks linked with checkpoint inhibitor therapy are not well addressed.
Methods: In cancer patients, a systematic review of the literature was undertaken on randomised
clinical trials (RCTs) comparing anti-PD/PD-L1 mono-immunotherapy (IMM) to chemotherapy (CTH)
procedures. The primary endpoint was the rate of pneumonitis in IMM compared CTH.
Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor
response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH (III)
comparison of cardiotoxicity grades in IMM to others (IV) cardiotoxicity grade difference between IMM
and other studies having lung cancer and other cancer subgroups and in IMM compared with
chemotherapy (CTH) only studies (V) outcome of IMM compared with others (in all studies and in lung
cancer/other cancers subgroups) as well as in IMMs compared with CTH only studies and (VI)
difference in mortality in the same groups. Random model, leave-one-out- analysis and meta-
regression were performed.
Results: Thirteen RCTs studying 7,246 patients for pneumonitis and 11 RCTs studying 6574 patients
for cardiotoxicity were included; Both high-grade and all-grade pneumonitis were higher among
patients in the IMM arm when compared to the CTH arm (OR =4.39, 95% CI =1.65–11.69, P=0.003
and OR =2.46, 95% CI =1.29–4.6, P=0.007). Tumor response rate was significantly better in the
immunotherapy arm (OR =2.31, 95% CI =1.62–3.29, P<0.001). PFS and OS were longer in patients
who received IMM compared to patients in the CTH arm (HR =0.75, 95% CI =0.65–0.85, P<0.001,
and HR =0.71, 95% CI =0.66–0.77, P<0.001). There was no difference in all grade cardiotoxicity
among all recruited studies (RR: 1.15; 95% CI: 0.73–1.80; p = 0.55) or in subgroups of lung cancer
(RR: 0.68; 95% CI: 0.22–2.09; p = 0.50) or other cancers (RR = 1.27; 95% CI: 0.78–2.08; p = 0.34).
Similarly, no difference was present in high grades cardiotoxicity among all recruited studies (RR:
1.47; 95% CI: 0.87–2.46; p = 0.15) or in subgroups of lung cancer (RR: 0.80; 95% CI: 0.25–2.50; p =
0.70) or other cancers (RR: 1.71, 95% CI: 0.96–3.06; p = 0.07).
Conclusions: When compared to traditional CTH regimens for NSCLC and melanoma, anti-PD-1
therapy caused more high-grade and all-grade pneumonitis, but not anti-PD-L1 therapy. Other than
that, high-grade adverse events were more common in the CTH arm. Tumor response rate, PFS, and
OS are all significantly improved with IMM over CTH. These findings can be utilised to help guide
therapy selection and set treatment expectations for these patients. Cardiotoxicity was statistically
insignificant regardless the treatment regimen either chemotherapy or dual immunotherapy. The use
of anti-PD/PDL1 provided better response and survival rates when used in lung cancer subgroup.
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
2
Keywords: Immunotherapy; pneumonitis; cardiotoxicity; pembrolizumab; survival; response.
1. INTRODUCTION
1.1 Immune Checkpoint Inhibitors
The landmark paper published in 1996 experimentally demonstrated for the first time the idea that one
of the immune system checkpoints, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), could be targeted
with a monoclonal antibody to enhance anti-tumor immunity, which eventually led to treatment of
cancer in mouse model [1]. This was a discovery that granted the authors the 2018 Nobel prize in
Medicine. Fifteen years after the publication of the paper, the first monoclonal antibody targeting
human CTLA-4 (ipilimumab), was approved to treat melanoma [2]. Other immune checkpoints were
subsequently studied as potential therapeutic targets, including programmed death receptor ligand 1
(PD-L1) [3,4].
Checkpoint inhibition therapy, specifically antibodies targeting programmed cell death protein 1 (PD-1)
and PD- L1 on lymphocytes and tumor cells, plays an important role in downregulating immunologic
tumor escape mechanisms [5]. Although these therapies have shown remarkable success in
treatment of various malignancies including NSCLC and melanoma [6,7], anti-PD-1 and anti-PD-L1
have unique toxic effects which are referred to as immune-related adverse events (IRAEs) [8].
Pneumonitis is defined as inflammation of the lung parenchyma, and has been described in <10% of
patients receiving anti-PD-1/PD-L1 therapy either alone or in combination, and appears to occur more
commonly in patients with lung cancer [9,10]. Cardiac complications include arrhythmias as
ventricular tachycardia and atrial fibrillation, pericardial effusion, pericarditis, myocardial infarction,
cardiac myositis, cardiomyopathy, death from cardiac arrest or acute heart failure [11].
In this study, we aimed to analyze all grades of pneumonitis in anti-PD-1/anti- PD-L1 treated patients
in comparison to standardized chemotherapy (CTH) protocols and if anti-PD/PDL1 had higher
incidence of cardiotoxicity compared with other treatment protocols.
2. METHODS
2.1 Search Strategy and Study Selection
This systematic review was conducted according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines [12] (Fig. 1).
The PubMed, MEDLINE and EMBASE databases were searched for publications containing anti- PD-
1 and anti-PD-L1 immunotherapy (IMM) by the words “Nivolumab” OR “Pembrolizumab” OR
“Pidilizumab” OR “Atezolizumab” OR “Durvalumab” OR “Avelumab” OR “BMS936559” OR
“Pidilizumab” OR “Ipilimumab” [13]. All studies comparing mono-immunotherapy versus other
single/multiple treatments that reported all grades of pneumonitis or any cardiac complications were
included. Cardiac complications included arrhythmias as ventricular tachycardia and atrial fibrillation,
pericardial effusion, pericarditis, myocardial infarction, cardiac myositis, cardiomyopathy, death from
cardiac arrest or acute heart failure. These studies reported pulmonary complications including
pneumonitis, pneumonia, interstitial lung disease, pleural effusion, and aspiration pneumonia. The
bibliography of all included studies and related meta-analyses were searched to identify further
articles that could potentially be recruited, i.e., backward snowballing. Inclusion criteria were phase II
or III comparative randomized clinical trials (RCTs) that had two arms (in the form of IMM vs.
CTH/targeted therapy). Exclusion criteria were ongoing trials; non-comparative RCT, phase I RCT,
RCT with monotherapy/single arm or dose-escalation trials, RCT with three or more comparative
arms, two-armed studies but in the form of IMM vs. IMM or IMM vs. Placebo, less than 50 patients, no
pulmonary complication reported, non- English articles, and no full-text available.
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
3
Two authors (M.B. and M.R.) independently reviewed the electronic reports identified by the searches.
In case of discrepancies, they were resolved by consensus meeting. The quality of included studies
was assessed using The Cochrane Collaboration’s tool for assessing risk of bias in RCTs [14] (Fig. 2).
Fig. 1. PRISMA of the meta-analysis for A) pneumonitis reporting RCTs and B) Cardiotoxicity
reporting RCTs
2.2 Study Outcomes
The primary endpoint was the pneumonitis and cardiotoxicity rate in IMM compared to CTH.
Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor
response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH (III)
comparison of cardiotoxicity grades in IMM to others (IV) cardiotoxicity grade difference between IMM
A
B
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
4
and other studies having lung cancer and other cancer subgroups and in IMM compared with
Chemotherapy (CTH) only studies (V) outcome of IMM compared with others (in all studies and in
lung cancer/other cancers subgroups) as well as in IMMs compared with CTH only studies and (VI)
difference in mortality in the same groups.
Fig. 2. Risk of bias in RCTs assessed by using the Cochrane Collaboration’s tool for A)
Pneumonitis and B) Cardiotoxicity
Subgroup analyses were conducted for the occurrence of pneumonitis based on the cancer type
[NSCLC, melanoma and others (including head & neck, renal cell carcinoma and urothelial
carcinoma)] and immunotherapy treatment type (anti-PD1 (as Nivolumab or Pembrolizumab) or anti-
PD-L1 (as Atezolizumab)). High grade adverse events were defined as grade 3 or higher identified by
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAEv.4) [15] that
means Severe, Life-threatening and Death for grade 3, 4 and 5, respectively.
2.3 Data Extraction and Statistical Analysis
Data were expressed in the same way they were expressed in the included studies (i.e., frequency
and percentage for categorical variables and mean ± standard deviation or median and range (or
interquartile range) for continuous variables).
Data on study design, study period, country, study center, trial phase (II or III), cancer type,
comparison arms, doses of drug administered, inclusion/exclusion criteria, treatments arms, sample
size, PD-L1 tumor cell expression percent groups, pathology and post-immunotherapy surgery, were
retrieved. The following patient characteristics were obtained: age, sex, smoking, Eastern Cooperative
Oncology Group Performance Status (ECOG-PS), cancer stage, response rates, PFS, OS,
pneumonitis (all grade/ high grade), cardiotoxicity complications, response (complete and partial
responders, using Response Evaluation Criteria in Solid Tumor (RECIST) criteria, were considered as
responders), and all-cause mortality.
All-cause mortalities were derived from the natural logarithm of the provided hazard ratio (HR) or from
Kaplan–Meier overall survival curves at the end of follow-up with aid of GetData Graph Digitizer
software 2.26 (http://getdata-graph-digiti zer.com/); the standard error (SE) was derived from the 95%
confidence interval (95% CI) or log rank P value [16]. Odds ratios (ORs) with 95% CI for pneumonitis
or cardiotoxocity events were calculated by means of the DerSimonian-Laird [inverse variance (IV)]
method [17]. Relative risk [risk ratio (RR)] with 95% CI was similarly calculated for events with
incidence higher than 10% to avoid exaggeration of the risk [18]. Random-effect model was used for
statistical outcome pooling, computing risk estimates with 95% CI.
A
B
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
5
Table 1A. Criteria of the included Pneumonitis studies
Author
Year
Study period
Study
Cancer type
Comparison arms (IMM vs. CTH)
Brahmer
2015
2012-2013
Phase III RCT
Squamous cell NSCLC
Nivolumab vs. Docetaxel
Borghaei
2015
2012-2013
Phase III RCT
NSCLC
Nivolumab vs. Docetaxel
Motzer
2016
2012-2014
Phase III RCT
Renal-cell carcinoma with a clear-
cell component
Nivolumab vs. Everolimus
Reck
2016
2014-2015
Phase III RCT
PD-L1-positive NSCLC
Pembrolizumab vs. Platinum based CHT
Robert
2014
2013-2014
Phase III RCT
Melanoma
Nivolumab vs. Dacarbzine
Weber
2015
2012-2014
Phase III RCT
Melanoma
Nivolumab vs. ICC (either dacarbazine or carboplatin+
paclitaxel)
Ferris
2016
2014-2015
Phase III RCT
Head and neck squamous cell
carcinoma
Nivolumab vs. Standard, single-agent systemic therapy
(methotrexate, docetaxel or cetuximab)
Fehrenbacher
2016
2013-2014
Phase II RCT
NSCLC
Atezolizumab vs. Docetaxel
Bellmunt
2017
2014-2015
Phase III RCT
Urothelial Carcinoma
Pembrolizumab vs. investigator's choice of chemotherapy
between paclitaxel, docetaxel or vinflunine
Hamid
2017
2012-2013
Phase II RCT
Advanced melanoma
Pembrolizumab vs. investigator's choice of chemotherapy
between carboplatin, carboplatin+ paclitaxel, dacarbazine,
paclitaxel alone or oral temozolomide
Rittmeyer
2016
2014
Phase III RCT
Squamous and NSCLC
Atezolizumab vs. docetaxel
Herbst
2016
2013-2015
Phase II/III RCT
Lung cancers
Pembrolizumab vs. Docetaxel
Carbone
2017
2014-2015
Phase III RCT
NSCLC
Nivolumab vs. Platinum-based CTH
CTH; chemotherapy, IMM; immunotherapy, NSCLC; non-small cell lung cancer, RCT; randomized clinical trial
¶ Name of chemotherapy and No. of studies details; Docetaxel: 5, Platinum-based: 2, Everolimus: 1, Dacarbazine: 1, Either Dacarbazine or Carboplatin+ Paclitaxel: 1,
Either Methotrexate or Docetaxel: 1, Either Paclitaxel, Docetaxel or Vinfluine:1, Either Carboplatin plus Paclitaxel, Dacarbazine, Paclitaxel alone or oral Temozolomide: 1
Recent Developments in Medicine and Medical Research Vol. 7
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6
Table 1B. Criteria of the included Cardiotoxicity studies
Author
Year
Study
Cancer type
Comparison arms
(immunotherapy vs. CTH)
Doses of drug administration
Borghaei
2015
Phase III RCTs
NSCLC
Nivolumab vs. Docetaxel
Nivolumab 3 mg/kg vs. Docetaxel 75 mg/m2
Eggermont
2016
Phase III RCTs
Melanoma
Ipilimumab vs. Placebo
Ipilimumab 10 mg/kg vs. Placebo
Fehrenbacher
2016
Phase II RCT
NSCLC
Atezolizumab vs. Docetaxel
Atezolizumab 1200 mg vs. Docetaxel 75 mg/m2
Herbst
(Pem 2mg)
2016
Phase II/III RCT
NSCLC
Pembrolizumab vs. Docetaxel
Pembrolizumab 2 mg/kg vs. docetaxel 75 mg/m2
Herbst
(Pem 10 mg)
2016
Phase II/III RCT
NSCLC
Pembrolizumab vs. Docetaxel
Pembrolizumab 10 mg/kg vs. docetaxel 75 mg/m2
Hodi
2014
Phase II RCT
Melanoma
Ipilimumab vs. Ipilimumab +
Sargramostim
Ipilimumab 10mg/kg IV plus Sargramostim 250 μg
Hodi
2016
Phase II RCT
Melanoma
Ipilimumab + Placebo vs.
Nivolumab + Ipilimumab
Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab
3 mg/kg plus placebo
Kwon
2014
Phase III RCTs
Prostate cancer
Ipilimumab vs. Placebo
Ipilimumab 10 mg/kg or placebo
Larkin
(Ipi vs. Niv)
2015
Phase III RCTs
Melanoma
Nivolumab alone, Nivolumab plus
ipilimumab, or Ipilimumab alone
3 mg/kg of Nivolumab (plus ipilimumab-matched placebo);
or 3 mg /kg of ipilimumab (plus Nivolumab-matched
placebo).
Larkin
(Ipi vs. Niv + Ipi)
2015
Phase III RCTs
Melanoma
Nivolumab alone, Nivolumab plus
ipilimumab, or ipilimumab alone
1 mg/kg of Nivolumab plus 3 mg/kg of Ipilimumab, followed
by 3 mg/kg of Nivolumab for cycle 3 and beyond; or 3 mg
/kg of Ipilimumab (plus Nivolumab-matched placebo).
Ribas
2013
Phase III RCTs
Melanoma
Tremelimumab vs. Standard of care
CTH (temozolomide or
dacarbazine)
Tremelimumab 15 mg/kg vs. (dacarbazine 1000mg/m2 or
temozolomide 200 mg/m2)
Robert
2014
Phase III RCTs
Melanoma
Nivolumab vs. Dacarbzine
Nivolumab 3 mg/kg vs. Dacarbazine 1000 mg/m2
Robert
(Pem 2W vs. Ipi)
2015
Phase III RCTs
Melanoma
Pembrolizumab every 2 weeks vs.
Ipilimumab
Pembrolizumab 10 mg/kg or ipilimumab 3 mg/kg
Robert
(Pem 3W vs. Ipi)
2015
Phase III RCTs
Melanoma
Pembrolizumab every 2 weeks vs.
Pembrolizumab every 3 weeks vs.
Ipilimumab
Pembrolizumab 10 mg/kg or ipilimumab 3 mg/kg
NSCLC; non-small cell lung cancer, RCT; randomized clinical trial
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
7
Assessment of publication bias was done by visual inspection of funnel plots. Hypothesis testing for
equivalence was set at the two-tailed 0.05 level. Hypothesis testing for statistical homogeneity was set
at the two-tailed 0.10 level and was based on the Cochran Q test, with I2 values of 0–25%, 26–50%,
and 51–100% representing low, moderate, and high heterogeneity, respectively [19].
Sensitivity analysis using “leave one out analysis” and meta-regression were performed, and results
were reported as regression coefficient (i.e., Beta). Variables included in meta-regression were age,
gender, performance status (PS), smokers and radiotherapy.
This meta-analysis was performed using meta and metafor packages in R (version 3.3.3 R Project for
Statistical Computing). Review Manager Version 5.3 (The Cochrane Collaboration, The Nordic
Cochrane Centre and Copenhagen, Denmark) was used to perform the risk of bias assessment.
3. RESULTS
3.1 Eligible Studies and Characteristics of Studies
Fig. 1 shows an outline of the systematic review process for pneumonitis and cardiotoxicity. For
clinical outcomes, 1,568 studies were identified for pneumonitis and 2822 for cardiotoxicity. After
removal of duplicates, 1,493 and 2722 studies were screened, respectively. Twenty and 32 full text
articles were assessed for eligibility, respectively. Thirteen [20-32] met our inclusion criteria with 7,246
patients included [3,704 (51.12%) in the IMM arm and 3,542 (48.88%) patients in the other arm] for
pneumonitis, and 11 RCTs studying 6574 patients with 3234 (49.19%) patients in IMM arm and 3340
(50.88%) patients in the other arm for cardiotoxicity. As far as pneumonitis concerns, 7 NSCLC RCTs
were included with 4,164 patients (2,101 in the IMM arm and 2,063 patients in the other arm). Three
RCTs were on melanoma patients (n=1,390). The RCTs compared mono-immunotherapy to CTH
(Docetaxel in 5 of them, Platinum-based in 2 studies, Dacarbazine in 1 study and Everolimus in 1
study), while the remaining studies reported different investigator’s choice of chemotherapy (Tables
1,2). Regarding cardiotoxicity, three NSCLC RCTs that included 1588 patients, subclassification of
those showed 782 in IMM arm and 776 in the other arm. Moreover, seven RCTs were included for
melanoma patients (n = 4190), and only one RCTs for prostate cancer that had been included
according to our inclusion criteria. In addition to the above-mentioned studies, we included five RCTs
that compared mono-immunotherapy to CTH (four studies used Docetaxel, one study used
temozolomide or dacarbazine), those studies had 2631 patients, subclassification showed 1320 in
IMM arm and 1311 patients in CTH arm.
The pooled pneumonitis mean follow-up was 10.9 and 8.9 months in the IMM and CTH arms,
respectively, while the pooled cardiotoxicity mean follow-up was 18.69 and 18.52 months in IMM and
other arm, respectively.
All-grade pneumonitis occurred in 3.13% of the IMM arm compared to 2.06% in the CTH arm, while
high- grade pneumonitis occurred in 1.32% of the IMM arm compared to 0.45% in the CTH arm.
Pneumonitis-related mortality occurred in 0.17% among the IMM compared to 0% among the CTH
group. Among chemotherapy regimens, everolimus had the highest percentage of patients developing
all-grade pneumonitis (14.61%), followed by docetaxel (0.52%), then platinum-based CTH (0.24%)
and dacarbazine (0%). In contrast to the IMM. Similarly, everolimus had the highest rate of high-grade
pneumonitis (2.77%), followed by platinum-based CTH and docetaxel (0.24% vs. 0.17%), then
dacarbazine (0%), in contrast to the IMM (Table 3).
3.2 Meta-Analysis of the Outcomes
Pneumonitis
3.2.1 Pneumonitis in immunotherapy
A higher rate of all-grade pneumonitis was found in all immunotherapy arms (OR =4.39, 95% CI
=1.65–11.69, P=0.003) (Fig. 3A, Table 4). On subgroup analysis, the occurrence of all-grade
Recent Developments in Medicine and Medical Research Vol. 7
Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy
8
pneumonitis was highest among patients with NSCLC (OR =3.54, 95% CI =2.02–6.22) and melanoma
(OR =9.82, 95% CI =2.27–42.42), but not in head & neck, renal cell carcinoma and urothelial
carcinoma patients (OR =1.62, 95% CI =0.12–21.11). Subgroup analysis of immunotherapy type (anti-
PD-1, nivolumab or pembrolizumab or anti-PD-L1, atezolizumab) showed that only anti-PD-1
treatment is associated with higher all-grade pneumonitis (OR =4.11, 95% CI =1.50–11.22).
Table 3. Incidence of all and high grades pneumonitis among different chemotherapeutic agent
compared to immunotherapy in the corresponding studies
No. of Studies
IMM
CTH
CTH agent ¶
All grade pneumonitis
5
3.04%
0.52%
Docetaxel
2
3.76%
0.24%
Platinum-based CTH
1
1.43
0.00%
Dacarbazine
1
3.94
14.61%
Everolimus
High grade pneumonitis
5
1.37%
0.17%
Docetaxel
2
1.88%
0.24%
Platinum-based CTH
1
0%
0%
Dacarbazine
1
1.48%
2.77%
Everolimus
¶ The remaining studies mentioned different Investigator's choice of chemotherapy.
Similarly, the occurrence of high-grade pneumonitis in the IMM arm was found among all included
studies (OR =2.46, 95% CI =1.29–4.69, P=0.007) (Fig. 3B, Table 4). On subgroup analysis, high-
grade pneumonitis was higher among NSCLC patients (OR=3.70, 95% CI =1.72–7.96), while there
was no difference among melanoma patients [OR =4.75 (0.54, 41.97)] or other cohorts (OR =1.78,
95% CI =0.24–12.98). Subgroup analysis of immunotherapy type showed that anti-PD-1 treatment is
associated with higher pneumonitis (OR =2.32, 95% CI =1.19–4.51); this effect was not seen in anti-
PD-L1.
3.2.2 High-grade morbidity
Grade 3–5 adverse events occurred more frequently in the CTH than the IMM arm (RR =0.46, 95% CI
=0.37–0.56, P<0.001).
3.2.3 Response in immunotherapy
Response rate is in favor of immunotherapy arm (RR =2.00, 95% CI=1.49–2.67; P<0.001).
3.2.4 Survival in immunotherapy
PFS and OS are longer in patients who received IMM in comparison to patient in the chemotherapy
arm (HR =0.75, 95% CI =0.65–0.85, P<0.001 and HR =0.71, 95% CI =0.66–0.77, P<0.001
respectively).
Pneumonitis outcomes are summarized in Fig. 3.
Cardiotoxicity
3.2.5 Cardiotoxicity in immunotherapy
There was no difference in all grade cardiotoxicity among all recruited studies (RR: 1.15; 95% CI:
0.73–1.80; p = 0.55) or in subgroups of lung cancer (RR: 0.68; 95% CI: 0.22–2.09; p = 0.50) or other
cancers (RR = 1.27; 95% CI: 0.78–2.08; p = 0.34). Similarly, no difference in high grades
cardiotoxicity among all recruited studies (RR: 1.47; 95% CI: 0.87–2.46; p = 0.15) or in subgroups of
lung cancer (RR: 0.80; 95% CI: 0.25–2.50; p = 0.70) or other cancers (RR: 1.71, 95% CI: 0.96–3.06; p
= 0.07).
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Fig. 3. Pneumonitis outcome summary
3.2.6 Response in immunotherapy
No difference in response between comparative arms (IMM vs others) could be identified; (RR: 1.41;
95% CI: 0.91–2.17; p = 0.12). While lung cancer showed a higher response rate (RR: 1.65; 95% CI:
1.27–2.15; p = 0.0002), no statistically significant difference in response regarding other types of
cancers could be identified but heterogeneity exists (I2 = 93; p < 0.0001). On restricting studies to
those comparing response in IMM versus CTH only, immunotherapy arm showed a higher response
rate (RR: 1.68; 95% CI: 1.25–2.26; p < 0.001).
Fig. 4. Cardiotoxicity outcome summary
3.2.7 End of follow-up overall mortality
There was no statistically significant difference regarding the end of follow-up overall mortality in
immunotherapy versus others in all recruited studies (RR: 0.84; 95% CI: 0.69–1.02; p = 0.08), but
heterogeneity exists (I2 = 59; p = 0.005). On subgroups analysis, patients received immunotherapy
showed lower mortality versus the other arm in lung cancer (RR: 0.80; 95% CI: 0.65–0.97; p = 0.03),
but this was not statistically evident in the other included types of cancer (RR: 0.86; 95% CI: 0.63–
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1.16; p = 0.32) but heterogeneity exists (I2 = 72%; p = 0.0007). After including IMM versus CTH
studies only, lower mortality was evident in IMM arm (RR: 0.73; 95% CI: 0.56–0.95; p = 0.02).
Table 4. Leave one out analysis of high-grade A) pneumonitis studies and B) cardiotoxicity
studies
A) Study (Pneumonitis)
OR (95% CI)
B) Study (Cardiotoxicity)
RR (95% CI)
Omitting Borghaei 2015
2.42 [1.22; 4.78]
Omitting Kwon 2014
0.776 [0.415; 1.453]
Omitting Brahmer 2015
2.59 [1.29; 5.23]
Omitting Borghaei 2015
1.115 [0.703; 1.768]
Omitting Fehrenbacher 2016
2.46 [1.29; 4.69]
Omitting Fehrenbacher 2016
1.137 [0.718; 1.801]
Omitting Ferris 2016
2.63 [1.30; 5.31]
Omitting Herbst 2mg/kg 2016
1.259 [0.793; 1.998]
Omitting Motzer 2016
3.98 [2.01; 7.90]
Omitting Herbst 10mg/kg 2016
1.242 [0.783; 1.971]
Omitting Reck 2016
2.59 [1.25; 5.36]
Omitting Eggermont 2016
1.137 [0.718; 1.801]
Omitting Robert 2014
2.46 [1.29; 4.69]
Omitting Hodi 2014
1.164 [0.737; 1.840]
Omitting Weber 2015
2.46 [1.29; 4.69]
Omitting Hodi 2016
1.203 [0.759; 1.909]
Omitting Bellmunt 2017
2.17 [1.15; 4.09]
Omitting Larkin (Ip, Niv) 2015
1.137 [0.718; 1.801]
Omitting Hamid (2mg vs CTH)
2017
2.59 [1.29; 5.22]
Omitting Larkin (Ip, Niv + Ip) 2015
1.137 [0.718; 1.801]
Omitting Hamid (10mg vs CTH
2017
2.40 [1.22; 4.73]
Omitting Ribas 2013
1.137 [0.718; 1.801]
Omitting Rittmeyer 2016
2.32 [1.19; 4.51]
Omitting Robert 2014
1.293 [0.808; 2.070]
Omitting Herbst 2mg/kg 2016
2.57 [1.21; 5.43]
Omitting Robert (Pem 2W, Ip) 2015
1.196 [0.755; 1.895]
Omitting Herbst 10mg/kg 2016
2.57 [1.21; 5.44]
Omitting Robert (Pem 3W, Ip) 2015
1.196 [0.755; 1.895]
Omitting Carbone 2017
2.32 [1.19; 4.51]
CI = Confidence Interval; OR = Odds Ratio; RR = Relative Ratio
Table 5. Meta-regression results of different variable on all and high grades pneumonitis
Beta ± SE, P-value
Beta ± SE, P-value
Beta ± SE, P-value
All grade pneumonitis
All studies
Only NSCLC
Among anti-PD1
Age
0.2798 ± 0.2411, P=0.2459
0.4290 ± 0.3231, P=0.1842
0.2663 ± 0.2433, P=0.2738
Female%
0.0210 ± 0.0348, P=0.5452
-0.0663 ± 0.0883, P=0.4526
0.180 ± 0.0354, P=0.6110
PS≥1
-0.0380 ± 0.0260, P=0.1440
0.0866 ± 0.1266, P=0.4943
-0.0378 ± 0.0260, P=0.1459
Smokers
0.0954 ± 0.0588, P=0.1043 ¶
0.0946 ± 0.0651, P=0.1461
0.0952 ± 0.0588, P=0.1051
RTH
-0.0162 ± 0.1463, P=0.9117
-0.0162 ± 0.1463, P=0.9117
-0.0162 ± 0.1463, P=0.9117
High grade pneumonitis
All studies
Only NSCLC
Among anti-PD1
Age
0.4080 ± 0.2269, P=0.0721
0.0415 ± 0.3712, P=0.9110
0.3856 ± 0.2286, P=0.0916
Female%
0.0254 ± 0.0319, P=0.4265
0.0351 ± 0.0970, P=0.7177
0.194 ± 0.0329, P=0.5565
PS≥1
-0.0239 ± 0.0448, P=0.5937
-0.0148 ± 0.1421, P=0.9173
-0.0229 ± 0.0448, P=0.6087
Smokers
0.0051 ± 0.0701, P=0.9416
-0.0023 ± 0.0753, P=0.9762
0.0080 ± 0.0702, P=0.9095
RTH
-0.0727 ± 0.1545, P=0.6381
-0.0727 ± 0.1545, P=0.6381
-0.0727 ± 0.1545, P=0.6381
PS: performance status, RTH: radiotherapy
Outcomes summary are shown in Fig. 4.
3.3 Sensitivity Analysis
Leave one out analysis of high-grade pneumonitis and all grade cardiotoxicity studies were conducted
and revealed robustness of the results (Table 4).
3.4 Meta-regression
Six levels of meta-regressions were done assessing the effect of different variables (age, gender,
performance status, smoking and radiation) on all-grade and high-grade pneumonitis first in all
studies, then among NSCLC related studies, and among anti-PD-1 studies alone. This showed an
obvious trend of higher pneumonitis among smokers (Beta =0.10, P value =0.104) and elderly
patients (Beta=0.41, P=0.072). The same trend was noted regarding smoking in NSCLC studies
(Beta=0.10, P=0.146) (Table 5).
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4. DISCUSSION
In the present meta-analysis, the risk of all-grade pneumonitis was higher among all immunotherapy
arms when compared to standard chemotherapy regimens in NSCLC, melanoma, and other tumor
types, similar to previous studies [33,34]. Similarly, the incidence of high-grade pneumonitis
secondary to anti-PD-1 treatment was higher in IMM compared to CTH, as reported previously [35].
The risk of pneumonitis was highest in smokers, elderly patients, and patients with NSCLC when
compared to other tumor types. Interestingly, this effect was not seen in anti-PD-L1 treatment. High
grade morbidity overall was higher in the traditional chemotherapy arm than IMM, suggesting that
while pneumonitis is a potential limitation to IMM, it may still overall have a superior safety profile to
CTH. Similarly, tumor response, PFS, and OS were all favored the immunotherapy arm.
Four Prior RCT reported two cases of cardiac arrest and two cases of cardio-respiratory arrest in
Ipilimumab 10 mg/kg arm when compared with placebo-related death [20] and another one reported
acute cardiac failure-related mortality in Atezolizumab 1200 mg when compared with Docetaxel 75
mg/m2 [36]. Myocardial infarction death was reported in Herbst et al. three arm trial when they
compared Pembrolizumab 10 mg versus docetaxel arms but not in Pembrolizumab 2 mg versus
docetaxel arms [36,37]. So, we aimed to pool many studies to identify the actual incidence and
properly estimate the risk of those apparently rare events with such effective treatments. No
difference in all/high grades cardiotoxicity was evident in our meta-analysis, and so this meta-analysis
met its end point of providing evidence for absence of significantly higher horrific cardiotoxicity
mentioned by some of the published RCTs as mentioned earlier.
This is the first meta-analysis to report the incidence of pneumonitis and cardiotoxicity in IMM in
relation to different chemotherapeutic agents and to assess the effect of age, gender, smoking,
performance status and radiotherapy on incidence of pneumonitis with immunotherapy through meta-
regression. In 2016, Nishino and his colleagues [34] compared the incidence of PD-1 inhibitors related
pneumonitis among different tumor types (NSCLC, melanoma and renal cell carcinoma) and
therapeutic regimens including nivolumab or pembrolizumab. Among their study, the majority of the
included articles were Phase I RCTs (n=12 articles), whereas our study also evaluated efficacy as
only phase II and III studies were included.
Prior meta-analyses on this topic report an all-grade pneumonitis incidence between 2.28–3.69%,
high-grade pneumonitis between 1.65–2.87%, and an incidence of all- grade pneumonitis up to 4.27%
in the NSCLC subgroup (Table 6) [38-41]. Anti-PD-1 was associated with higher incidence of all grade
pneumonitis between 3.62–3.3.90%, while anti-PD-L1 was associated with either insignificant
incidence or protective effect against pneumonitis [33,35,42,43]. Our findings were similar, and in the
current analysis, all-grade pneumonitis was most common with everolimus with a rate of over 1 in 7.
To our knowledge, no pneumonitis cases were reported with dacarbazine (DTIC).
Wu and colleagues [33] conducted a meta-analysis to evaluate the incidence of pneumonitis in Phase
II, III and IV RCT with participants receiving PD-1 inhibitors. They reached the same conclusion that
PD-1 inhibitors were associated with an increased risk of pneumonitis in a dose-independent manner,
compared with routine chemotherapeutic agents with different frequency and severity in various tumor
types. Similar to our results, Khunger et al. reported in his recently published single arm
(immunotherapy arm) meta-analysis that there was a higher incidence of pneumonitis with anti-PD-1
compared to anti- PD-L1 [35]. Finally, we found that immunotherapy had lower high-grades treatment
related morbidities compared to chemotherapy similar to prior results by Costa et al. [43].
The occurrence of pneumonitis seen in this meta-analysis is relatively rare, anti-PD-1 specific, and
most pronounced in smokers, the elderly, and patients with primary lung cancer. This is likely due to
underlying lung impairment in these patients [33]. Interestingly, we did not find a similar effect from
prior radiation in lung cancer studies in the meta-regression analysis, but this may be attributed in part
to the small number of studies that reported radiation (n=3) [6,37,44]. Although the risk of pneumonitis
must be considered prior to initiating checkpoint inhibition therapy, our results confirm that in all other
metrics, immunotherapy has a superior profile to traditional CTH in NSCLC and melanoma. Most
clinical trials exclude patients with prior radiation, radiation pneumonitis, interstitial lung disease,
autoimmune disease, clinically significant lung disease, hypoxia and decreased performance status,
so we are not able to assess the full risk of pneumonitis in these at-risk groups.
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Table 6. Published Meta-analyses on Immunotherapy-Induced Pneumonitis
First Author, year
Studies
Patients
Cancer
types
Results: All studies
Results: Only NSCLC
Results: Among anti-PD-1
Abdel-Rahman,
2016[40]
11
6671
All
AGP: OR = 3.96 (95% CI, 2.02-7.79)
HGP: OR = 2.87 (95% CI, 0.90-9.20)
AGP: OR = 3.25 (95% CI, 1.51-7.00)
NR
Costa, 2017[41]
9
5353
All
AGP: RR = 2.28 (95% CI, 0.76-6.88)
NR
NR
Khunger, 2017[42]
19
5038
NSCLC
NR
NR
AGP(anti-PD-1) = 3.62 (95% CI, 2.36-4.87)
HGP(anti-PD-1) = 1.15 (95% CI, 0.57-1.73)
AGP (anti- PD-L1) = 1.37 (95% CI, 0.80-1.94)
HGP (anti-PD-L1) = 0.41 (95% CI, 0.00-0.85)
Wu, 2017[43]
16
6360
All
AGP = 3.29% (95% CI, 2.72-3.98)
HGP = 1.65% (95% CI, 1.25-2.16)
AGP = 4.27% (95% CI, 3.26-5.58)
HGP = 2.04% (95% CI, 1.37-3.03)
AGP (anti-PD-1 vs. CTH): OR = 3.90 (95% CI,
1.93-7.85)
HGP (anti-PD-1 vs. CTH): OR = 3.55 (95% CI,
1.29-9.76)
AGP; All-grade Pneumonitis, HGP; High-grade Pneumonitis, NR; not reported
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This study is limited by limited clinical time that immunotherapy has been available; therefore, follow-
up time is short and the number of clinical trials is not large enough to fully evaluate the safety of PD-1
inhibitors and their side effects. Heterogeneity in individual studies was addressed partially through
subgroup analysis, although this remains a limitation in particular due to the relatively small sample
size. Finally, our analysis was conducted at the study level rather than individual patient data level,
meaning the potential variables at the patient level were not involved in the analysis [45].
While various grades of cardiotoxic events were described with the use of immune checkpoint
inhibitors including myocarditis, HF, heart block, myocardial fibrosis and cardiomyopathy, the exact
mechanism of such complications is not fully understood. Johnson et al. [46] described two cases of
fulminant myocarditis and myositis associated with combination of ipilimumab plus nivolumab where
histological analysis showed that the myocardium, the cardiac sinus and the atrioventricular nodes
were infiltrated by lymphocytes, and macrophages. Also, high expression of PD-L1 was demonstrated
on affected cardiomyocytes and on infiltrating CD8+ T cells. Thus, we may conclude that cardiac
toxicities that arise with the use of immune checkpoint inhibitors are mostly immune mediated. In
previous reports, these toxicities were successfully managed using systemic high dose steroids
[11,47]. Based on this, we recommend exploring the role of low dose steroids in decreasing immune
checkpoint inhibitors cardiotoxicities in future prospective studies.
Immune-checkpoint blocking antibodies have also been reported to induce higher complications in
other organs. For example, endocrine, gastrointestinal and cutaneous complications in cancer
patients treated with immune-checkpoints inhibitors were studied by Abdel-Rahman and colleagues
[48–50]. In their papers, they concluded that the use of immune check point inhibitors is associated
with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, colitis,
skin rash, pruritus and vitiligo compared with control. On the other hand, this was not demonstrated
for cardiotoxicity. In fact, a meta-analysis of anti PD1/PDL1 immunotherapy randomized clinical trials
has shown how cardiotoxicity was statistically insignificant regardless of the treatment regimen
(chemotherapy or immunotherapy) [51]. Also incidence of venous and arterial thromboembolic events
in patients treated with immune-checkpoints inhibitors are similar to control arms, suggesting that
thromboembolic risk in many cancer setting is small [52].
Finally, an economic analysis of immune-checkpoint inhibitors for lung cancer treatment showed that
lung cancer expenditures will double between 2020 and 2040 [53], to reach US$6,839 for patients and
US$179,571 for insurance companies. Vergnenegre and Chouaid in their analysis concluded that the
costs of these agents remain the major factor preventing their use in developing countries [54].
5. CONCLUSIONS
The incidence of high-grade and all-grade pneumonitis is higher in anti-PD-1 therapy but not in anti-
PD-L1 therapy when compared to traditional CTH regimens for NSCLC and melanoma. High-grade
adverse events were otherwise more common in the CTH arm. Tumor response rate, PFS, and OS
are all substantially improved with IMM over CTH. These results can be used to guide therapy
selection and set expectations for treatment effect in these patients. Cardiotoxicity was statistically
insignificant regardless the treatment regimen either chemotherapy or dual immunotherapy. The use
of anti-PD/PDL1 provided better response and survival rates when used in lung cancer subgroup.
CONSENT
It is not applicable.
ETHICAL APPROVAL
It is not applicable.
Recent Developments in Medicine and Medical Research Vol. 7
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14
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Journal of Thoracic Disease, 11(2): 521-534, 2019.
_____________________________________________________________________________________________________
1Department of Surgery & In-Charge, Burn Unit, NEMCARE Hospital, Guwahati, Assam, India.
2Burn Unit, NEMCARE Hospital, Guwahati, Assam, India.
*Corresponding author: E-mail: bpsdr@rediffmail.com, bpsarmadr@gmail.com;
Chapter 2
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Experience with Burn Prevention Program in North
Eastern India: A Recent Study
Bhupendra Prasad Sarma1*, Kabita S. Choudhury2 and Dipak Sarma2
DOI: 10.9734/bpi/rdmmr/v7/13779D
ABSTRACT
Burn injuries are among the most devastating of all injuries and a major public health concern
worldwide.Despite the fact that burn injuries are a leading cause of morbidity and mortality in India,
community-based interventions in the form of multi-strategic and multi-focused preventive
programmes are lacking. This study, conducted in the North Eastern Indian state of Assam, aims to
reduce the occurrence of burn accidents, morbidity, and mortality from burn injuries by focusing on
sensitising the community through a well-structured preventive programme. The tools used in the
preventive programmes included participatory community seminars, the use of print, electronic, and
social media, as well as lectures and demonstrations in schools.The analysis of inpatient and
outpatient records of burn injured patients treated in the burn unit, as well as the scoring system in the
school education programme and social media participants, aided in determining the impact of Burn
Preventive Programs (BPP). A comparative analysis of the results in the early (Block I) and late (Block
II) parts of the study period was performed for ease of assessment.. The results revealed a significant
decrease in the percentage of patients reporting from areas where BPP was implemented.There was
also a decrease in percent TBSA burn in the majority of patients in Block II when compared to Block
I.Water was used to extinguish fires in 48.9 percent of Block I patients and 78.0 percent of Block II
patients.Water was also used to cool burn wounds by 52.3 percent of Block I patients and 83.4
percent of Block II patients.While 80.9 percent of people in Block I applied inappropriate topical
treatments to their wounds, only 34.6 percent did so in Block II. Increased public awareness was
reflected in an increase in the percentage of patients reporting to a burn unit within 7 hours of injury
and a significant reduction in firecracker burns from 21.9 percent (Block I) to 7.8 percent (Block II).
Similarly, improved awareness among students was evident in the majority of students' improved
scores and reduction in burns in the latter part of Block II. The findings indicate that BPP has had a
positive impact on society.
Keywords: Burn prevention; first aid; public awareness; school education.
1. INTRODUCTION
Burn injuries are among the most devastating of all injuries and a major public health concern
worldwide [1,2]. Approximately 90% of burns occur in low and middle-income countries, which lack
the necessary infrastructure to reduce the incidence and severity of burns [3,4]. However, reduction in
preventable burn deaths can be achieved by investment in safe living conditions and equitable access
to medical care.
Estimates of the occurrence of burn injuries in India are most likely educated guesses. J. W. L. Davis
[5] reported a yearly incidence of two million burn injuries, of which 0.5 million receive clinic or hospital
outpatient care, 0.2 million are admitted to hospitals, and 50000 succumb to the injuries. The figures
given may be an underestimation because many burn injuries, particularly among the rural population
remain unreported. According to the data published by National Health Portal of India (Last updated in
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
18
2016)( https://www.nhp.gov.in/disease/skin/burns#:) 7 million people suffer from burn injuries every
year with 1.4 lakhs (0.14 million) death and 2.4 lakhs (0.24 million) suffering from various disabilities.
75% of the burn injuries occur at home and 80% of the victims are the women and children [6]. In
recent years, increase in the number of terrorist violence, bus, train and airplane accidents, fire in the
high-rise buildings and industrial accidents have all contributed to the swelling in the number of
casualties of burns [7].
Inadequate treatment facilities in the country as a whole, compounded by ignorance, superstition and
misconception prevailing in the community in general, have made the burns management far from
adequate. About 60 existing burn units, mostly located in the major cities of the country, are grossly
insufficient to provide burn care to the large number of burn injured patients [8]. The scenario in the
North East India, consisting of seven states (where this study was done) is still worse. A large number
of patients of this region are still deprived of proper care because of the poor facilities for burn care in
the government and private institutions.
Burn injuries are therefore better prevented than treated. There are encouraging reports of reduction
of incidence and mortality of burns in developed countries due to effective implementation of Burn
Prevention Program [9]. The author published a study on the positive impact of Burn Prevention
Program (BPP) on the community as a whole in respect of First Aid and Prevention of burn accidents
[10]. This study was conducted in two hospitals in the state of Assam, namely Indian Oil Corporation
(Assam Oil Division) Hospital, Digboi and Guwahati Refinery Hospital, in a period of 13 years (1994 to
2007). Both the hospitals being Industrial hospitals, the main focus of activities was on the employees
and their dependants of the oil industries. Other people were targeted through school education
programs and programs organized in collaboration with organizations like Lions Clubs and Rotary
clubs.
The Burn Unit of Indian Oil Corporation Limited (Assam Oil Division) Hospital (known as AOD
Hospital), Digboi, started Burn Prevention Program (BPP) in 1994 with the aim of reducing the
incidence of burns by raising the awareness level of the community in general. The burn unit of AOD
Hospital catered to the needs of the employees and dependants of Indian Oil Corporation Limited,
besides 2 million people residing in a large area around Digboi. The unit was manned by two general
surgeons, trained in burns management, with four nurses and four paramedical staff.
The Burn Prevention Program was extended to Guwahati, the capital city of Assam (one of the North
Eastern states), from early 2005. A population of 2.5 million of the city was thus included in the BPP.
All preventive tools were continued to be used there with the additional help of the staff of Guwahati
Refinery Hospital. Though there was no formal burn unit in this hospital, BPP was done regularly;
better reach out to the masses was achieved through electronic and print media. School education
program was continued with inclusion of more schools in the program [10].
Subsequently, the BPP was continued through the Burn Unit of Burn Care Foundation, in the city of
Guwahati (the capital city of Assam), with addition of more prevention tools. In the COVID 19
pandemic year (2020), due to loss of social contact amongst the people, BPP had to be carried out
digitally and through social media. BPP was implemented with some changed concept, namely,
Primary, Secondary and Tertiary Prevention Program, aimed at reduction of incidence through
education of people, reduction of severity by proper use of first aid measures and reduction of
complications of burns by appropriate tertiary care.
The Burn Unit of Burn Care Foundation, a trust of NEMCARE Hospital, Guwahati, is a 10 bedded
tertiary Burn Care Unit, catering to the needs of the seven NorthEastern states of India. This unit,
equipped with ICU beds, operation theatre and all modern burn care equipments, is manned by a
dedicated and trained burn care team. Use of advanced burn management protocols in the burn unit,
like proper fluid resuscitation, use of modern burn wound covers and routine use of Early Excision and
Skin Grafting in full thickness burns, have improved morbidity and mortality of burn patients. Patients
with majors burns, referred from different neighboring states and those from the state of Assam and
the city of Guwahati are the beneficiaries of the burn unit. There being other hospitals in the city,
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
19
which treat burn injured patients, the number of patients treated in this unit do not represent the
incidence of burns in the region.
The Burn unit is also engaged in Burn Prevention Programs like-Public Awareness Programs, School
Education Programs, erection of hoardings (with writings on First aid and Prevention of Burns) at
public places, publication of articles in news papers and journals, Talks and Interviews on television
and Talks and Writings in social media. Most of the tools of Burn Prevention were being used by the
author since 1994, with addition of Annual Burn Care Day and use of social media in recent past. The
burn unit also organized Training Programs for doctors, nurses and paramedics on Essential Burn
Care in the entire North East India to boost up the burn care in the region.
The present study was the analysis of the records of the BPP undertaken by the Burn Unit of Burn
Care Foundation, aiming at ascertaining the impact of the program on the community as a whole. The
inpatient records of the burn unit and the records of school education and public awareness programs
from 2010 to 2020(10 years) were analyzed. These records of the two periods- namely 2010 to 2015
(Block I) and 2016 to 2020 (Block II) were compared to have a feed back on improved impact of the
program on the society.
2. MATERIALS AND METHODS
A data base was created on the admitted patients as regards to their nature of injury, circumstances
leading to the injuries, the social, educational and economic status of the patients, nature of first aids
received, treatment modalities and the results of treatment received. The records of each patient were
collected from the format used by Burn Unit and later on from format provided by WHO for World Burn
Registry. These formats were filled up by doctors and nurses while the patients were undergoing
treatment in the burn unit. The records of the patients treated in Out Patient Department (OPD) were
collected from the filled-up formats used in the burn unit.
The structured preventive programs of the present study were designed to cover 3 million population
of the city of Guwahati only. As the awareness level on Prevention and First Aid in burns of the
targeted people was low and the incidence of burns was high amongst all groups, the prevention
program was designed to cover topics on general awareness on the subject.
The study was approved by the hospital ethical committee.
The tools for prevention program used are described below:
2.1 Seminars and Discussions
Participatory community sessions were organized at public places in the entire city of Guwahati. A
total of 35 such sessions were organized. Adult males and females from all socio-economic status
participated. Following topics were discussed by audio-visual means in those sessions.
a. Causation, types and first aid in burns, with emphasis on use of water for extinguishing fire and
cooling the burn wounds.
b. Avoidance of any topical application on burn wounds as first aid.
c. Preventive measures to be adopted in the kitchen, other places at home and in the industry to
prevent fire accidents.
d. Identification of hazards of fire and burn accidents that looms large at household and at
workplace.
e. Importance of early reporting to hospital after occurrence of burn injuries.
2.2 School Education Program
A total of 70 schools were included in the program. Thirty-five schools were covered in each Block.
Two programs were conducted in each school annually at a gap of six months. The participating
students were from VIII, IX and X standards. Audio-visual presentations on various aspects of burns
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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were the main tool of prevention program in all the schools covering 4200 students in both the Blocks.
Seventeen schools in each Block were also provided with reading materials on burns on first visit.
Eighteen schools in each block received only audio-visual presentation. The students of these schools
did not receive reading materials.
Students at each school were provided with written questionnaire, containing ten questions (Appendix
I), to be answered immediately, on the second visit. They were also given five tasks on burn
prevention for implementation at home (appendix II). The questionnaire had 10 scores and the tasks
on preventive measures had 10 scores. These were evaluated on the basis of performance of the
participating students.
2.3 Publication of Articles
Articles on First Aids and Prevention of Burns were published in the house Journals, periodicals and
newspapers.
2.4 Display of Banners and Posters
Banners and posters containing messages on First Aid and Prevention of Burns were displayed at
public places.
The following tools were added in the preventive programs in later part of Block I.
2.5 Special Preventive Program before Diwali
Diwali, a popular festival of light is celebrated by lighting earthen lamps and candles and bursting fire
crackers. Burn injuries of hands and faces are of common occurrences every year due to careless
handling of fire crackers during the festival. Special BPP were arranged three weeks preceding the
festival to educate the people on safe handling of fire and crackers. The program included one
common school education program inviting students of 7-8 schools in a large auditorium, one
community session annually (in addition to the routine annual program of prevention), display of
in Diwali. From 2019 onwards, we started the slogan-
appeal, the local administration of each district, enacted legislation to limit the time and place of
fireworks during the festival, which helped in reduction of burn accidents.
2.6 Publication of Books and Booklets
A book on burn injuries, written in local language and two booklets, written in English and Assamese
were distributed amongst the students and the common people.
2.7 Interactions with the Electronic and Print Media
This was done by arranging 3-4 press meets every year, so that mass contact could be achieved
through the print and electronic media.
2.8 Talks on Television Channels
Minimum three talks on First Aid and Prevention of Burns were arranged in television channels every
year. One skit on Burn Prevention was also produced and telecasted by Doordarshan ( Government T
V channel).
2.9 Burn Care Day
Since 2015, a day-long participatory community program involving the doctors, nurses, paramedics,
hospital administrators, students and common people were organized. This annual event was aimed
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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at making the people, including medical professionals aware of Burn Prevention and also the
problems faced by burn injured patients. Audio-visual talks on First Aid and Prevention of Burn
Accidents were arranged for the participants. Illustrative talk on newer modalities of treatment and
their positive effects on all types of burns was another tool of public awareness, used. A leading
journalist and a celebrity like a film star were invited to the session for better publicity of the event.
2.10 Use of Social Media
In the COVID 19 affected year (2020), with no community gathering, BPP was continued through
social media like Face book and You Tube. Access to internet and social media by youth being
higher, we used these media to spread the message of burn prevention and also to collect feedback.
Three talks, with illustrations, on Causation, First Aid and Prevention of Burns were uploaded in Face
Book and You Tube. A questionnaire containing 10 short questions (Appendix III) was also uploaded
after one month. The feedback received through comments and messenger was recorded.
Two Webinars were also organized in that year to make people aware on burn prevention before the
festival of Diwali.
Impact of BPP was assessed by analyzing the data obtained from the records of patients treated in
the burn unit and from the scores of the students and participants in BPP.
The relevant data were collected from the computerized inpatient and outpatient records, which were
regularly updated from the formats used to collect data from the patient and the attendants at the time
of reporting to hospital and thereafter. Since 2015, we started using the format of World Burn
Registry, supplied by WHO. These formats contained the histories with special reference to date and
time of occurrence of burn accident, causative factors of burns, types of clothing worn at the time of
incidence, education and social status of the patients and the nature of first aid received at the site of
injury. Collected data also included number of inpatients and outpatients, their age and sex and
percentage of burns, treatment received and follow ups.
2.11 Data Analysis
Data was entered and analyzed in SPSS software version 25.0 for windows. For difference in
-test was used. A value of P<0.05 was considered
statistically significant. For data analysis mean and SD were used as descriptive statistics.
3. RESULTS
A total of 3647patients were treated in the Burn Unit from October 2010 to October 2020 (10 years);
1270 as inpatients and 2377 as out patients. 3514 (96.3%) patients were from Assam. while 133
(3.6%) were from other North-Eastern states. Patients from Assam included 2110 (57.8%) numbers
from the city of Guwahati and 1404 (38.4%) from other parts of Assam (Table 1). There were 2047
males and 1600 female patients. 1298 (35.5%) patients were below 18 years, 971(26.6%) were
between 19 40 Years of age. Data also indicated that there were 2858(78.3%) numbers of minor
burns (<20%TBSA) and 789 (21.6%) numbers of major burns in the study. Major Burns (>20% TBSA)
were commonly seen amongst the young people (19-40 years); they were less common in children
and elderly. (χ2 = 402.51, DF = 9, P < 0.0001, Highly Significant) (Fig. 1). Analysis also revealed
that there was significant reduction of burns (χ2 = 111.27, DF = 3, P < 0.0001) in children (1-18 yrs)
and young adults (19-40yrs) in Block II (Table 2). Data analysis also revealed that percentage of
major burns was significantly reduced (X2 =17.195 P <0.0001) in Block II in comparison to Block I
(Table 3).
3.1 Number of Patients Reporting to Burn Unit
A total of 1315 patients reported to the burn unit for treatment in Block I; 389 were treated as
inpatients and 926 as outpatients. In Block II, out of 2332 patients reporting for treatment, 881 were
inpatients and 1451 as outpatients. The increased number of patients reporting to Burn unit in Block II
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
22
could be attributed to increased number of referrals from different medical facilities, as more people
came to know about the improved burn care of the tertiary burn care unit. This increase cannot be
linked to the incidence of burns in the region. But, on analyzing the locations of the patients, from
where they reported for treatment, it was found that there was significant reduction of percentage of
patients in Block II (Chi Square=683.66 P<0.0001) (86.3% in Block I and 41,8% in Block II) from the
city of Guwahati, where the Prevention Program was primarily implemented (Table 1).
Table 1. Number and percentage of patients reporting from different locations
Locations
Block I
Block II
Total
Guwahati
1135
86.3%
975
41.8%
2110
57.8%
Other parts of Assam
160
12.1%
1244
53.3%
1404
38.4%
Other States of NE
20
1.5%
113
4.8%
133
3.6%
All locations
1315
2332
3647
Figures in the parentheses show column wise percentages
Chi Square=683.66 P<0.0001. Highly significant
Relation of Age with Percentage of Burns
Total Patients- 3647 Minor –2858 Major- 789
Fig. 1.
χ2 = 402.51, DF = 9, P < 0.0001, Highly Significant
Table 2. Number of burn cases according to age
Age
2010-2015
Block I
2016-2020
Block II
2010-2020
Total
0-18 Yrs
549(41.7%)
749 (32.1%)
1298 (35.5%)
19-40 Yrs
397(30.1%)
574 (24.6%)
971 (26.6%)
41-60Yrs
258(19.6%)
531 (22.7%)
789 (21.7%)
Above 60 Yrs
111 (8.4%)
478 (20.4%)
589 (16.2%)
Total
1315
2332
3647
Figures in the parentheses show column wise percentages
χ2 = 111.27, DF = 3, P < 0.0001, Highly Significant
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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Table 3. Types of burns- block wise
Burn Type
2010-2015
Block I
2016-2020
Block II
2010-2020
Total
Minor(<20%TBSA)
981
(74.6%)
1877
(80.4%)
2858
(78.3%)
Major (>20%TBSA)
334
(25.3%)
455
(19.5%)
789
(21.6%)
Total
1315
2332
3647
Figures in the parentheses show column wise percentages
X2 =17.195 P <0.0001 Highly significant
3.2 Methods Used to Extinguish Fire
Out of 1315 patients, who reported to the burn unit in Block I, 644 (48.9%) poured water, 395 (30.0%)
used blanket and 158(12.0%) rolled on the ground to extinguish fire. Rest 15 (2.2%) patients ran out
of fear and sustained major burns. In Block II, out of 2332 patients, a significantly increased number
(P < 0.0001) i.e., 1819 (78.0%) poured water to extinguish fire, 140 (6.0%) used blankets (significant
decrease P < 0.0001), 233 (10.0%) rolled on the ground and rest 140(6.0%) patients ran shouting for
help, and thereby courting major burns (Table 4).
3.3 First aid Measures
688 (52.3%%) patients poured water to cool the burn wounds in Block I; while a significantly
increased number of patients -1947 (78.0%) did so in Block II (P < 0.0001). 160 patients (6.8%) with
minor burns of the limbs reported to the burn unit with their burnt limbs submerged in bucket full of
water, indicating better awareness on first aids. Inappropriate topical applications, like toothpaste, egg
yolk, ghee, boiled and mashed potato, grease, ashes etc. over the burn wound as first aid, were noted
in 1065 patients (80.9%) in Block I. But the number of people resorting to inappropriate applications
came down significantly (P < 0.0001) to 802 (34.6%) in Block II (Table 4).
Table 4. First Aid measures
Block I
n=1315
Block II
n=. 2332
Statistical Test
1.Extinguished fire by
a) Pouring water
644(48.9%)
1819 (78.0%)
*P < 0.0001
b) Using blanket
395 (30.0%)
140 (6.0%)
*P < 0.0001
c) rolled on ground
158 (12.0%)
233(10.0%)
P = 0.056
d) Ran around
15(2.2%)
140 (6.0%)
*P < 0.0001
2. Poured water on burn
wound
688 (52.3%%)
1947(78.0%)
*P < 0.0001
3.Topical application
(Inappropriate)
1065 (80.9%)
802 (34.6%)
*P < 0.0001
Figures in the parentheses show column wise percentages
*P ≈ Highly significant
3.4 Reporting Time in Hospital
Analysis of the reporting time to hospital revealed that 397 (30.1%) patients reported within 7 hours in
Block I, as against 1737 (74.3%) patients reporting within 7 hours in Block II. It was also evident that
90.8% patients reported to burn unit within 15 hours in Block II and 84.4% reported within the same
time in Block I (Table 5).
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Experience with Burn Prevention Program in North Eastern India: A Recent Study
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3.5 Causes of Burns
While analyzing the agents causing burns, it was revealed that the number of burn injuries caused by
other agents remaining almost at par in two blocks, there was significant reduction (P < 0.0001) in the
burns caused by firecracker injury in Block II in comparison to Block I (Table 6).
3.6 School Education Program
A total of 4200 students of 70 schools participated in the School Education Program organized in two
blocks. All students took part in feedback by filling up the written Questionnaire introduced in both the
Blocks. Scores of students of two groups were compared for better assessment of impact of
education. Results revealed moderate, but significant improvement in scores of the students, who
were provided with reading materials along with audio-visual presentations. The students, who were
not given any reading material, did not recall the presentations so well as compared to the other group
(Table 7).
3.7 Use of Social Media
A total of 620 people responded to the questionnaire, uploaded in Facebook. Majority of them could
recall and scored good marks. Out of 10 marks, 95 (15.3%) participants got 1-2 marks, 290 (46.7%)
participants got 2- 5 marks, 215 (34.6%) got 5-8 marks and 20 (3.2%) of them scored between 8-10
marks (Table 8).
Table 5. Reporting time to hospital
Time
Block I
No & PC of patients
Block II
No. & PC of patients
Within 1- 7 hours
397 (30.1%)
1736 (74.3%)
Within 7 - 15 hours
720 (54.7%)
384 (16.5%)
Within 15-24 hours
154 (11.7%)
102 (4.3%)
Within 24 72 hours
106 (8.0%)
64 (2.7%)
Within 72 100 hours
75 (5.7%)
24 1.0%)
More than100 hours
17 (1.2%)
19 (0.8%)
Total patients
1315
2332
Figures in the parentheses show column wise percentages
Table 6. Causes of burns
Block I
No. of Pts
(%)
Block II
No. of Pts
(%)
Total
No. of Pts
(%)
χ2
P- Value
Flame burn
390
(29.6%)
958
(41.0%)
1348
(36.9%)
47.09
*P<0.0001
Scald
508
(38.6%)
894
(38.3%)
1402
(38.4%)
0.031
P=0.8604
Electric burn
84
(6.3%)
210
(9.0%)
294
(8.0%)
7.772
*P= 0.005
Chemical burns
23
(1.7%)
57
(2.4%)
80 (2.1%)
3.846
*P =0.05
Contact burns
22
(1.6%)
30
(1.2%)
52
(1.4%)
0.894
P= 0.344
Cracker burns
during Diwali
288
(21.9%)
183
(7.8%)
471
(12.9%)
147.7
*P<0.0001
Total
1315
2332
3647
Figures in the parentheses show column wise percentages
*P ≈ Significant
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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Table 7. Scoring in School Education (written feedback)
Year
Schedule
Score 1-6
No. of
students
Score 7-14
No. of students
Score 15-20
No. of students
No. of students
Total
Statistical test
2010-2015
Block I
Students receiving Audio-
visual presentation & reading
materials
243
(24.3%)
503
(50.3%)
254
(25.4%)
1000
2100
*P < 0.0001
Students receiving Audio-
visual presentation only
593
(53.9%)
278
(25.2%)
229
(20.8%)
1100
2016- 2020
Block II
Students receiving Audio-
visual presentation & reading
materials
152
(15.2%)
609
(60.9%)
239
(23.9%)
1000
2100
*P < 0.0001
Students receiving Audio-
visual presentation only
396
(36.0%)
465
(42.2%)
239
(21.7%)
1100
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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Table 8. Social media response
Total number of participants = 620
Total marks = 10
Marks
Total
Percentage
1- 2
95
15.3
2- 5
290
46.7
5 - 8
215
34.6
8 -10
20
3.2
4. DISCUSSION
Non availability of accurate data on incidence of burns in India seriously limits planning for burns
management and preventive strategies. Inadequate treatment facilities have deprived many deserving
le. The patients are
mostly from poor socio-economic status. Majority of the patients end up with severe morbidity or
mortality [9] Amongst those who survive, a major burn injured patient (above 20% TBSA) takes at
least a month or two to be fit enough to leave the hospital He/she takes another three to four months
to resume his /her normal work [6].
The tertiary Burn Care Unit (where the present study was done) with modern burn care facilities,
catered to the need of all referred cases from primary and secondary care units of the entire North
Eastern States. But, as there were other government and private facilities located in the city, many
patients were treated in those facilities as well. Hence the patient reporting to the unit did not
represent the incidence of burns in the locality. However, analysis of the data revealed that there was
a definite reduction of percentage of patients reporting from the city of Guwahati to the Burn Unit in
the Block II, indicating that Burn Prevention Program undertaken in the city had positive impact.
Reduction of number of burn injuries amongst the children and young adults in Block II was another
indication of positive impact of School Education Programs in our study. These results also
corroborate with the findings of the earlier study of the author, where the patients reporting to the burn
unit from a particular captive locality, showed significant reduction of average admission per year in
the Block II, after community based BPP [10]. Similar reduction of admission of burn injured children
after community-based intervention program was also shown in an injury prevention study [11]. Two
out of four included studies in a Cochrane review reported a significant decrease in pediatric burn and
scald injury in the intervention compared with the controlled community [12]. Another community-
based intervention study showed that due to regionalization of burn care and intensification of fire
prevention initiatives, there was reduction in incidence of death and hospitalization resulting from
burns [13].
The effectiveness of the BPP was also ascertained by use of first aid measures like pouring of water
on burn wounds, avoidance of application of topical agents as first aid measure and decrease in
number of fire cracker burns during Diwali. Reduction of percentage of major burns in Block II in
comparison to Block I in the present study indicated better awareness on methods of extinguishing
fire and better first aid measures. Similar reduction of major burns in later period than former was also
shown in the earlier study of the author done in the state of Assam [10]. A study of first aid and initial
management for childhood burns in Vietnam revealed that cooling of the burn wound surface by cold
water was applied only in 27.17% of their cases. The authors recommended public education on first
aid measures to improve compliance [14]. The present study which showed improved compliance to
cooling of burn wounds by application of cold water, after community participative education program,
was in agreement with these recommendations. The significant reduction of percentage of major
burns in Block II, in comparison to Block I in our study, can also be attributed to increased number of
people resorting to cooling of the burn wounds.
As many patients, especially from rural areas wasted time by resorting to unconventional treatment
and application of herbal medicines, before coming to the hospital [15], we had difficulty in
resuscitating them. Repeated messages on importance of early reporting to hospital given through
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
27
prevention program in our study, improved compliance. This was evident from increased percentage
of patients reporting to burn unit within 7 hours in Block II in comparison to Block I. Similar
improvement in average reporting time to hospital (15 hours Block I and 8 hours in Block II) was
noticed in the earlier study of the author [10].
The task of educating students was easier as they were found to be more receptive and were known
to spread the messages to their parents and friends. This fact was corroborated by the study done by
M. H. Keswani in the schools of Bombay. He documented that the students exposed to BPP could
recall the imparted knowledge on questioning without hesitation; but it was not the case with those
students who were not exposed to such program [16]. Our study also revealed better awareness and
better scoring by the students getting education- both audio-visual presentation and reading materials,
than those, who were given only audio-visual presentation in both the blocks. Better scoring by the
students even without getting reading materials in Block II could be attributed to their exposure to
television talks and social media presentation in the later part of the study. Many students transmitted
the information to their parents and friends as well. In the earlier study of the author, where students
were evaluated by their scored marks in written questionnaire, it was found that they could retain the
imparted knowledge much less after 6 months, than what they could immediately after education [10].
the absence of social media and less impact of television in the period of earlier study. In another
study, where follow up was done in a school-based scald prevention program, the authors showed
that students could recall 7.6 out of 10 scald hazards, told to them. In the same study, 65 -70%
children reported the use of the safety items shown to them, in their residence, for a variable period of
time [17]. Our results also showed significant reduction of burns amongst school going children in the
later period of Block II, indicating positive impact of education. In another study, where evaluation of
prevention program of scald and burn injury in young children was done, the parents and guardians of
the exposed children were found to be 1.5 5 times more aware of the prevention message than
those not exposed to the program [18]. In another study, the authors found that, in localities with burn
prevention programs, there was a reduction in the rate of burn-related hospitalizations of infants, from
1.39 to 1.05 per 1000 infants (p<0.05), in contrast to localities where programs did not exist. The
greatest change was in middle and high socio-economic communities. The prevention programs had
no similar effects on school-aged children. They concluded that injury prevention programs are
effective in reducing burn-related hospitalizations among infants and toddlers, especially from more
affluent communities, but not among school-aged children [19].
Our attempt at using social media as tool for burn prevention in the COVID 19 affected year, showed
encouraging result, as majority of the participants could reply to our short questionnaires even after a
month of uploading the presentation on Burns. This could be an effective tool of burn prevention, as a
sizeable number of people now use social media. Our inference has been corroborated by a study in
a school in Bangladesh which showed that the students had previous knowledge of First aid and
prevention of burns, as 32% of them had regular and 45.3% had sometimes access to internet [20].
The decreased incidence of firecracker burns during Diwali in Block II of our study, indicated that,
burn prevention messages transmitted by special campaign just before the Diwali, along with the strict
legislation, limiting playing with firecrackers, by the district administration, did percolate to the targeted
masses. The significant reduction of burns during Diwali in this study was also attributed to the
addition of talks on prevention of air pollution by fire crackers along with the burn prevention program.
As the air pollution has already reached an alarming proportion in the country leading a public health
hazard, people cannot afford to increase the air pollution by bursting fire crackers. [21]. Our findings
burn injuries due to fire crackers continues to fall due to proper legislation, strict implementation and
4.1 Future Prospect of Study
The present Prevention Program is another attempt to make people aware on Burn Prevention
Module in a thickly populated city. The earlier study on prevention of Burns was done in a scarcely
populated peripheral area of the state. In both the studies, we attempted to make the people in
general and the students in particular aware on the basic aspects of Prevention and First Aid in Burns.
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
28
The primary objective being fulfilled to certain extent, there is every scope to make the program more
scheduled to cover the targeted people in more systematic way. Our study revealed that a particular
group of people-namely electrical workers sustain ghastly burn injuries with high mortality and
morbidity. Lack of awareness on burn injury prevention being the primary cause, a structured
preventive program with hazard identification and mitigation may prove useful for them. The
comparison of information acquired and retained by the workers who are exposed to BPP with those
not exposed (Control), will be a better proposition for judging the effectiveness of the program. In a
study of school-based scald prevention program, the authors documented that those children who
received the program, showed considerable improvement in hazard identification at the post test,
while children in the controlled school showed minimal improvement [26].
The program of Burn Prevention in this state of North East India has been able to make some impact
on the targeted people in a positive direction. It can now be the basis upon which further improvement
on the program can be made.
7. CONCLUSION
Burn Prevention Program aimed at educating the people and the students in a thickly populated city,
has served the purpose to a certain extent. The impact of BPP was evident from significant lowering
of percentage of patients reporting from the targeted location and incidence of firecracker burns
during Diwali. Students participating in the school education program showed better awareness as
was evident from decrease number and severity of burns amongst them and from better recall of the
preventive measures on questioning. Use of social media as a tool of Burn prevention has also shown
promising result. It can be concluded that community-based preventive program can reduce burn
injuries and severity of burns.
ACKNOWLEDGEMENT
The authors are thankful to the Management of NEMCARE Hospital, Guwahati for providing the help
and support necessary for carrying out the prevention program and also for allowing publishing the
results. Our sincere thanks are also due to the staff and colleagues of the Burn Unit of NEMCARE
Hospital for their active participation in the program.
The authors are thankful to Mr. L Smith MD. of Medical Research Archive Journal (where this article
was published in Vol 9, Issue 7, July 2021) for allowing us to print the article (with minor modifications)
as a book chapter in the book- Recent Development in Medicine and Medical Research.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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3. Murray CJL, Lopez AD: The Global burden of disease: a comprehensive assessment of
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10. Sarma BP. Prevention of burns: 13 years' experience in Northeastern India. Burns.
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young children by community-based intervention. Inj Prev. 1998;4(3):176-180.
12. Turner C, Spinks A, McClure RJ, Nixon J. Community-based interventions for the prevention of
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DOI: 10.1136/ip.6.4.259-a
14. Lam N, Dung N. First aid and initial management for childhood burns in Vietnam--an appeal for
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15. Shanmugakrishnan RR, Narayanan V, Thirumalaikolundu subramanian P. Epidemiology of
burns in a teaching hospital in south India. Indian J Plast Surg. 2008;41(1):34-37.
16. Keswani MH. The prevention of burning injury. Burns. 1986;12(8):533-539.
17. Moore J, Morath K, Harré N. Follow-up study of a school-based scalds prevention programme.
Health Education Research. Oxford University Press. 2004;19:430-439.
18. Macarthur C. Evaluation of Safe Kids Week 2001: prevention of scald and burn injuries in young
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19. Peleg K, Goldman S, Sikron F. Burn prevention programs for children: do they reduce burn-
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ChowdhuryABMA. Burn Prevention and First Aid knowledge among high school students in
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Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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APPENDIX 1
Quiz Questionnaire
1. Why use of water is superior to use of blanket in extinguishing fire?
2. Why topical application immediately after sustaining burn injury is harmful?
3. Why floor level cooking is dangerous?
4. What type of clothes should one wear while cooking in the kitchen?
5. How do you pour kerosene in a burning stove or lantern?
6. What precautions will you take to prevent burns in children?
7. What is the harm if the kitchen utilities are stored above the cooking range?
8. What precaution should you take if you smell leakage of LPG in your kitchen?
9. What precautions do you take while enjoying fireworks during Diwali?
10. How long pressure bandage/garments should be used to prevent development of scar and
contractures?
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
31
APPENDIX 2
Recommendations for Implementation at Home
1. Cooking should be done only at a platform, not at floor.
2. Identify one hazard in your resident, which can lead to burn accident. Suggest corrective
measure to prevent it.
3. Open doors and windows of the kitchen, before you light the LPG stove.
4. Do not put rack for storing materials just above the cooking range.
5. Do not allow the younger children (brothers and sisters) to play with match sticks, candles and
electric switches.
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
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APPENDIX 3
Questions in Social Media
1. What is the most common mode of burn injury in children?
a. By hot liquids
b. By flame
2. Blister formation over a burn wound means -
a. Superficial burn
b. Deep burn
3. What should a person do when his clothes catch fire?
a. Run for help.
b. Stop, drop and roll on the ground.
4. What will you apply over the burn wound as first-aid?
a. Pour water till burning pain subside.
b. Apply tooth paste or ghee over the burn wound
5. What will you do when half burnt clothes sticks to the burn wound?
a. Try to remove the half-burnt clothes.
b. Leave them as it is till the patient reaches hospital.
6. In the kitchen, what is recommended?
a. Floor level cooking
b. Cooking on a platform
7. What type of clothes one should wear while cooking?
a. Synthetic clothes
b. Cotton clothes
8. Where will you recommend storing the materials in kitchen?
a. Above the cooking stove
b. Below or side of the cooking stove?
9. How will you fill the stove with kerosene?
a. While the stove is burning.
b. After putting off the light of the stove.
10. What will you do if you suspect leakage of LPG in the kitchen?
a. Switch on the electric light
b. Open the doors and windows of the kitchen.
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
33
Biography of author(s)
Bhupendra Prasad Sarma
Department of Surgery & In-Charge, Burn Unit, NEMCARE Hospital, Guwahati, Assam, India.
Research and Academic Experience: Academic -
1. Senior Faculty in Post Graduate training course (DNB) at NEMCARE Hospital for last 2years
2. Senior Faculty in Training in Essential Burn Care for doctors and nurses for last 10 years
3. Course Director and Faculty in Burn Nursing course affiliated to NSDC, Govt. Of India for last 4 years
4. Regional Coordinator for Pilot Project in Prevention of Burn Injuries, Ministry of Health, Govt. Of India for 4 years
Research- In Burn Care and Prevention of Burns
Research Area:
1. Prevention of Burns amongst urban population.
2. Infection control in Burn unit.
3. Efficacy of different burn wound covers in treatment of burn wounds.
Number of Published Papers: Thirteen research papers published in national and International Journals.
Special Award: Received Dr Bhimandas Bilwani Oration Award from National Academy of Burns India in 2019
Any other remarkable point(s) 1.As the President of Assam Chapter of Association of Surgeons of India(ASI), received the Best
Chapter Award from ASI in 2005,for organizing the first ever Free Operation Camp at Nalbari , Assam. Forty major and minor
operations were done in a single day free of charge for the benefit of poor patients.
2. Authored thirteen books on Health subjects, Yoga and Travel in Assamese , English and Hindi.
Kabita S. Choudhury
Burn Unit, NEMCARE Hospital, Guwahati, Assam, India.
Research and Academic Experience:
1. 1.Faculty in Training Programs on Burn Prevention for last 10 years
2. Faculty in essential Burn Care training programs for last 4 years
Research Area:
1. Infection control in Burn Unit
2. Use of different anti- microbial in burn wound dressings
Number of Published Papers: One paper published as co-author.
Any Other Remarkable PointS:
1. Trained in Burns Management at Masina Hospital and Wadia Hospital for Children
2. PG Diploma in Maternal & Child Health
Recent Developments in Medicine and Medical Research Vol. 7
Experience with Burn Prevention Program in North Eastern India: A Recent Study
34
Dipak Sarma
Burn Unit, NEMCARE Hospital, Guwahati, Assam, India.
Research and Academic Experience:
1. Junior Faculty in Training Programs on Burn Prevention for last 5 years
2. Junior Faculty in essential Burn Care training programs for last 2 years
Research Area:
1. Infection control in Burn Unit
2. Use of different anti- microbial in burn wound dressings
Number of Published Papers: One paper published as co-author.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Medical Research Archives, 9(7), 2021.
_____________________________________________________________________________________________________
1BME Research Lab. Sosei Ltd., Japan.
2Hamamatsu Human Research Lab. Ltd., Japan.
3Josai International University, Japan.
*Corresponding author: E-mail: tshimura@tuba.ocn.ne.jp;
Chapter 3
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Derivation of Diagnostic Criteria for a Slight
Cognitive Impairment Using CKPT (Japanese
Version of CWPT): A Recent Study
Takaki Shimura1*, Eriko Okuyama2 and Hironori Ohsugi3
DOI: 10.9734/bpi/rdmmr/v7/14139D
ABSTRACT
Objective: CWPT, which is able to detect a slight cognitive impairment in PCSD(Preclinical Stage of
Dementia) or MCI(Mild Cognitive Impairment), is attracting attention as a neuropsychological test that
allows screening at the stage where we must rely on expensive testing equipment such as PET, MRI
and X-CT. CWPT is a test for identifying colors and remembering episodes while reading a story
containing Color Words, so it can be easily translated and used in various languages. From the
viewpoint of brain function measurement, the initially applied instruments were an electroence-
phalograph and a near-inferred spectroscopy. Therefore, the purpose of this paper is to show
foreign researchers how to derive the diagnostic criteria in Japan.
Methods: Diagnostic criteria were derived by analyzing large-scale data. At this time, since it is
impossible to perform MMSE on all the subjects, CKPT was performed after receiving a report that I
was normal. As shown in the evidence in the previous paper, the CKPT results show a normal
distribution for each age, so a method to check the distribution by subjecting the subjects who disturb
the normal distribution of the resulting histogram to trial and error is achieved.
Results: The total number of subjects used for the diagnostic criteria was 1325, and 199 subjects
were excluded. The average value ±SD, and the average value ±1.5SD were derived as the
diagnostic criteria for male and female in their 60s, 70s, and 80s.
Conclusion: Using the derived diagnostic criteria, we have gained a foothold to develop various
CKPT applications.
Keywords: CWPT; CKPT; neuropsychological test; PCSD; MCI; slight disorder.
1. HISTORY OF THE RESEARCH
Before the concept of MCI and PCSD was denominated in the field of dementia [1], our research
started to detect slight declines in brain function. From the viewpoint of brain function measurement,
the initially applied instruments were an electroencephalograph (EEG) and a near-inferred
spectroscopy (NIRS [2]). Then, we reached the hypothesis that the slight decline in cognitive function
should be measured as a decline in the prefrontal lobe, because the prefrontal lobe is the commander
of human behavior. Operational definitions of cognitive impairment have varied widely in diagnosing
mild cognitive impairment (MCI). Identifying clinical subtypes of MCI has further challenged diagnostic
approaches because varying the components of the objective cognitive assessment can significantly
impact diagnosis [3,4].
As final goal was to find any methods used at the screening, I noticed neuropsychological tests
instead of measuring instruments. Then color words discern test (CWDT) and Color words pick-out
test (CWPT [5-9]) were invented.
Recent Developments in Medicine and Medical Research Vol. 7
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT (Japanese Version of CWPT): A Recent Study
36
In CWDT, color words are shown using different colors like Fig. 1. Subjects should discern if the
meaning and the printed color of the word is matched or not. If mismatched, make a cross(X) and if
matched, make a circle(〇). Although this test is an application of Stroop Test [10] which is well-
known as one of the prefrontal lobe tests, it cannot totally extract slight declines of the prefrontal lobe
functions.
Fig. 1. Sample of CWDT in English
In CWPT, a story including color words are shown first like Fig. 2a. Subjects should read the story
memorizing the episode of it, and simultaneously pick-out color words discerning the matching of
meaning and printed color of them. After a certain period of time, the subjects stop the task of
determining the color words of Story, and answer Questions (Fig. 1b) regarding the episode
memorized without seeing Story. As explained above, CWPT is an improved version of CWDT with a
short-term memory function examination.
Fig. 2a. Sample of Story of CWPT
Fig. 2b. Sample of Questions
After two presentations at international conferences [11-12], we published a paper [13] on the
evidences of CWPT. Then we developed an English version of conducting CWPT and published a
QUESTIONS (select one)
What was Renate going for?
(shopping, surfing, swimming, forget)
What color was her bag?
(red, pink, yellow, forget)
STORY
Last Sunday, Renate went swimming with her red bag
Alone. She went up the hill and could see a long gray
sandy beach below. There were red, pink, blue and
yellow umbrellas like flowers.
Recent Developments in Medicine and Medical Research Vol. 7
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT (Japanese Version of CWPT): A Recent Study
37
mini review [14] seeking collaborators who used it. Since the third international conference [15] was
postponed due to the new coronavirus and the opportunity for announcement was lost, I decided to
make that presentation on this paper.
2. OBJECTIVE
CWPT, which is able to detect a slight cognitive impairment in PCSD(Preclinical Stage of Dementia)
or MCI(Mild Cognitive Impairment), is attracting attention as a neuropsychological test that allows
screening at the stage where we must rely on expensive testing equipment such as PET, MRI and X-
CT. CWPT is a test for identifying colors and remembering episodes while reading a story containing
Color Words, so it can be easily translated and used in various languages. Therefore, the purpose of
this paper is to show foreign researchers how to derive the diagnostic criteria in Japan.
3. METHODS
3.1 Essential Consideration on Data Collection
Analytical data for deriving diagnostic criteria require uniformity and randomness in collection of
analysis data.
Uniformity means that the test tools used when applying CKPT to subjects are the same, that the
testers who explain the subject using the tools are trained to be at the same level and that the
environment in which the test is performed, such as the brightness and the distance from the adjacent
subject, must meet certain criteria.
Randomness of data collection should be taken into consideration that the areas where the CKPT
data was collected, are random such as urban areas and rural areas, and that the occupations of the
subjects are varied.
3.2 Data Collection Method
As for the CKPT data collection method, Guidance, CKPT implementation, Lecture on correct
understanding of dementia, Lecture on life guidance that does not fall into dementia, and CKPT
scoring were performed according to the protocol shown in Fig. 3, where CKPT scoring and Lecture
on correct understanding of Dementia is done at the same time. What we devised is that the subjects
can receive Lecture on life guidance while looking at their own results of CKPT.
Fig. 3. Protocol of data collection The right column is the venue where the subjects are, and
the left column is the room where the supporters score
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3.3 Scouring Method and Index 1
The criteria for Story scoring are based on the following rules of Table 1.
Table 1. The criteria for Story scouring
Division
Scoring criteria
Correct answer
Correct 〇 or X is attached to color words
Wrong answer
Wrong 〇 or X is attached to color words
Oversight
Color words that the subject forgets to attach 〇 or X
Mistaken answer
〇 or X is attached to characters other than color words
The diagnostic value Index1 of CKPT was obtained by multiplying the number of correct answers and
the correct answer rate of episodic memory.
3.4 Selection of Healthy People
Only the data of healthy subjects are required for analysis of the diagnostic criteria of CKPT. At the
time of evidence examination [13], MMSE [16] was applied to all subjects, and the cut-off value was
27 points. However, large-scale data collection is required to obtain the diagnostic reference value,
making it impossible to perform MMSE on all subjects. Therefore, we decided to exclude the person
who says "I have no brain disorder" but disturbs the normal distribution by applying his Index1 to the
histogram of his age. This work was accomplished by trial and error of exclusion and normal
distribution examinations. Finally, the exclusion conditions are completed.
4. ETHICAL CONSIDERATION
For this paper, all subjects have agreed to use their data while keeping their personal information
confidential.
5. RESULTS
5.1 Analysis Data Collected
Total analysis data collected was 1325, and the breakdown of the regions is shown in Table 2. In the
case of urban area, small cities and rural areas are mixed.
Table 2. The breakdown of regions collected
Regions
Number
Urban area of big cities (Tokyo)
82
Urban area of middle cities (Hamamatsu,Okayama etc.)
256
Small cities (Iwata,Fukuroi,Mishima etc.)
559
Rural area
428
5.2 Exclusion and Used Data for Analysis
Exclusion was performed by trial and error as shown in 3.4, and the exclusion conditions obtained
from the examinations are summarized on Table 3. With regard to the task of adding ◯X to the color
words of STORY, the exclusion conditions of Wrong answer, Oversights and Mistaken answer in Table
1 are shown. The condition of QUESTIONS for memory is where the correct answer is zero. The
number of subjects excluded from collected data was 199, even if one of the exclusion conditions was
met.
Eventually, the number of subjects used in the analysis is shown in Table 4 by gender and age.
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5.3 Normality Examination
Prior to analysis of diagnostic criteria, a normality test of the histogram of each group was performed.
The examination was done using Shapiro-Wilk Test. The results are shown in Table 5. When the
significance probability p shown in the table is less than 5%, it is judged as "not significantly following
the normal distribution". If the opposite p is 5% or more, it is determined that “this data cannot be said
not to follow a normal distribution”, that is, “follows a normal distribution”.
Table 3. Exclusion conditions
No.
Items
Conditions
1
Story scoring
Wrong answer ≧2
2
Oversight ≧4
3
Mistaken answer ≧1
4
Wrong answer. =1
and Oversight ≧2
5
Questions
No correct answer
Table 4. Analyzed data
Gender
Age
Number
Mail
Sixties
126
Seventies
109
Eighties
34
Female
Sixties
433
Seventies
357
Eighties
67
Table 5. Normality of Index1
If p value is 0.05 or more, it follows normal distribution.
Gender
Age
Statistics
Degrees of freedom
Significance of probability p
Mail
Sixties
.981
126
.078
Seventies
.985
109
.255
Eighties
.981
34
.791
Female
Sixties
.994
433
.091
Seventies
.993
357
.117
Eighties
.970
67
.107
5.4 Diagnostic Criteria
Distribution parameter of Index1, such as the average value, the average value ±SD, and the average
value ±1.5SD, were calculated using the data shown in Table 5 whose normality was confirmed. It is
shown in Table 6.
Table 6. Distribution Parameter of Index1
Average-1.5SD or less: 0.067, Average-SD or less: 0.159
Male
Average
-1.5SD
Average
-SD
Average
Average
+SD
Average
+1.5SD
Sixties
5.1
7.3
11.7
16.1
18.3
Seventies
5.0
7.0
10.7
14.4
16.2
Eighties
3.0
4.9
8.6
12.3
14.2
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Female
Average
-1.5SD
Average
-SD
Average
Average
+SD
Average
+1.5SD
Sixties
5.9
7.9
11.9
15.9
17.9
Seventies
4.6
6.6
10.6
14.6
16.5
Eighties
2.3
4.5
8.8
13.1
15.3
The diagnostic criteria using Index1 were set as shown in Fig. 4 using Average ±SD and Average
±1.5SD. In the figure, the values of Index1 which are shown in Table 6 are applied to derive the actual
diagnosis criteria. For example, in the case of sixties male, if Index1 is 18.3 or more, it is Excellent, if
Index1 is 16.1 or more and less than 18.3, Good, if Index1 is 7.3 or more and less than 16.1, Normal,
and if Index1 is 5.1 or more and less than 7.3, Slight disorder, respectively. Furthermore, when Index1
is less than 5.1, it is determined that doctor's diagnose is needed.
Fig. 4 Diagnostic criteria
6. SUMMERY
Following the procedure for deriving the diagnostic criteria for CKPT, the data collection of 1325
subjects, the extraction of subjects without brain disorder, and the examination of normal distribution
were described in this order, and finally the diagnostic criteria were derived.
7. CONCLUSION
In this paper, the method of deriving the Japanese CWPT (CKPT) diagnostic criteria in Japan was
described. We are looking for collaborators to spread CWPT in the world, and if you are interested,
please refer to this derivation method and decide to give me e-mail. It is also noted that the English
version of the CWPT test form, PowerPoint and manuals for the test are already prepared14).
ACKNOWLEDGEMENTS
We would like to thank the Shizuoka Prefecture Life Support Center staff, Fukuroi City and Iwata City
Elderly Welfare Division staff, and many other volunteers for their help in collecting and scoring this
data. In addition, I would like to express my gratitude to Mrs. Atsuko Suzuki of BME Lab. in Sosei
Limited Led. who has done reviewed all of scoring data.
Recent Developments in Medicine and Medical Research Vol. 7
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT (Japanese Version of CWPT): A Recent Study
41
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
1. Spering RA, PS Aisen et al. Toward defining the Preclinical stages of Alzheimer’s disease:
Recommendations from the National Institute on Aging-Alzheimer’s Association Working-groups
on diagnostic guidelines for Alzheimer’s disease. The journal of the Alzheimer’s Association.
2011;7(3):280-292.
2. Takaki Shimura et al. Evaluation of CKPT using NIRS. Prefrontal Lobe Measurement using
Near Infrared Spectroscopy-Evaluation of Early Detection Methods and Rehabilitation Methods
of Dementia. CORONA PUBLISHING CO. Ltd., ISBN978-4-339-0722-8 C3704. 2009;113-118.
3. Jak AJ, Bondi MW, Delano-Wood L, Wierenga C, Corey-Bloom J, Salmon DP, Delis DC.
Quantification of five neuropsychological approaches to defining mild cognitive impairment. The
American Journal of Geriatric Psychiatry. 2009 May 1;17(5):368-75.
4. Lopez OL, Becker JT, Jagust WJ, Fitzpatrick A, Carlson MC, DeKosky ST, Breitner J, Lyketsos
CG, Jones B, Kawas C, Kuller LH. Neuropsychological characteristics of mild cognitive
impairment subgroups. Journal of Neurology, Neurosurgery & Psychiatry. 2006 Feb
1;77(2):159-65.
5. Takaki Shimura etal. Japan Patent No.4887720.
6. Takaki Shimura etal. CN Ap. 200480020902. 6.
7. Takaki Shimura etal. Germany Pt No.1641813.
8. Takaki Shimura etal. UK Pt No.1649813.
9. Takaki Shimura etal. Korean Pt No.0735647.
10. Stroop JR. Studies on interference in serial verbal reactions. 1935;XⅧ(6):643-662.
11. Takaki Shimura, Eriko Okuyama and Hironori Ohsugi. A Neuropsychological test(CKPT: Color
Word Pick-out Test) to be able to detect slight disorder of prefrontal lobe; classify the level of the
preclinical stage of dementia, the 24th International Conference on Neuroscience and
Neurochemistry, July 22-24,2018, Birmingham UK; 2018.
12. Takaki Shimura, Eriko Okuyama and Hironori Ohsugi. A neuropsychological test for mild
cognitive impairment and preclinical stage of dementia, global conference on oral health &
mental disorders. July 01-02 2019, Rome Italy; 2019.
13. Takaki Shimura, Eriko Okuyama and Hironori Ohsugi. CWPT(Color Words Pick-out Test)
Available for Classifying the Slight Disorder on the Preclinical Stage of Dementia, HSOA
Journal of Alzheimer’s and Neurodegenerative Diseases. 2019;5(2):100028.
14. Takaki Shimura, Eriko Okuyama, Keiko T Evans: Mini Review of English Version of CWPT
(Color Words Pick-out Test), Archives in Neurology & Neuroscience. ISSN:2641-1911.
15. Takaki Shimura, Eriko Okuyama and Hironori Ohsugi: A neuropsychological test(CWPT: Color
Word Pick-out Test) to be able to be used for screening of PCSD and MCI of dementia, 5th
International Conference on Brain & Spine, March 16-17, Kuala Lumpur, Malaysia.
16. Folstein, MF et al. Mini-mental state: A practical method for grading the cognitive state of
patients for the clinician. Journal of Psychiatric Research. 1975;12(3)189-198.
Recent Developments in Medicine and Medical Research Vol. 7
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT (Japanese Version of CWPT): A Recent Study
42
Biography of author(s)
Prof. Takaki Shimura
BME Research Lab. Sosei Ltd., Japan.
He was born in Tokyo in 1941. He is the President of Sosei Ltd. From 1965 to 2000, he worked in Fujitsu Ltd. and Fujitsu
Laboratories Ltd. developing Ultrasound imaging, X-ray imaging by flat panel detector, Remote health care system by TV (2000-
1979), and Fault location diagnosis method on digital circuit, Shinkansen passenger automatic guidance system and Laser
printer (1979-1965). From 2000 to 2007, he worked in Tokai University as a professor, focusing on research on elderly care. He
graduated Tokai University majoring Atomic Industry in 1965. He got PhD degree from Tokyo University in 1995 and
Engineering fellow of the Japan Society of Ultrasound in Medicine in 2005. He is an honor director of Japan Society for Early
Stage of Dementia and the chairman of BME on Dementia Group of the Japanese Society for Medical and Biological
Engineering. His research interest is Biomedical engineering on Dementia, including Neuropsychological screening tests,
Observation methods and Non-drug therapy. He has more than 10 research articles. He received Paper Award and New
Technology Development Award from the Japanese Society for Medical and Biological Engineering.
Dr. Eriko Okuyama
Hamamatsu Human Research Lab. Ltd., Japan.
Research and Academic Experience: She Graduated from Fujita Health University in1980. She became a licensed Medical
Technologist in Japan in 1980. She obtained PhD. degree from Seirei Christopher University in 2015.
From 2009 to the present, she has represented the Hamamatsu Institute of Human Sciences, Ltd. She served as a Vice
President, Japan Society of Early Dementia, President, Tokai Regional Division, Japan Dementia Care Society, and President,
Shizuoka Dementia Care Professional Association.
Research Area: Her research field is on prevention and dementia care
Number of Published papers: She has more than 10 Published papers
Any other remarkable point(s): She is a President of 21th Annual Conference of Japan Society for Early Stage of Dementia
41A
Recent Developments in Medicine and Medical Research Vol. 7
Derivation of Diagnostic Criteria for a Slight Cognitive Impairment Using CKPT (Japanese Version of CWPT): A Recent Study
43
Dr. Hironori Ohsugi
Josai International University, Japan.
Research and Academic Experience: He Graduated from Seirei Christopher University in 2008. He became a licensed
physical therapist in Japan in 2008. He obtained PhD. degree from Seirei Christopher University in 2013. He served as a
research assistant at Kyoto Tachibana University since 2013 to 2015. He is serving as an assistant professor at Josai
International University since 2016. He is serving as a delegate of Japan Society for Early Stage of Dementia.
Research Area: His Research Area includes physical therapy and rehabilitation
Number of Published papers: He has 10 Published papers
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
HSOA Journal of Alzheimer’s and Neurodegenerative Diseases, 6: 046, 2020.
41B
_____________________________________________________________________________________________________
1Department of Physiology, Jawaharlal Nehru Medical College, Wardha, India.
*Corresponding author: E-mail: dalia_biswas@ yahoo.co.in;
Chapter 4
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Study about Empowering Clinicians with Lifestyle
Changes for Management of Diabetes
Dalia Biswas1* and P. A. Nikose1
DOI: 10.9734/bpi/rdmmr/v7/14099D
ABSTRACT
Aim: To assess the effect of Neurobics and Sanskar Remodelling in Diabetic management.
Method: The interventional, nonrandomised, pre and post study was carried out at the Department of
Physiology, Jawaharlal Nehru Medical College, Wardha. The study lasted one year, and the
participants were diabetic patients aged 15 to 90 years old, both sexes included. Only 63 of the 210
patients recruited were eligible for the study group.
A total of 57 people were chosen from the general population to serve as the control group.
In both groups, blood sugar and WHO-QOL were measured.
Results: Between the pre and post test findings of the study group, there was a statistically significant
decrease in BMI, FBS, and PPBS. The WHO-QOL-Bref tool was used to examine the four domains.
This study found that the intervention used for the study group resulted in improvements in all four
domains.
Conclusion: The study concludes that the lifestyle modification programmes employed in this study,
such as Neurobics and Sanskar Remodelling, can be used in conjunction with routine drugs to treat
diabetes.
Keywords: Neurobics; sanskar remodelling; diabetes.
1. INTRODUCTION
WHO estimates that in 2030 there will be an increase of 70% in the number of cases of diabetes in
developed countries, and 42% in developing countries. This is likely to affect 366 million people by
2030 [1]. 2011 National Diabetes factsheet released on 26th Jan 2011 estimates about 246 million
diabetics worldwide in the year 2010 with prevalence rates of 11.3% among the adults of 20-65 age
group [2].
There were a few clinical trials, but they were usually underpowered, had design and conduct issues,
and the majority employed antidiabetes medicines as the intervention. Fortunately, in recent years,
clear good outcomes from multiple randomised controlled studies involving lifestyle intervention have
become available. A number of large-scale RCTs (i.e., Da Qing DPS, MALMO Feasibility Study,
Finnish DPS, United States DPP, Indian DPP, SLIM, and Japanese DPS trials) have been performed
in persons who are at risk for T2DM (overweight/obese, IGT and/or IFG) in order to evaluate lifestyle
modification of diet and physical activity [3-4]. The Finnish Diabetes Prevention Study(DPS) was one
of the first controlled, randomized studies to show that type 2 diabetes is preventable with lifestyle
intervention [5].
Diabetes self-management education (DSME), the process of teaching people to manage their
diabetes, has been considered an important part of the clinical management of diabetes since the
1930s. The goals of DSME are to optimize metabolic control and quality of life and to prevent acute
and chronic complications, while keeping costs acceptable [6,7].
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Study about Empowering Clinicians with Lifestyle Changes for Management of Diabetes
43
The resource intensive interventions used in clinical efficacy trials need to be translated into
pragmatic, more affordable, programmes, that can be delivered not only in routine clinical practice but
also that retain their effectiveness [8]. Despite advances in Diabetes management, many people with
diabetes have less than optimal metabolic control and continue to suffer from preventable
complications. The gap between optimal evidence-based medicine and actual practice can be great,
dependent not only on the ability of the clinician to make changes in practice patterns but also on the
central role of the patient in implementing optimal management plans in daily life [9]. In addition to
problems in implementing intensive treatment, questions arose concerning the effects of these
regimens on quality of life (QOL) for patients. Intensive regimens also posed new dilemmas for health
care practitioners and patients, not the least of which was the dramatic increase in risk for episodes of
severe hypoglycemia when patients attempted to lower blood glucose (BG) levels. It quickly became
clear that the greatest challenge to contemporary diabetes treatment was overcoming the many
psychobehavioral and social–environmental barriers to optimal self-management [10].
An ancient Indian saying is “Aahar, Baivhaar and Vichar is the key to healthy living. Relating to this
age old dictum, one has to practice healthy eating ( their own diet depending upon environment,
culture and biodiversity), healthy behaviour which can be achieved by Sanskar Remodelling and
Positive thinking which can be practiced by a technique called as Neurobics. Neurobics and Sanskar
Remodelling are Lifestyle modification programmes(LSMP) and are variants of Rajyoga meditation.
Our hypothesis was to test whether Neurobics and Sanskar Remodelling can be of additive support in
the management of Diabetes.
2. METHODS
This was a interventional nonrandomised pre and post study, conducted in the Department of
Physiology, Jawaharlal Nehru Medical College, Wardha. The period of Study was 1 year and study
participants were diabetic patients, aged between 15-90 years including both sexes.
In this study, 210 patients were recruited and only 63 were eligible for the study group. The control
group was selected from population, comprising of 57 patients.
Both the group of subjects were oriented to AADE7TM Self Care Behavior Framework, but the
subjects in the orientation group were given the intervention. They were taught neurobics through
video session by trained facilitators and to sanskar remodelling(SRM) through lecture by
experienced Rajyoga trainers. They practised neurobics and SRM daily for 10 min in the morning and
10 min in evening. This group was reviewed in the centre every weekend for the first 3 months and
after every fortnight for the last 3 months. Patients were called to Physiology department for all
investigations. Compliance was addressed using a log book where signature of subjects were taken
for attending all sessions of 20 hours. Compliance to the programme was taken with an adherence
more than 90%. Pre-test and Post test datas were taken before the onset and after completion of the
study. Patients were referred to their attending Physicians if they required medical care during the
intervention.
Neurobics in this study was performed as a simple exercise of visualization of cosmic colors and
concentrating the cosmic color of yellow, visually on the pancreas [11].
The next intervention given was Sanskar Remodelling for behavior change. The positive thoughts
brought about a behavioural change. In this, the person is sitted upright and concentrates on a point
of white light.
2.1 Outcome Measures
Data collection period was 3 months. All data were collected by the facilitators.
Blood Glucose was measured using a Glucometer namely BG03-Dr Morepen, Gluco one Blood
Glucose monitoring system.
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Study about Empowering Clinicians with Lifestyle Changes for Management of Diabetes
44
Quality of Life assessment was done using the WHOQOL –BREF , Field trial version ,1996
questionnaire. It has 30 questions which assesses 4 domains namely Physical, Mental, Social and
Environmental. All the raw scores were converted to 0-100% scale score , using the WHOQOL score
chart.
2.2 Program Evaluation & Statistical Analysis
Reliability test of Pilot study was calculated using test retest method.
Statistical analysis was done using descriptive and inferential statistics using Wilcoxan. Signed Rank
test, z-test for difference between two mean and chi square test.
2.3 Ethical Clearance
Institutional Ethical Committee permission was taken vide reference number DMIMS(DU)/IEC/2013-
14/310.
3. OBSERVATIONS AND RESULTS
Table 1. Comparison of FBS in study group at pre and post test
Mean
N
Std.
Deviation
Std. Error
Mean
Difference
z-value
p-value
Pre Test
227.76
63
42.460
5.35
16.06±
14.57
8.74
0.000
S,p<0.05
Post Test
211.69
63
42.38
5.33
Graph 1. Comparison of FBS in control group at pre and post test Blood Sugar (FBS) in two
groups
Table 2. Comparison of mean difference in FBS in two groups
Group
Mean Difference
SD
z-value
p-value
Study Group
16.06
14.57
6.63
0.000
S,p<0.05
Control Group
1.40
8.54
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45
3.1 Postprandial Blood Sugar
Table 3. Comparison of PPBS in study group at pre and post test
Mean
N
Std.
Deviation
Std. Error
Mean
Difference
z-value
p-value
Pre Test
372.73
63
65.51
8.25
21.84±
17.88
9.69
0.000
S,p<0.05
Post Test
350.88
63
67.18
8.46
Graph 2. Comparison of PPBS in control group at pre and post test
Table 4. Comparison of mean difference in PPBS Glucose in two groups
Group
Mean Difference
SD
z-value
p-value
Study Group
21.84
17.88
7.26
0.000
S,p<0.05
Control Group
2.56
9.50
3.2 WHO-QOL Domains
Table 5. Comparison of WHO-QOL domains in study group at pre and post test
WHO QOL Domains
Mean
N
Std.
Deviation
Std. Error
Mean
Difference
z-value
p-value
Domain 1
Pre Test
53.50
63
12.23
1.54
16.68±12.14
10.90
0.000
S,p<0.05
Post Test
70.19
63
10.85
1.36
Domain 2
Pre Test
42.79
63
14.82
1.86
25.12±16.67
11.96
0.000
S,p<0.05
Post Test
67.92
63
15.05
1.89
Domain 3
Pre Test
57.95
63
19.36
2.43
12.34±19.54
5.01
0.000
S,p<0.05
Post Test
70.30
63
11.05
1.39
Domain 4
Pre Test
35.87
63
12.12
1.52
24.76±14.82
13.24
0.000
S,p<0.05
Post Test
60.61
63
12.86
1.62
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Study about Empowering Clinicians with Lifestyle Changes for Management of Diabetes
46
Graph 3. Comparison of WHO-QOL domains in control group at pre and post test
Table 6. Correlation of WHO-QOL in 4 domains in study group
Domain 1
Domain 2
Domain 3
Domain 4
Correlation ‘r’
0.989
0.774
0.767
0.023
p-value
0.0001,S
0.0001,S
0.0001,S
0.857,NS
4. DISCUSSION
Observational studies have provided firm evidence that multiple life style intervention decreases the
risk of type 2 diabetes.
The improvement in sugar level findings in the study group (Lifestyle intervention group) correlates
with finding of many researches namely Jaana Lindstrom et al (2003). In their study named as “Finish
Diabetes Prevention Study”(DPS) they found that the intensive lifestyle intervention produced long
term beneficial changes in biochemical parameters namely plasma glucose and reduced diabetes risk
[12]. Marco Mensink et al (2003) found in their study that lifestyle interventions improved glucose
tolerance, even in less active population. This result was found after a 2 -hour combined diet and
physical activity intervention programme, on glucose tolerance, in Dutch subjects [13]. Kazue
Yamaoka et al (2005) in their met analysis of RCT’S on efficacy of Lifestyle education to prevent
T2DM, concluded that lifestyle education was effective for reducing both 2-n. plasma glucose and RR
(relative risk) in high risk individuals and may be a useful tool in preventing diabetes [14]. Uzung Yoon
et al (2012) reported the result of 7 trials on efficacy of lifestyle intervention in reducing diabetes
incidence in patients with impaired glucose tolerance. Considering the heterogeneity in LSM
interventions and follow up time, the systematic review concluded that LSM can have a beneficial
effect on the incidence of diabetes [15].
The present study showed statistical improvement in all the 4 domains namely physical, mental, social
and environmental in the study group which points to the importance of the interventions given.
Rubin RR et al in their review study found that duration and type of diabetes are not consistently
associated with quality of life, and better glycemic control is associated with better quality of life [16].
Hervas A et al conducted a study which aimed to evaluate the impact of diabetes mellitus type 2 on
52.4
37.66
37.26
49.38
38.36
50.38
38
50.96
0
10
20
30
40
50
60
70
80
Domain 1 Domain 2 Domain 3 Domain 4
WHO QOL Domain
Mean and SD
Pre Test Post Test
Recent Developments in Medicine and Medical Research Vol. 7
Study about Empowering Clinicians with Lifestyle Changes for Management of Diabetes
47
health related quality of life. This study concluded that T2DM is related to a worse perception of QOL
related to health, and that impact of certain diseases on the patients should not be measured only
through quantification of objective clinical parameters (such as morbidity and mortality) [17]. Ruth
Kalda et al examined the factors that most strongly influenced the quality of life. They found that
patients who were less aware of the disease had a significantly higher quality of life score [18].
5. CONCLUSION
With all these findings we finally conclude that Life style modification programme used in our study
like Neurobics and Sanskar –Remodelling can empower clinicians in the management of diabetes
along with routine medications.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.
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6. Task Force to Revise the National Standards, The American Diabetes Association. National
standards for diabetes self-management education programs. Diabetes Educ. 1995;21:189–93.
7. Bartlett EE. Historical glimpses of patient education in the United States. Patient Educ Couns
1986;8:135–49.
8. Schwarz PE, Greaves CJ, Lindstrom J, Yates T, Davies MJ. Nonpharmacological interventions
for the prevention of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(6):363-73
9. David G. Marrero, Jamy Ard, Alan M. Delamater, Virginia Peragallo-Dittko, Elizabeth J. Mayer-
Davis, Robin Nwankwo, and Edwin B. Fisher. Twenty-first century behavioral medicine: A
context for empowering clinicians and patients with diabetes. Diabetes Care. 2013;36(2):463-
470.
10. Linda A. Gonder-Frederick, Daniel J. Cox, Lee M. Diabetes and behavioral medicine: The
second decade. Journal of Consulting and Clinical Psychology. 2002;70(3):611–625.
11. Diana W. Guthrie, Maureen Gamble. Energy therapies and diabetes mellitus. Diabetes
Spectrum. 2001;14(3):149-153.
12. Eriksson KF, Lindgärde F. Prevention of Type 2 (non-insulin-dependent) diabetes mellitus by
diet and physical exercise the 6-year Malmö feasibility study. Diabetologia. 1991;34(12):891-
898.
13. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes
Prevention Programme (IDPP) .The Indian Diabetes Prevention Programme shows that lifestyle
modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired
glucose tolerance (IDPP-1). Epub. 2006;49(2):289-97.
14. Prevention Study (DPS). Diabetes Care 2003; care.diabetesjournals.org.
15. Uzung Yoon, Lai Lai Kwok, Athanasios Magkidis. Efficacy of lifestyle interventions in reducing
diabetes incidence in patients with impaired glucose tolerance: A systematic review of
randomized controlled trials. From Metabolism, diet and disease Washington, DC, USA. BMC
proceedings. 2012;29-31.
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16. Rubin RR, Peyrot M . Quality of life and diabetes. Diabetes Spectrum. 1999;15(3):205-18.
17. Hervás A, Zabaleta A, De Miguel G, Beldarráin O, Díez J. Health related quality of life in
patients with diabetes mellitus type 2. Centro de Salud de Tafalla, Navarra.
adolhervas@hotmail.com. 2007;30(1):45-52.
18. Ruth Kalda, Anneli Rätsep and Margus Lember. Predictors of quality of life of patients with type
2 diabetes. Patient Preference and Adherence. 2008;2:21-26.
Recent Developments in Medicine and Medical Research Vol. 7
Study about Empowering Clinicians with Lifestyle Changes for Management of Diabetes
49
Biography of author(s)
Dr. Dalia Biswas
Department of Physiology, Jawaharlal Nehru Medical College, Wardha, India.
She is presently working as Professor in the Dept. of Physiology, Jawaharlal Nehru Medical College (JNMC), Wardha. She has
keen interest in conducting studies on Lifestyle modification for different diseases. She is a Research guide. She has presented
many of her research papers in conferences, has 6 books and monographs & has multiple copyrights to her credit. She has
also been a guest speaker in many forums. She has received special trainings in Medical Education Technology , Computer
training , Accupressure training ,Rajyoga meditation, Basic course in Medical Education Technology, Advanced course in
Medical Education Technology, Basic Administrative skills and Education course, Curriculum Implementation Support
program by MCI, Nodal Centre ,Training in Technical capacity building etc. She has Departmental Contributions- 1.Setting
up of Central Electrophysiololy Lab- First of its kind in the country, 2.Setting up of Exercise Physiology Lab, Setting a Museum
in the department, 3. Setting up of Mind- Body – Medicine Clinic at Acharya Vinoba Bhave Rural Hospital, Sawangi(Meghe) ,
Wardha- A pioneering feat in the country. A host of University Assignments like Vice dean, Convenor Of University Exam cell
and many membership of different bodies in the University has been handled by her.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
International Journal of Advances in Medicine, 3(2): 357-363, 2016.
_____________________________________________________________________________________________________
1Department of Conservative Dentistry and Endodontics, Jaipur Dental College Rajasthan, India.
2Department of Periodontology and Oral Implantology, Sawai Mansingh Medical College & Hospital, Jaipur, Rajasthan, India.
3Department of Conservative Dentistry and Endodontics, BHABHA College of Dental Sciences and RC, Bhopal, India.
4Department of Conservative Dentistry and Endodontics, Bishop James Memorial Health Care Centre, Jalpaiguri, West Bengal,
India.
*Corresponding author: E-mail: sangeeta.meena89@gmail.com;
Chapter 5
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
A Comparative Clinical Study on Healing Potential of
Different Scaffolds
Sangeeta Nawal1*, Rajesh Nawal2, Pallavi Kumbhare3 and Mousumi Sarkar4
DOI: 10.9734/bpi/rdmmr/v7/13388D
ABSTRACT
The development of surgical bioactive additives for regulation of the inflammation and enhance
healing plays a critical role in clinical practice nowadays, inorder to speed up the process of healing
this case report is presented to compare the additives with PRF as a common scaffold. PRF improves
periapical healing when combined with other additions like Bone Graft (BG) and Mineral Trioxide
Aggregate (MTA). The purpose of this comparative clinical study was to assess the periapical healing
potential of plasma rich fibrin (PRF) as a scaffold in conjunction with MTA and bone graft. This
investigation included two patients with a history of trauma and a significant periapical radiolucent
lesion. The affected teeth were obturated with gutta percha utilising AH plus sealer after access
opening and biomechanical preparation. Following that, periapical surgery was performed, and blood
was collected from the patients to prepare PRF.A mixture of PRF and MTA was placed in the
periapical defect of the first patient, whereas a mixture of PRF and BG was placed in the periapical
defect of the second patient. A one-month, three-month, six-month, and one-year follow-up was
performed to assess clinical and radiographic healing. Clinically, both patients were asymptomatic.
The combination of PRF and BG resulted in superior radiographic healing.
Keywords: Periapical lesion; Mineral Trioxide Aggregate (MTA); Bone Graft (BG); Platelet Rich Fibrin
(PRF); β- Tricalcium Phosphate; Platelet Rich Plasma (PRP).
1. INTRODUCTION
The use of a patient's own blood to improve healing is an unique concept in dentistry. Platelets play a
key role in wound healing by forming clots and releasing growth factors that help to initiate and
promote wound healing [1]. Scaffolding is a three-dimensional framework that contains growth factors
and aids in the healing process. It can be - Natural-Collagen, Platelet Rich Fibrin (PRF) and Platelet
Rich Plasma (PRP). Synthetic - Polyglycolic acid, Polylactic acid [2]. PRF, a commonly used scaffold
in regenerative endodontics, contains a fibrin matrix that aids in fibroblast and endothelial cell
migration and is a source of growth factors for revascularization [3]. (MTA) has been shown to be an
effective alternative for creating artificial root-end barriers and inducing faster periapical healing in
cases of single-visit apexification and large periapical lesions [4]. This comparative clinical study was
taken up to evaluate the periapical healing of PRF as scaffold along with MTA and bone graft at our
Department of Conservative Dentistry & Endodontic. Ethical clearance was taken from the institutional
ethical committee. Patients were asked to sign the informed consent form for treatment procedure and
publication of their report and photographs after proper explanation. Along with scaffold of PRF
various additives like Bone graft, Mineral Trioxide Aggregate can also be used to enhance periapical
healing. Most commonly used bone grafts include β-Tricalcium phosphate, Freeze dried bone graft,
Emdogain, Octacalcium phosphate, bioactive glass. The combination of PRF membrane as a matrix
and Mineral trioxide aggregate.
Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
51
Schematic-diagram-representing-preparation-of-platelet-rich-fibrin
2. CASE 1
A 20 year-old male complaining of discoloration of the upper left front teeth reported to the
department. On intraoral examination, Ellis class III fracture of 21 but no abnormal mobility, swelling
or pus exudation was noticed. There was history of dental trauma 6 years back. A periapical
radiograph was taken using the standardized techniques, which demonstrated a large radiolucent
lesion around the apex of 21 with ill- defined margins. 21 failed to respond to thermal and electric pulp
testing, whereas control teeth (11 and 31) responded with in the normal limits and there was no
relevant medical history.
After endodontic treatment, surgical endodontic therapy of 21 was planned. Root canal therapy was
done using K files by step back method and obturated with Gutta percha and AH Plus sealer.
3. PREPARATION OF SCAFFOLD
Simultaneous to surgery, PRF preparation was done using 10 ml of intravenous blood collected from
antecubital vein. Blood was collected in a 10-ml sterile tube without anticoagulant and immediately
centrifuged at 3,000 revolutions per minute for 10 minutes. After 10 minutes, the middle layer of PRF
was clearly visible between RBCs at the base and acellular plasma on top. Using a sterile tweezer
PRF was withdrawn from the tube and transferred onto a sterile dapen dish (Fig. 1).
Fig. 1. Preparation of PRF
Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
52
4. SURGICAL PROCEDURE
Using surgical spirit extraoral antisepsis was carried out followed by local anaesthesia and
Oshchenbein Luebke incision was given flap was reflected. On raising flap surgical window was
prepared followed by removal of granulation tissue and sent for biopsy. The PRF prepared
simultaneously was mixed with MTA on sterile glass slab and filled into the intrabony defect to cover
the defect. The flap was repositioned and secured in place using 3-0 non absorbable silk with
interrupted sutures. Sutures were removed 5 days postoperatively. Patient’s regular clinical and
radiographic follow up was done at 1 month, 3month and 6 month interval (Fig. 2).
Fig. 2.1. Pre-Operative Radiograph
Fig. 2.2. After Conventional root canal therapy
Fig. 2.3. After root resection
Fig. 2.4. 1 month follow up
Fig. 2.5. 3 month follow up
Fig. 2.6. 6 month follow up
Fig. 2.7. 1 year follow up
5. CASE 2
A 21 year-old male complaining of fractured lower anterior tooth reported to the department. On
intraoral examination, Ellis class III fracture of 31 but no abnormal mobility, swelling or pus exudation
Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
53
was noticed. There was history of dental trauma 12 years back. A periapical radiograph was taken
using the standardized techniques, which demonstrated a large radiolucent lesion around the apex of
31 and 32 with well defined margins. 31,32 failed to respond to thermal and electric pulp testing.
After conventional endodontic treatment surgical endodontic therapy of the mandibular left central and
lateral incisor was planned. Root canal therapy of 31 and 32 was carried out by step back technique
using K files and obturated with Gutta percha and AH Plus sealer. Surgery was carried out in a similar
manner as in case 1 by raising Oshchenbein Luebke flap.
PRP was again prepared in a similar manner as in case 1 but it was mixed with bone graft on sterile
glass slab and filled into the intrabony defect. The flap was repositioned and sutured. Sutures were
removed 1 week postoperatively. Patient’s regular clinical and radiographic follow up was done at 1
month, 3month, 6 month and 1 year interval (Fig. 3).
Fig. 3.1. Pre-Operative Radiograph Fig. 3.2. After Conventional root canal therapy
Fig. 3.3. After root resection Fig. 3.4. 1 month follow up
Fig. 3.5. 3 month follow up Fig. 3.6. 6 month follow up
Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
54
6. DISCUSSION
After periapical surgery and placement of a mixture of, PRF + MTA or PRF + Bone graft, healing of
both the cases was evaluated at 1 month, 3months, 6 months and 1 year period. Clinically both the
cases were asymptomatic at all these time periods. Radiographically better healing was seen with
PRF and Bone graft combination. Strindberg in 1956, Bender et al in 1966 and Mor in 2004 have all
advocated radiographic healing as the accepted criteria for successful outcome of periapical surgery
along with clinical absence of symptoms.
PRF offers various advantages, simple to prepare, obtainable by autologous blood sample, minimal
blood manipulation without anticoagulants, no addition of external thrombin, absence of
immunological reaction, natural fibrin framework with growth factors within, economical and quick
option compared with recombinant growth factors [5]. The cytokines within the fibrin mesh are
gradually released as the network of fibrin disintegrates [6]. The PRF accelerates the healing of
wound edges [7]. According to Simonpieri et al. [8] the use of this platelet and immune concentrate
provides 4 advantages: 1) Fibrin clot maintains and protects the grafted biomaterials and PRF
fragments act as connectors between bone particles. 2) Integration of fibrin network into the
regenerative site facilitates cellular migration, esp. endothelial cells necessary for the neo-
angiogenesis vascularization and survival of the graft.3) Platelet cytokines (PDGF, TGF- IGF-1) are
gradually released as the fibrin matrix resorbs, leading to enhanced healing [9], 4) Leukocytes and
cytokines in the fibrin network self-regulate inflammation and infection.
In our study MTA was used along with PRF because of its superior sealing ability and biocompatibility
over conventional filling materials. In vivo studies have shown that MTA has the capacity to induce
bone, dentin and cementum formation.
In comparison to other root end filling materials, MTA leads to regeneration of periapical tissues
including periodontal ligament and cementum [10]. The combination of PRF membrane as a matrix
and MTA has been demonstrated to be an effective alternative for creating artificial root-end barriers
and to induce faster periapical healing for single visit apexification of the cases with large periapical
lesions [11,12].
In the second case bone graft β- tricalcium phosphate was used along with PRF. Several case reports
have demonstrated healing with mature bone and haemopoietic marrow in periapical areas by using
this bone graft [13]. Beta-tricalcium phosphate (β-TCP) is an osteoconductive bone graft which gets
chemically resorbed with a concomitant release of bioactive ions [14]. Besides promoting wound
healing, bone growth, and maturation, PRF mixed with β-tricalcium phosphate bone graft has the
advantages of graft stabilization, wound sealing, hemostasis, and improved handling properties [13].
In our study healing observed with this combination was better as compared to PRF and MTA
combination.
7. CONCLUSION
Addition of PRF to MTA and β-Tricalcium Phosphate allograft accelerates regenerative capacity of
bone [15]. When used in combination, they give a predictable clinical and radiographic evidence of
bone formation. Based on finding in our cases and those reported by others it appears that the
combination of PRF and bone graft provide better healing than MTA and PRF. Although for more
conclusive results a wider clinical study needs to be undertaken [16,17].
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
1. Mazumdar P, Nag D, Bhunia S. Treatment of Periapical Lesion with Platelet Rich Fibrin. Indian
Medical Gazette. 2013;28-33.
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3. Naik B, Karunakar P, Jayadev M, Marshal VR. Role of Platelet rich fibrin in wound healing: A
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in human cell culture. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and
Endodontology. 2009;108(1):48-55.
8. Simonpieri A, Del Corso M, Sammartino G, Ehrenfest DMD. The relevance of Choukroun’s
platelet-rich fibrin and metronidazole during complex maxillary rehabilitations using bone
allograft. Part I: A new grafting protocol. Implant Dentistry. 2009;18(2):102-111.
9. Mazor Z, Peleg M, Garg AK, Luboshitz J. Platelet-rich plasma for bone graft enhancement in
sinus floor augmentation with simultaneous implant placement: patient series study. Implant
Dentistry. 2004;13(1):65-72.
10. Kim S, Kratchman S. Modern endodontic surgery concepts and practice: A review. Journal of
Endodontics. 2006;32(7):601-623.
11. Fernandes M, de Ataide I. Nonsurgical management of periapical lesions. Journal of
Conservative Dentistry. 2010;13(4):240.
12. Chhabra N, Singbal KP, Kamat S. Successful apexification with resolution of the periapical
lesion using mineral trioxide aggregate and demineralized freeze-dried bone allograft. Journal
of Conservative Dentistry. 2010;13(2):106.
13. Jayalakshmi KB, Agarwal S, Singh MP, Vishwanath BT, Krishna A, Agrawal R. Platelet-rich
fibrin with β-tricalcium phosphate—a noval approach for bone augmentation in chronic
periapical lesion: A case report. Case reports in dentistry; 2012.
14. Bashutski JD, Wang HL. Periodontal and endodontic regeneration. Journal of Endodontics.
2009;35(3):321-328.
15. Borie E, García D Oliví, Orsi IA, Garlet K, Weber B, Beltrán Vand Fuentes R. Platelet-rich fibrin
application in dentistry: A literature review Int J Clin Exp Med. 2015;8(5):7922–7929.
16. Mousavi SM, Zarei M, Hashemi SA, Ramakrishna S, Chiang WH, Lai CW, Gholami A, Omidifar
N, Shokripour M. Asymmetric membranes: a potential scaffold for wound healing applications.
Symmetry. 2020;12(7):1100.
17. Preethi GU, Unnikrishnan BS, Sreekutty J, Archana MG, Anupama MS, Shiji R, Pillai KR,
Joseph MM, Syama HP, Sreelekha TT. Semi-interpenetrating nanosilver doped polysaccharide
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Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
56
Biography of author(s)
Dr. Sangeeta Nawal
Department of Conservative Dentistry and Endodontics, Jaipur Dental College Rajasthan, India.
She is an Assistant Professor at Jaipur Dental College and Consultant since September 2017 at Nawal’s Ivory Dental Clinic,
Jaipur, india. She has work experience of 5 years. She has done her Post graduation (M.D.S) in Conservative Dentistry and
Endodontics. She was honoured for her "Excellence in Academics" by People’s Dental Academy, Bhopal for distinction and
gold medal in various subjects during her graduation. She was also awarded by Indian Academy of Aesthetic and Cosmetic
dentistry for presentation on aesthetics dentistry and by Dental Student Welfare Association of India and Dental Surgeon
Association of India for best presentation in Bhopal 2015. She also conducted workshop on topic Basics in rotary Endodontics
and delivered lecture on topic Endodontic Regeneration in Denasia 5th National Dental Conference 2019 Jaipur. She has done
an original research in Endodontics. She is member of Indian Association of Conservative Dentistry and Endodontics and also
have 7 publications in reputed journals. She is an author of book Lasers in Dentistry (Published by Lambert Academic
Publishers). She was also awarded for intensive training of full mouth rehabilitation & contemporary comprehensive dentistry by
Impart education on February 2020.
Dr. Rajesh Nawal
Department of Periodontology and Oral Implantology, Sawai Mansingh Medical College & Hospital, Jaipur, Rajasthan, India.
He was an Assistant Professor in the Department of Periodontics at Government Dental College & Hospital, Nagpur &
Aurangabad and also worked as senior resident at Sawai Mansingh medical college & hospital, Jaipur. He has done his Post
graduation (M.D.S) Periodontology and oral Implantology in June 2015 (Maharashtra University of Health Science, Nair
Hospital Dental College, Mumbai) Presently, he is the Director & Consultant in Nawal’s Ivory Dental Clinic, Jaipur and has work
experience of 8 years. He was awarded by WCOI Diplomate in Nov 2016. He delivered lecture on topic Easy implants in
Denasia Dental Conference 2018 Goa. He is member of Indian Society of oral Implantologists. He has 2 publications in reputed
journals. He is a co-author of book Lasers in Dentistry (Published by Lambert Academic Publishers).
Dr. Pallavi Kumbhare
Department of Conservative Dentistry and Endodontics, BHABHA College of Dental Sciences and RC, Bhopal, India.
She is Assistant Professor in BHABHA College of Dental Sciences and RC and practicing dentistry since 2012 till present in
EkDantam Multispeciality Dental Clinic, Bhopal, India. She has done her post graduation (M.D.S) in Conservative Dentistry and
Endodontics. She was awarded by Indian Endodontic Society, for best paper presentation 2017 in Gaziabad. She is member of
Indian Association of Conservative Dentistry and Endodontics. She has 5 publications in reputed journal. She is now a
practicing Endodontist in Bhopal and associated with many dental clinics as an Endodontist and Aesthetic consultant.
Recent Developments in Medicine and Medical Research Vol. 7
A Comparative Clinical Study on Healing Potential of Different Scaffolds
57
Dr. Mousumi Sarkar
Department of Conservative Dentistry and Endodontics, Bishop James Memorial Health care centre, Jalpaiguri, West Bengal,
India.
She has done her post graduation (M.D.S) in Conservative Dentistry and Endodontics. She has working experience of 5 years.
She was awarded for best paper presentation in Indore. She is member of Indian Association of Conservative Dentistry and
Endodontics. She has 5 publications in reputed journal. She has done Fellowship in medical cosmetology. She is now
practicing as an Endodontist at Bishop James Memorial health care centre, Jalpaiguri (West Bengal) and associated with many
dental clinics as an Endodontist and Aesthetic consultant.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Saudi Journal of Oral and Dental Research, 2(1): 9-13, 2017.
_____________________________________________________________________________________________________
1Department of Paediatrics, University of Khartoum, Sudan.
2Department of Obstetrics and Gynaecology, Sidra Medicine, Doha, Qatar.
*Corresponding author: E-mail: osamaelshazali@hotmail.com;
Chapter 6
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Counselling for Down Syndrome, are We Doing it
Right?
Osama Hafiz El Shazali1* and Hala Abdullahi2
DOI: 10.9734/bpi/rdmmr/v7/14168D
ABSTRACT
Down syndrome is the commonest genetic condition, affects about 1:700 life born. DS is associated
with many conditions e.g. Cardiac, Learning difficulties, Gastrointestinal, Endocrine and
haematological. Parents need to counselled know about the condition to ensure the long term
wellbeing of children.
In this article we will discuss the guidelines for counselling and review the literature of studies
addressing the issue of the quality of counselling in Down Syndrome.
Keywords: Children with down syndrome; counselling.
1. INTRODUCTION
Down syndrome (DS) is the most common chromosomal abnormality, affecting around one in every
700 babies born. Prenatal testing for DS [1–3] is currently recommended by the American College of
Obstetrics and Genecology (ACOG) and the American College of Medical Genetics for all pregnant
women, regardless of age. Despite the fact that these recommendations exist in high-income
countries, more than 85 percent of mothers who have children with Down syndrome, first received the
diagnosis postnatally [4,5]. The outlook and survival for individuals with Down syndrome have
improved in the last four decades, it is crucial that healthcare providers are aware of the key elements
in counselling parents of children with DS to ensure that families receive up-to-date and balanced
information, that is delivered in a supportive manner.
Breaking bad news is one of the most important areas that are facing doctors on regular basis and it
is one of the most difficult areas for the doctors to deal with, but unfortunately doctors do not receive
adequate formal training in breaking bad news. Bad news may be defined as “any information which
adversely and seriously affects an individual’s view of his or her future” [6,7]. Communicating bad
news can be very difficult to the informer even to the most experienced physician, and can be a
devastating experience to the parents, this experience could influence the way they react or accept
the child illness in the long run [4,5].
Ralston reflecting on about what he learned about DS in the medicals school commented that
Lectures or seminars on DS or other genetic syndromes were geared toward the description of the
abnormalities and there was no stress on what this child can do and on their rich and valuable life [8].
Parents reported that their physicians talked little about the positive aspects of DS and rarely provided
enough up-to date printed materials or telephone numbers of other parents with children with DS,
some Parents reported that being frightened or anxious after learning the diagnosis, and very few
rated the overall experience as a positive one [5].
Studies from high income countries e.g. UK, Sweden, Australia, USA have reported strong parent’s
dissatisfaction with the way in which the diagnosis was conveyed to them during the immediate
postnatal period and also the support provided to them during the same period [5].
Recent Developments in Medicine and Medical Research Vol. 7
Counselling for Down Syndrome, are We Doing it Right?
59
Table 1 . Practice guidelines for communicating a prenatal or postnatal diagnosis of down
syndrome: recommendations of the national society of genetic counselors [10]
A. Tell the parents about the diagnosis as soon as possible, even if the diagnosis is suspected but not yet
confirmed. If the diagnosis has not been confirmed by karyotype, explain what physical features or
medical concerns are suggestive of the diagnosis
B. Ideally, the diagnosis should be delivered in person, by a healthcare professional with sufficient
knowledge of the condition. Health care providers should coordinate the message to ensure
consistency in the information provided to the family
C. Whenever possible, meet with both parents together
D. The family should be informed of the diagnosis in their preferred language. If possible, a professional
medical interpreter should be present at the time of disclosure.
E. Discuss the diagnosis in a private, comfortable setting, free from interruptions. Allow time for questions
and make plans for a follow-up conversation.
F. Parents should be provided with accurate and up-to-date information. Information should be given with
a balanced perspective, including both positive aspects and challenges related to Down syndrome.
G. Provide the information in a sensitive and caring, yet confident and straightforward manner, using
understandable language that is clear and concise
H. Use neutral language and avoid using value judgments when starting the conversation, such as “I’m
sorry” or “Unfortunately, I have bad news”.
I. Use sensitive language and avoid outdated or offensive terminology. In the newborn setting, the baby
should be present, and should be referred to by name. Use person-centric language, emphasizing that
this is a baby who has Down syndrome, rather than a “Downs baby” or a “Down syndrome child.”
J. Allow time for silence tears. Do not feel that you need to talk to “fill the silence’’. Offer the family time
alone.
K. Assess the emotional reactions of the parents, and validate these feelings. Use active listening and
empathic responses to support the parents.
L. Informational resources should be provided, including contact information for local and national
support groups, up-to-date printed information or fact sheets, and books. The opportunity to meet with
families who are raising a child with Down syndrome, when appropriate, referrals to other specialist
may also be helpful e.g. cardiologist.
Table 2. Essential information for the initial discussion of a diagnosis of down syndrome [10]
A. Down syndrome (DS) is caused by extra genetic material from chromosome 21. DS may be suspected
based on physical findings, but the diagnosis is confirmed by chromosome analysis.
B. Individuals with DS have a variable range of intellectual disability from mild to moderate.
C. Babies with DS have delays in achieving developmental milestones and benefit from early intervention
including physical, occupational and speech therapy
D. 80% of babies with DS will have hypotonia.
E. 50% of babies with DS have one or more congenital abnormality: 40–60% of babies with DS have a
heart defect and 12% have a gastrointestinal defect that may require surgery. Assistance with referrals
to specialists is appropriate for identified complications
F. Children with DS are more like other children than they are different. Raising a child with DS may
involve more time commitment than typical children
G. Individuals with DS can participate in community sports, activities, and leagues.
H. Individuals with DS can learn in a special education class or may be included in regular classes and
most can complete high school
I. Individuals with DS can be employed competitively or in a workshop setting.
J. Individuals with DS can live independently or in a group home
K. Individuals with DS have friends and intimate relationships.
L. Life expectancy extends into the 50s or 60s.
M. Information on local support groups, advocacy organizations, early intervention centers, printed
material, fact sheets, books, and specialist referral as needed, and the option to contact a family
raising a child with DS should be offered
N. A personalized recurrence risk for future pregnancies should be offer
Recent Developments in Medicine and Medical Research Vol. 7
Counselling for Down Syndrome, are We Doing it Right?
60
There are good clinical practice guidelines for the delivering of bad news and for the management of
children with DS (Tables 1 and 2) [9-16].
2. LITERATURE REVIEW
A study from Sudan [17] to determine if parents received any counselling for Down syndrome at the
time of the diagnosis and to assess the quality of the counselling received, The study included 109
newly diagnosed children with DS who were referred to the paediatric cardiology department for
echocardiography, 56 infants were females and 53 were males.
40 (37%) parents did not know that their children had been diagnosed or suspected to have DS and
they had no counselling about DS, although there were referred to the paediatric cardiology clinic with
a diagnosis of DS stated on the echocardiography referral form.
69 (63 %) knew about the diagnosis/ possibility of DS and were counselled about DS. But 22 out of
them (34%) felt that the counselling was not good enough, as it did not address their concerns and
anxiety.
Many studies tried to address the information that the counsellor should provide to the parents, and
how best this should be given [4,5,9,12,18,19,20]. Most studies were surveys of parents of DS
children who were asked to reflect on the way their healthcare providers delivered the diagnosis of
DS. A systemic review by Gysel et al. [21] of communication skills training advised that training in
communication skills should be offered to medical and nursing students and to senior medical
professionals as well.
Study by Sheets et al. [12] showed that parents appreciate information about the abilities and
potential of people with Down syndrome, as opposed to clinical details. Balancing clinical information
with other aspects of the condition, as well as a better understanding of the information parents
consider most important, may enable healthcare professionals to more effectively satisfy families’
informational needs following a new diagnosis of DS.
A study from Egypt showed that mother’s likes to be told early, to be told of others with a similar
condition, and to be informed of the prognosis [18]. The conversation must take place with both
parents in a quiet setting as soon as the diagnosis of DS is suspected. The timing of the disclosure of
specific DS related problems must be balanced with respect for the opportunity for parents to
welcome their child [16].
Study from Saudi [22] showed that the knowledge about DS among mothers was good, but
interestingly more than half the mothers were first told by the diagnosis of DS in the delivery room by
the midwife. Study from Thailand [23] concluded that health provision for children with DS needed to
be improved.
Training program for doctors in counselling of DS have been shown to increase the knowledge of
doctors and in decreasing the level of discomfort felt by them during the counselling process [18].
There are good clinical practice guidelines for the delivering of bad news and for the management of
children with DS [6,7, 9-16]. The use of such protocols should be encouraged as it make it easier for
doctors to counsel the parents and this in return should help in providing the best care to the children.
3. CONCLUSION
Most of the studies showed that the parents feel that the quality of counselling that they received was
not good and even some studies showed some parents did not receive any counselling at all.
Counselling of parents f need to be improved, this issue should be addressed by issuing local
guidelines or following the published guidelines.
Recent Developments in Medicine and Medical Research Vol. 7
Counselling for Down Syndrome, are We Doing it Right?
61
Counselling of parents is very important for the long term care of the children, so it must be done in a
sensitive and a compassionate manner. Formal training to paediatrician in counselling skills and in
delivering bad news should be implemented.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
1. ACOG Committee on Practice Bulletins. ACOG practice bulletin No. 77: Screening for fetal
chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217–227.
2. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 88: Invasive
prenatal testing for aneuploidy. Obstet Gynecol. 2007;110(6):1459–1467.
3. Driscoll DA, Gross SJ. First trimester diagnosis and screening for fetal aneuploidy. Genet Med.
2008;10(1):73–75.
4. Skotko BG, Capone GT, Kishnani PS, et al. Postnatal diagnosis of down syndrome: Synthesis
of the evidence on how best to deliver the news. Pediatrics. 2009;124(4):e751‒e758.
5. Skotko B. Mothers of children with Down syndrome reflect on their postnatal support. Pediatrics.
2005;115(1):64–77.
6. Baile W, Buckman R, Lenzi R, et al. SPIKES‒A six-step protocol for delivering bad news:
application to the patient with cancer. Oncologist. 2000;5(4):302‒311
7. Buckman R. How to break bad news: A Guide for Health Care Professionals. Baltimore: Johns
Hopkins University Press, 1992.
8. Ralston SJ. Reflection from the trenches: one doctor’s encounter with disability rights
arguments. In: Parens E, Asch A, eds. Prenatal Testing and Disability Rights. Washington DC:
Georgetown University Press; 2000.
9. Dent KM, Carey JC. Breaking difficult news in a newborn setting: Down’s syndrome as a
paradigm. Am J Med Genet C Semin Med Genet. 2006;142C(3):173–179.
10. Sheets KB, Crissman BG, Feist CD, et al. Practice guidelines for communicating a prenatal or
postnatal diagnosis of Down syndrome: Recommendations of the national society of genetic
counselors. J Genet Couns. 2011;20(5):432‒441.
11. Brasington CK . What I wish I knew then...reflections from personal experiences in counseling
about Down syndrome. J Genet Couns. 2007;16(6):731‒734.
12. Sheets KB, Best RG, Brasington CK, et al. Balanced information about Down syndrome: What
is essential? Am J Med Genet A. 2011;155A(6):1246‒1257.
13. American Academy of Pediatrics: Health supervision for children with Down syndrome.
Pediatrics. 2001;107(2):442–449.
14. American Academy of Pediatrics (AAP) Committee on Genetics. Policy Statement: Health
Supervision for Children with Down syndrome. Pediatrics. 2007;120(3):683–684.
15. Bull MJ; Committee on Genetics. Health supervision for children with Down syndrome.
Pediatrics. 2011;128(2):393–406.
16. Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J
Pediatr. 2010;169(12):1445‒1452.
17. Shazali OH El, Abdullahi H, Osman HES. Assessment of quality of counselling for down
syndrome in Sudan. Journal of Pediatrics & Neonatal Care. 2019;8(5):232–4.
18. Abdelmoktader AM, Abd Elhamed KA. Egyptian mothers’ preferences regarding how physicians
break bad news about their child’s disability: A structured verbal questionnaire. BMC Med
Ethics. 2012;2:13‒14.
19. Lunney CA, Kleinert HL, Ferguson JE 2nd, et al. Effectively training pediatric residents to
deliver diagnoses of Down syndrome. Am J Med Genet A. 2012;158A(2):384‒390.
20. Muggli EE, Collins VR, Marraffa C. Going down a different road: First support and information
needs of families with a baby with Down syndrome. Med J Aust. 2009;190(2):58‒61.
21. Gysels M, Richardson A, Higginson IJ. Communication training for health professionals who
care for patients with cancer: A systematic review of training methods. Supportive Care Cancer.
2005;13(6):356–366.
Recent Developments in Medicine and Medical Research Vol. 7
Counselling for Down Syndrome, are We Doing it Right?
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22. Naif Alosaimi M, Hakeem AH, Alfentokh OK, Alsomali AH. International Journal of Medicine in
Developing Countries. International Journal of Medicine in Developing Countries [Internet].
2020 [cited 2021 Sep 11];4(10):1595–600.
23. Rojnueangnit K, Khaosamlee P, Chunsuwan I, Vorravanpreecha N, Lertboonnum T, Rodjanadit
R, et al. Quality of life and comprehensive health supervision for children with Down syndrome
in Thailand. Journal of community Genetics.
Recent Developments in Medicine and Medical Research Vol. 7
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Biography of author(s)
Osama Hafiz El Shazali
Department of Paediatrics, University of Khartoum, Sudan.
Research and Academic Experience: More than 20 years experience in Academic medicine and research.
Research Area: Structural and acquired heart disease in Children.
Number of Published Papers: 24.
Any Other Remarkable Point: He is working with his colleagues in Africa to improve the paediatric cardiac services in Africa.
Hala Abdullahi
Department of Obstetrics and Gynaecology, Sidra Medicine, Doha, Qatar.
Research and Academic Experience: She has more than 15 years experience in academic medicine and research.
Research Area: Maternal and Foetal Medicine.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Journal of Pediatrics and Neonatal Care, 8(5): 232‒234, 2018.
_____________________________________________________________________________________________________
1Dental Concepts, Dental Clinic, Goa, India.
2Department of Prosthodontics, Goa Dental College & Hospital, Goa, India.
3Department of Prosthodontics, Bangalore Institute of Dental Sciences and Research Centre, Bengaluru, Karnataka, India.
4Consulting Prosthodontist, Bangalore, India.
*Corresponding author: E-mail: coraabigail25@gmail.com;
Chapter 7
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Case Report on Rehabilitation of a Class III
Hemimandibulectomy Patient with Twin-occlusion
Prosthesis
Cora A. Coutinho1*, Ivy F. Coutinho2, Divya Hegde3,
Chottakyatanahalli R. Vijayalakshmi3, Ruchika Iyer4 and Akansha Priya4
DOI: 10.9734/bpi/rdmmr/v7/4456F
ABSTRACT
The residual mandible deviates toward the resected side due to the mandible's discontinuity.
A hemimandibulectomy patient can be rehabilitated in a variety of methods. The patient described in
this case report underwent class III hemimandibulectomy owing to early squamous cell carcinoma of
left mandibular alveolus. He went to the prosthodontics department for rehabilitation of the defect
because he was having difficulty masticating and was also concerned about esthetics.
Objective: This case report describes a technique for rehabilitating a hemimandibulectomy with
complete dentures designed with twin occlusion to restore function and improve facial appearance.
Keywords: Hemimandibulectomy; mandibular deviation; paired occlusion; twin occlusion.
1. INTRODUCTION
Fabricating functional complete dentures for edentulous patients who have undergone
hemimandibulectomy is a very arduous and demanding endeavor. The most difficult situation
encountered during this procedure is the mandible's deviation to the resected side. The mandibular
deviation to the resected side is directly proportional to the tissue loss in the area where
hemimandibulectomy was performed [1].
A classification of mandibular defects has been described by Cantor and Curtis. Although the
classification system is suggested primarily for edentulous patients, it is also applicable to partially
edentulous patients. This system classifies defects based on remaining structures [2-4].
2. CANTOR AND CURTIS CLASSIFICATION [5] (Figs. 1a – 1f)
Fig. 1a. Class I - Mandibular resection involving alveolar defect with preservation of
mandibular continuity
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Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
65
Fig. 1b. Class II - Resection defects involve loss of mandibular continuity distal to the canine
area
Fig. 1c. Class III - Resection defect involves loss up to the mandibular midline region
Fig. 1d. Class IV: Resection defect involves the lateral aspect of the mandible, but are
augmented to maintain pseudo articulation of bone and soft tissues in the region of the
ascending ramus
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Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
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Fig. 1e. Class V - Resection defect involves the symphysis and parasymphysis region only,
augmented to preserve bilateral temporomandibular articulations
Fig. 1f. Class VI - Similar to class V, except that the mandibular continuity is not restored
In cases with Cantor and Curtis classes II, III, IV, and V, guide flange prosthesis would be a treatment
modality. For guide flange prosthesis to be effective, the sufficient number of posterior teeth that are
periodontally sound should be present in the opposite arch [6]. In patients where reconstruction is not
done after resection of the mandible, scar tissue formation occurs over a period of time that stiffens
the tissues and worsens prosthetic rehabilitation, leading to compromised treatment planning. Various
prosthetic treatments are available and depending upon the clinical situation, appropriate option
should be selected. Swoop proposed the use of a Palatal Ramp, [7] and Rosenthal suggested the use
of twin occlusion [8,9]. Various other authors too followed Rosenthal by modifying palatal ramp and
utilizing multiple maxillary teeth in the form of twin rows on the untreated side [10,11]. Mathew and
Thomas delivered a Guiding Flange Prosthesis to a Hemimandibulectomy patient [12]. Bandodkar et
al also rehabilitated a hemimandibulectomy patient with a guided flange prosthesis who underwent
hemimandibulectomy (from the left condyle to midline region) and a failed attempt at free fibula
grafting [13]. Bahri et al made use of (Maxillomandibular Fixation) MMF screws with orthodontic
elastics to improve the functioning of the guide flange prosthesis [14]. Sharma et al. rehabilitated a
hemimandibulectomy patient who was partially edentulous with twin occlusion prosthesis [15]. Ruby et
al. fabricated maxillary and mandibular acrylic complete denture using dynamic functional impression
technique and using neutral zone to rehabilitate an edentulous hemimandibulectomy patient [16]. This
case report describes prosthodontic management of a patient who has undergone
hemimandibulectomy and was rehabilitated with complete dentures using two rows of maxillary
posterior teeth on the unresected side/twin occlusion.
3. CASE DESCRIPTION
A 74-year-old male patient reported to the department of prosthodontics with the chief complaint of
difficulty in eating and poor appearance and wanted replacement of teeth. On eliciting the history, the
patient revealed the habit of tobacco chewing for 10 years and was diagnosed with early squamous
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Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
67
cell carcinoma involving left mandibular alveolus. Left-side hemimandibulectomy was performed 1
year ago; and after resection, reconstruction was not done, which resulted in greater deviation owing
to the scar tissue formed over a period of time, leading to compromised treatment planning. Patient
also underwent radiation therapy.
Extraoral examination showed facial asymmetry in the lower third of the face, decreased mouth
opening of 32 mm, significant deviation of mandible to left side of mouth opening, and drooping of the
corner of the mouth which was more prominent on the left side.
Intraoral examination revealed completely edentulous maxillary and mandibular arches with a left
mandibular defect from the midline. Both the ridges were smooth, round, well-keratinized mucosa with
sufficient height and width for support (Fig. 2).
The case was diagnosed as Cantor and Curtis Class III mandibular defect based on clinical and
radiographic examination (Fig. 3).
Preliminary impressions were made with irreversible hydrocolloid material (Algitex; DPI, Mumbai,
India) using stock trays and casts were poured with type II dental plaster. On the maxillary and
mandibular casts, a custom tray was fabricated with self-cure acrylic resin (Cold Cure; DPI RR,
Dentsply, India) and border molding was performed. Final impressions were made with zinc oxide
eugenol impression paste (Impression Paste; DPI, Mumbai, India). Denture bases were fabricated
and wax occlusal rims were made and functional occlusal record was obtained in wax placed lingual
to the maxillary posterior occlusal rim on the opposite side of the defect region and used as an index
to arrange the palatal row of the teeth. The patient’s tactile sense was used to assess the vertical
dimension of occlusion. The patient was advised to move his mandible as far as possible toward the
resected side and then gently close his mandibular jaw into the position to record a functional maxilla-
mandibular relationship. After articulation, two sets of non-anatomic teeth (Premadent, New Delhi,
India) were selected. Two rows of teeth were arranged in the posterior region of edentulous maxilla on
the unaffected side. First row of teeth were arranged as per contour of the patients ridge and the other
set were arranged palatal to the first row on the unaffected side in the maxillary arch on which the
mandibular teeth would occlude. The teeth arrangement in the mandible would have ended at 32
region and as this would lead to an abrupt termination of the denture, three teeth were added to that
region for esthetic purpose and were in mild contact. Try in was done to evaluate for esthetics,
phonetics and occlusion (Figs. 4 to 6). The processed dentures were assessed intraorally for occlusal
adjustments and border overextension (Figs. 7 and 8). Due to his prominent maxilla, the labial flange
was reduced to enhance his esthetics. Post insertion instructions were given to the patient and was
advised not to masticate on the defect side. He was instructed to do mouth opening and closing
exercises to improve the neuromuscular coordination. The patient was periodically followed up after 1
day, 1 week, 1 month, and 3 months. Initially the patient experienced difficulty in using the denture but
over the period of time he showed improvement in mastication and phonetics, and by 3 months he
was satisfied functionally and psychologically (Figs. 9 and 10).
Fig. 2A to C. (A) Intraoral view of maxilla; (B) Intraoral view of mandible; (C) Intraoral view of
mandible
Recent Developments in Medicine and Medical Research Vol. 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
68
4. DISCUSSION
Greater the tissue loss, greater will be the mandibular deviation to the resected side, thereby
compromising the prognosis of the treatment [5]. Resected mandible along with tissue loss causes
rotation of the mandibular plane on the defect side. The suprahyoid muscle pull causes inferior
displacement and rotation of the condyle, thereby causing an anterior open bite [17]. According to
Beumer et al., it was suggested that following maximum opening, the patient is asked to manipulate
the mandible by grasping the chin and moving the mandible away from the surgical side. These
movements tend to loosen scar contracture and improve maxillomandibular relationships [18].
Dentulous patients can be retrained to achieve acceptable maxillomandibular relationship with the
help of appliance like guide plane. However, it cannot be used in edentulous patients. Hence, these
patients cannot achieve adequate maxillomandibular relationship [11]. In this case report, the
definitive treatment to meet the functional and esthetic requirements of the edentulous
hemimandibulectomy patient would have been an implant-supported prosthesis [19]. But since the
patient had restrictions to undergo another surgery owing to financial constraints, an acrylic complete
denture with two rows of teeth on the maxillary denture on the unresected side of the mandible was
given. The palatal row of teeth intercuspated with the mandibular teeth and thus improved mastication
and the buccal row of teeth supported the cheeks [1]. Acrylic denture base resin was chosen as a
material of choice for the complete dentures because acrylic is esthetic, light in weight, less
expensive, and easy to fabricate and repair.
Fig. 3. Orthopantomogram showing the mandibular resection on the left side
Fig. 4A to C. (A) Teeth arrangement done (frontal view); (B) Teeth arrangement opposite to the
defect; (C) Teeth arrangement on the defect side
Recent Developments in Medicine and Medical Research Vol. 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
69
Fig. 5. Try-in stage, intraoral view showing twin occlusion on the opposite side of the defect
Fig. 6. Try-in stage, intraoral view showing the occlusion
Fig. 7 a,b. Final denture
Fig. 8. Intraoral view showing the occlusion with the final denture
Recent Developments in Medicine and Medical Research Vol. 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
70
Fig. 9. Pre- treatment
Fig. 10. Post treatment
5. CONCLUSION
Reconstruction and rehabilitation of a completely edentulous patient with hemimandibulectomy
defects poses a special clinical challenge. The treatment modality using a twin-occlusion complete
Recent Developments in Medicine and Medical Research Vol. 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
71
denture to the patient gave a significant improvement in mastication, speech, and esthetics and is
cost effective treatment procedures in economic constraints.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
1. Maxillofacial rehabilitation, In: Beumer J, Curtis T, Firtell D St. Louis:Mosby. 1979;90–169.
2. Cantor R, Curtis TA. Prosthetic management of edentulous mandibulectomy patients: part II,
Clinical procedures. J Prosthet Dent. 1971;25:546-55.
3. Desjardins RP. Occlusal considerations for the partial mandibulectomy patients. J Prosthet
Dent. 1979;41:308-15.
4. Kenneth FB. Complete denture treatment in patients with resected mandible. I Prosthet Dent.
1969;21:443-7.
5. Beumer J, Curtis T, Marunick MT. Maxillofacial rehabilitation: Prosthodontic and surgical
consideration. Ishiyaku Euro America, St. Louis. 1996;184-188.
6. Cantor R, Curtis TA. Prosthetic management of edentlousmandibulectomy patients. part 1.
Anatomic, physiologic and psychologic consideration. J Prosthet Dent. 1971;25(4):446–457.
DOI: 10.1016/0022-3913(71)90236-8.
7. Swoope CC. Prosthetic management of resected edentulous mandible. J Prosthet Dent.
1969;21(2):197–202.
DOI: 10.1016/0022-3913(69)90092-4.
8. Rosenthal LE. The edentulous patient with jaw defects. Dent Clin N Am. 1994;8:773–779.
9. Sureja R, Naveen YG, Sethuraman R, et al. Twin occlusion prosthesis: A ray of hope for
hemimandibulectomy patient–a case report. Eur J Dent Ther Res. 2014;3:231–233.
10. Marathe AS, Kshirsagar PS. A systematic approach in rehabilitation of hemimandibulectomy: a
case report. J Indian Prosthodont Soc. 2016;16(2):208–212.
DOI: 10.4103/0972-4052.164914.
11. Sahu SK, Motwani BK, Dani A. Prosthetic rehabilitation of edentulous hemimandibulectomy
patient: a clinical report. Clin Case Rep. 2017;5(11):1739–1742.
DOI: 10.1002/ccr3.1125.
12. Mathew A, Thomas S. Management of a hemimandibulectomy defect with a definitive guiding
flange prothesis. Pushpagiri Med J. 2012;3:132–134.
13. Bandodkar S, Arya D, Singh SV, Chand P. Guide flange Prosthesis for management of
hemimandibulectomy. National Journal of Maxillofacial Surgery. 2021;12(2):289.
14. Bahri R, Prakash P, Issar Y, Bhandari SK. Management of hemimandibulectomy patients with
guidance flange prosthesis using combination technique-A case report. IP Annals of
Prosthodontics and Restorative Dentistry. 2021;7(1):55-8.
15. Sharma R, Sharma A, Verma BP, et al. Twin-occlusion prosthesis: A glimmer of hope for
hemimandibulectomy patient. Indian J Dent Sci 2019;11:61–64.
DOI: 10.4103/IJDS.IJDS_89_18.
16. Ruby KM, Choudhary H. Pros thet ic management of hemimandibulectomy patient – a case
report. JMSCR. 2018;06(07): 158–162.
DOI: 10.18535/jmscr/v6i7.26.
17. Taylor TD. Diagnostic considerations for prosthodontics rehabilitation of the mandibulectomy
patient. In: Taylor TD. Clinical Maxillofacial Prosthetics. Chicago: Quintessence Publishing;
2000;155–170.
18. Beumer 3rd J, Marunick MT, Esposito SJ. Maxillofacial Rehabilitation. 3rd ed., Chicago:
Quintessence. 2011;87–89,118-20.
19. Goyal P, Manvi S, Arya S. Prosthodontic management of hemimandibulectomy patient:
implants, a better solution. J Dent Implant. 2016;6:37–40.
DOI: 10.4103/0974-6781.190385.
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Biography of author(s)
Dr. Cora A. Coutinho
Dental Concepts, Dental Clinic, Goa, India.
She has completed her BDS degree in 2015 from Maratha Mandal Dental College, Belgaum and MDS in 2020 from Bangalore
Institute of Dental Sciences, Bangalore, India. She is currently practising in her Clinic in Goa. She has 7 publications to her
credit.
Prof. Ivy F. Coutinho
Department of Prosthodontics, Goa Dental College & Hospital, Goa, India.
She is a Professor in the Department of Prosthodontics, Goa Dental College and Hospital. She completed her B.D.S. in 1984
and M.D.S. in 2001 from Goa Dental College and Hospital, Goa. She has seventeen national and international publications.
She has seven paper presentations at national conferences. She has contributed to writing a chapter on “A case Report on
fabrication of a non- integrated hollow ocular prosthesis using soap spacer” in the book New Frontiers in Medicine and Medical
Research Volume 3, page no: 69-79.
Prof. Divya Hegde
Department of Prosthodontics, Bangalore Institute of Dental Sciences and Research Centre, Bengaluru, Karnataka, India.
She is a professor and head of department of prosthodontics at Bangalore institute of dental sciences and research center
Bangalore with 18 years of experience in the field of prosthodontics. She completed her BDS in 1998 and MDS in
Prosthodontics in the year 2002 from AB Shetty Institute of Dental Sciences, Mangalore, India. Her areas of interest are
esthetic dentistry including implant dentistry. She has several publications in national and international journals.
Recent Developments in Medicine and Medical Research Vol. 7
Case Report on Rehabilitation of a Class III Hemimandibulectomy Patient with Twin-occlusion Prosthesis
73
Dr. Chottakyatanahalli R. Vijayalakshmi
Department of Prosthodontics, Bangalore Institute of Dental Sciences and Research Centre, Bengaluru, Karnataka, India.
She is working as a Senior Lecturer in Bangalore Institute of Dental Sciences, Bengaluru, India. She has completed her BDS
from Govt dental college and research institute, Bangalore in 2011 and MDS from College of Dental Sciences, Davangere in
2017. Her areas of interest include Fixed Prosthodontics, Implant and Maxillofacial Prosthodontics.
Dr. Ruchika Iyer
Consulting Prosthodontist, Bangalore, India.
She completed BDS from Sinhgad Dental College and Hospital, Pune in 2016 and MDS from Bangalore Institute of Dental
Sciences, Bangalore in 2020. She has done 7 publications. She is currently practicing in a private clinic in Bangalore.
Dr. Akansha Priya
Consulting Prosthodontist, Bangalore, India.
She is working as a Consultant Prosthodontist and also practicing in a private clinic in Bangalore. She has completed her BDS
degree in 2015 from VS Dental College, Bangalore and MDS in 2020 from Bangalore Institute of Dental Sciences, Bangalore.
She has done 8 publications.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Int J Prosthodont Restor Dent, 10(1): 35–38, 2020.
_____________________________________________________________________________________________________
1Mater Misericordiae University Hospital, Dublin 7, Ireland.
2General, Geriatric and Stroke Medicine, St. James's Hospital, Dublin 8, Ireland.
*Corresponding author: E-mail: damaze2002@yahoo.com;
Chapter 8
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
The Evolution of Obesity: An Approach for
Evolutionary Advantage to a Disease
Keneilwe Malomo1 and Ontefetse Ntlholang2*
DOI: 10.9734/bpi/rdmmr/v7/3909F
ABSTRACT
Obesity is linked to several diseases and reduced life expectancy. The prevalence of this important
public health issue is increasing worldwide.
Aim: This paper highlights the evolution of obesity from the Paleolithic era to the present period and
promotes it as a disease rather than a survival advantage as it used to be perceived.
Methods: This is an overview of the evolution of obesity, including from a sociocultural perspective
throughout history and linking it to metabolic disorders, based on a narrative review of the literature.
Results: Obesity has been in existence since the paleolithic area and was considered advantageous
as it was associated with high social status and fertility. At the same time, physicians started to
associate with diseases, but it was not until the 1920s that more focus was on it as associated with
the disease.
Conclusions: Published literature on the history of obesity reveals that obesity has been present all
along. There seems to be an acknowledgment of obesity as a disease recently, politically, and
medically.
Keywords: Obesity; disease; Paleolithic era; Neolithic era; Greco-Roman and Byzantine era.
1. INTRODUCTION
Obesity is defined as an excessive fat accumulation that may impair health [1]. There are several
ways of predicting obesity, the common ones being waist circumference (WC), waist-hip ratio (WHR),
and body mass index (BMI). World Health Organization (WHO) defines obesity as a BMI greater than
or equal to 30 [1]. It is a common public health issue, and the prevalence is increasing worldwide. For
example, the global age-standardized prevalence of obesity doubled from 6.4% in 1980 to 12.0% [2].
Overall, about 13% of the world's adult population (11% of men and 15% of women) were obese in
2016 [1].
This paper will address the evolution of obesity from the Paleolithic era to the present age. It will
highlight the presence and perception of obesity in each period. Furthermore, emphasis will be on
obesity as a disease from medico-political and sociocultural perspectives. This is based on a narrative
review of available literature.
2. PALEOLITHIC ERA
The Paleolithic Era is prehistory from about 2.6 million years ago to around 10000 years ago [3].
Obesity studies from the Paleolithic era are based on figurines of that time. Paleolithic humans used
primitive stone tools, and they survived as hunters and gatherers [4]. As nomads, their food source
depended greatly on the environment and climate changes. Figurines curved during the Paleolithic
era may depict the sociocultural perspectives of the individual population. In this section, we reviewed
studies based on the figurines to emphasize obesity in the paleolithic era.
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The Evolution of Obesity: An Approach for Evolutionary Advantage to a Disease
75
Pontius, 1986 [5] described two important terms for studying prehistory; heuristic and iconodiagnosis.
In simple terms, she suggested using experience-based techniques to study and interpret prehistoric
art within a medical framework. The author highlighted two types of obesity- gluteal and abdominal.
Further emphasis was on the association of abdominal obesity with disease processes and sedentary
lifestyle contrary to the gluteal obesity (temporary energy storage) likened to camel's hump [5].
The most famous statue is of 'Venus of Willendorf', dated over 30 000 years ago [6]. It has provided
the earliest depictions of obesity [4,7]. This figurine depicts generalized obesity, central adiposity, and
large waist circumference. Venus (to the Romans) was attributed to representing Aphrodite, the Greek
goddess of love and beauty [8]. Seshadri, 2014 [5] postulated that in the hunter-gatherer society that
she (Venus) lived in, lower body mass index (BMI) was more common in women with consequent
infertility, and hence Venus could have been a model for hunter-gatherer women to aspire for, with no
chances of ever becoming one.
Another important paper examining obesity in the paleolithic era used photos and/or copies of one
hundred statues [9]. Ninety-seven of those studied were females, of whom 24 were skinny (mainly
young women), 15 were of normal weight, while more than half of them (51) were either overweight or
very obese. They found that the figurines examined revealed various types of obesity ranging from
belly only, belly and hips, belly and gluteal and hips, belly and hip and gluteal and femora, and diffuse
obesity. Furthermore, the paper reported that only seven statues were in the state of advanced
gravidity. Thus, we can deduce from this study that there might have been a double effect of
malnutrition with underweight, normal weight, overweight, and obesity in the Paleolithic era. We can
further deduce that based on the figurines studied, there were fewer statues in the state of gravidity,
and this questions the rationale of the Venus figurine (obese females) representing the goddess of
fertility. In the present time, we know that obesity is associated with the polycystic ovarian syndrome
and a reduced chance of conception [10].
We can conclude that obesity existed during the Paleolithic era, as depicted in the arts. The incidence
and prevalence at the time are unknown. The presence should be analyzed based on the
sociocultural perspectives of people of the time. They depended on hunting and gathering and were
prone to the effects of climate change and may be gaining extra fat was survival self-defense at times
of famine. Intuitively, it is safe to postulate that due to the sources and nature of food, obesity would
not be rampant.
3. NEOLITHIC ERA
The Neolithic Era began around 10,000 BC and ended between 4500 and 2000 BC in various parts
of the world [3]. Neolithic humans discovered agriculture and animal husbandry, which allowed them
to settle down in one area [11]. This was the first change in sourcing food. The revolution changed the
dynamics of the society from small clusters of hunter-gatherers to a large community of farmers [12].
The change also brought about an abundance of food, even though seasonal. Crop production led to
increases in carbohydrate-rich diets, and changes in dental microbiota [13] and domestication of cattle
(Bos taurus and Bos indicus) from wild aurochsen (Bos primigenius) led to extensive modifications of
the diet [14]. The changes in dental microbiota reflect historical dietary changes [13]. Furthermore,
Bogaard et al., 2013 [15], using a stable isotope, showed that early farmers used livestock manure
and water to enhance crop yields.
An illustration of the Neolithic era obesity, a female Greek figurine made of clay estimated from the 5th
Millennium BC depicting obesity, has been reported [16]. The figurine had visible characteristics of
female obesity, protrusion of the abdomen in a broad convexity, legs full, nearly round in section, and
thighs almost the same as the upper body.
It may be that obesity became more common as agricultural settlements began to take over from
hunter-gatherer tribes [15]. The process would need manpower and, hence, large communities to
work on the farms and herd animals [12]. The change from exercising all the time (hunt and gather) to
periodic work on the farms and sedentary lifestyle and having more food would lead to energy
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imbalance with built-up of positive energy leading to overweight and eventually obesity. The Neolithic
revolution would have widened the gap in sociocultural groups- the less well-off working for the rich.
4. GRECO-ROMAN AND BYZANTINE ERA
The Greco-Roman period is from 332 BC to 395 AD. The Byzantine Era began in 395 AD with the
division of the Roman Empire into western and eastern (Byzantine) empires and ended AD 641 with
Arab conquest [17]. Another source state that the Byzantine Empire ended in 1453 when it was
conquered by the Ottoman Turks [18]. Papavramidou and Christopoulou-Aletra, 2007 [19] wrote on
the views of selected writers of those times concerning obesity. They reported on the writings of Aulus
Cornelius Celsus (circa 25 BC), Dioscorides Pedanius (40-90 AD), Soranus of Ephesus (98-138 AD),
whose writings on the subject survived through Caelius Aurelianus (5th c. AD), Claudius Aelianus (3rd
C. AD), Oribasius (324-400 AD), Aetius of Amida (circa 450 AD), Alexander Trallianus (6th c. AD),
Paulus Aegineta (7th c. AD), and Theophilus Protospatharius (9th C. AD). It is interesting to note that
all selected writers addressed etiology, manifestations, and treatment of obesity.
They all postulated that a healthy body is balanced with moderate thin and fat, balanced
temperament, and retentive and natural faculties. However, regarding obesity, there has to be an
imbalance, i.e., gaining too much fat, having a warm or moist temperament against cold temperament,
and disorder of the retentive faculties. These points address the cause of obesity and point to possible
cures by trying to restore the imbalances.
Furthermore, the authors addressed the treatment of obesity by suggesting shifting the ill
temperament of the patient to a healthy one and reestablishing the balance of the humors [19]. The
treatment options they suggested focused on weight loss and included diet, medications, and change
in lifestyle, among others. Since the Byzantine world is around the Mediterranean, the diet suggested
is thought to be a Mediterranean diet. Mediterranean diet has been shown to reduce obesity [20] and
has a protective effect on weight gain and type 2 diabetes mellitus [21].
This section shows that obesity and its management were considered by physicians of the time.
Interestingly, the focus is on a Mediterranean diet as healthy, ie rich in fish, fruits, and vegetables in
the present era.
5. THE REFORMATION ERA
The Reformation era in Europe in 1517 with Martin Luther's '95 Theses' and ended in 1648 with the
Treaty of Westphalia, which ended the Thirty Years' War [22]. It was a period characterized by
religious, social, and political changes. In addition, it was a period when the globalization of the
economy and the exchange of foods across continents occurred [23].
Saint Francis de Sales, the Catholic reformer, in the early seventeenth century, had been quoted to
allude to overeating as not good for the body, "Eating only to satisfy our appetite is tolerated, but is
not in itself praiseworthy, and eating to excess is dangerous" [23]. Therefore, we can deduce that it
might have been about excess eating leading to obesity or corpulence. An example of obesity during
the Reformation era includes the Protestant reformer Martin Luther [24, 25]. Portraits of the time also
depict obesity, e.g., of Alessandro Del Borro [26], Rubenesque [27], and Henry the VIII [28].
6. INDUSTRIALISATION AND URBANISATION
The industrial revolution of the 1850s led to easy accessibility to processed foods, e.g., white sugar
and flour [29]. On the other hand, industrialization shifted towards added sugars and a high-fat diet in
a heterogeneous pattern depending on the region and culture. Simultaneously, the occupations
required less energy to be expended, and the new technologies allowed those in each occupation to
engage in increasingly sedentary work [30]. The technologies included packaging, refrigeration,
cookers, fire, and electricity, among others, i.e., food technology to make food easily accessible [30].
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For rapid access, transportation changed from walking and horse-drawn vehicles to trains, cars,
electric scooters, and buses. In addition, transportation of goods involved trucks and lorries and, most
notably, rail networks [29]. These changes would lead to energy preservation, which would be
converted to fat and lead to obesity.
Urbanization described as a shift from rural to urban dwelling also had an impact on weight. In urban
areas, there is limited engagement in sports and easy access to television and associated media
advertising high fat, high carbohydrates food, and hence energy imbalance leading to overweight
and/or obesity [30]. Having stated that, efforts to reduce overweight and hypertension and their health
sequelae should address the dietary changes and reductions in physical activity in both urban and
rural populations [31] and brought about by rural-urban shift.
In China, for example, there has been a rapid growth of population dwelling in urban areas. The
economic opportunities are a strong pull factor stimulating migration, and the effect provides a large
labour pool for productive activities in urban areas [31]. According to Popkin, 2008 [32], the rapid
decline in energy expenditure of the population, linked with the enormous shift towards a diet with
more energy density from edible oils and animal source foods, have resulted in a rapid increase in the
distribution of the body mass index (BMI) of the Chinese population, particularly adults.
This section shows that industrialization and urbanization brought about a high energy/ high-fat diet
and reduced energy expenditure. The consequence of this would be increased weight.
7. SOCIOCULTURAL PERSPECTIVE
Social and cultural perspectives of the body size of different populations/regions dictate the
bodyweight of those populations. A person's culture permeates every aspect of their life, including
how they think about fatness and thinness and all other facets of living in the world [33].
7.1 Chinese
Like other Asian countries, the Chinese diet has shifted from a more traditional plant-based diet to a
westernized, highly processed diet [34]. As a result, the money elasticity for the demand for edible oil
rose significantly between 1989 and 1993 and was positive at all income values [30]. These high-
calorie/ high-fat diets can increase the incidence and prevalence of overweight and obesity.
Guldan, 2010 [34] reported that Asian childhood overweight dietary patterns include snacking and
eating out; consumption of fast food, sweetened beverages, and excessive meat; unhealthy
macronutrient energy proportions; and a preference for refined grains. Furthermore, overweight or
obese adolescents tended to view TV programs and become less physically active [35]. Using data
from China Health and Nutrition Survey, a longitudinal survey from 1989 to 1997, Luo and Hu, 2002
[36], reported that the prevalence of obese children aged 2-6 years increased from 1.5% to 12.6% in
urban areas and prevalence of overweight increased from 14.6 to 28.9% in the same period.
Changes in social status have resulted in a rapid increase in the distribution of the Chinese
population's body mass index (BMI), with adult male overweight status tripling and overweight female
status doubling between 1989 and 2000 [32]. Furthermore, Popkin, 2008 [32] reported that more than
1.2% of the Chinese adult male population has become overweight or obese each year over the past
decade, while among adult men from Australia, the UK, and the United States, the annual rate of
increase was slightly less. These changes could be attributed to a rapid decline in energy
expenditures and a high caloric/ high-fat diet.
7.2 Sub-Saharan Africa
In Africa, with particular reference to sub-Saharan Africa, social epidemiology reveals that females
(sex) and women (gender) regard plumpness as a sign of beauty, fertility, and well-being [37,38]. This
social depiction is more on ethnic lineages [39]. When a female is due to get married is fatten to
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prepare her for pregnancy, breastfeeding, and social status as a married woman in the community
[39]. These cultural connotations lead to females being more overweight and/or obese in this part of
Africa.
The expectation of certain cultures of women to be overweight/obese precludes the concerned society
from noticing or appreciating obesity as a chronic disease rather than a sign of beauty, pride, health,
and wellness [38]. Culture as a changing phenomenon is influenced by national and international
media, occupations, psychosocial factors, and notably the advent of the modeling industry that might
have doubled malnutrition- thinness and fatness in the same communities. Holdsworth et al., 2004
[37] found that Senegalese women preferred overweight BMI to normal BMI and concluded that the
term 'overweight' made little sense to those Senegalese women and could have important
implications for developing public health policies. Overweight and obesity are on the rise in sub-
Saharan Africa, with women being disproportionately affected compared to men [40].
7.3 Western Countries
In the United States and other western countries, there is an increasing trend of consuming meals
outside of the home; however, the diet tends to have higher fat/higher calories and less healthy food
[41]. Stewart et al., 2006 [42] reported that almost three-quarters of people surveyed usually eat out at
least once a week, and the pattern was attributable to growing consumer demand for a variety of
foods, convenience, and entertainment. Furthermore, a systematic review and meta-analysis revealed
the low cost of high calories/ high-fat diet compared to a healthy one [43]. Data from a population-
based study showed that high adherence to the Mediterranean Diet Score and Healthy Eating Index,
both inversely associated with BMI and obesity, led to higher monetary costs than a low adherence
[44].
Advertising of high calorie/ high-fat diet could promote a culture of unhealthy eating [41]. The target
mainly is children's programs [45]. Advertising junk food and fast food increases children's requests
for those particular foods and products, snacking increases while watching TV or movies, and late-
night screen time may interfere with getting adequate amounts of sleep, which is a known risk factor
for obesity [46]. Moreover, the western culture towards food is excess, with ever-increasing portion
sizes, instant gratification, and the 'more for less' mindset [47].
Studies of acculturation showed that when people move from one culture to another, they lose their
original culture towards diet [48,49]. In addition, western culture associates obesity with men's social
status but places increasing pressure on women to be thin, leading to gender disparities [49]. These
sociocultural factors affect gender disparities in excess weight gain in developed countries, such that
more women than men are obese, whereas more men than women are overweight [49].
7.4 Obesity as a Disease
Cheng 2006 [7] reported that obesity as a risk factor for cardiovascular disease was recognized by
Hippocrates (460-c375 BC) and further mentioned that Hippocrates pointed out the shortened life
expectancy of the obese versus slender. Hippocrates condemned overeating and linked it to
cerebrovascular disease: "A city that lies exposed to the hot winds. . . . Most of the inhabitants have a
rather flabby physique. . . . When they are more than fifty years old they are paralyzed by catarrhs
supervening from the brain. . . ." [50].
Galen (c129-210 AD), whose work was somehow based on Hippocrates' work, also supported
reaching a balance to keep the body healthy [51]. Galen proposed six factors, air and environment;
food (diet) and drink; sleep and wake; motion (exercise) and rest; retention and evacuation; and
passions of the mind (emotions) and recommended that these factors should be used in moderation
since too much or too little would put the body in imbalance and lead to disease or illness [51].
Papavramidou and Christopoulou-Aletra, 2007 [19] reported on Greco-Roman and Byzantine era's
view of obesity. They reported on ten writers of that era, from Aulus Cornelius Celsus (circa 25 BC) to
Theophilus Protospatharius (9th c. AD), whose writings focused on etiology, presentation, and
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management of obesity. They all described a healthy body as one in absolute balance, i.e., balance in
humors, balance in temperament, balance in thin and fat and natural faculties, with imbalance leading
to either underweight or overweight/obese and management being restoration and maintenance of the
imbalances.
The Gulstonian Lectures in 1850 [52] focused on obesity as a disease. In the lecture, Chambers
described the etiology, presentation, and management, focusing on physiology and pathophysiology.
The letter highlighted that obesity was common and disease but received little attention.
Obesity was brought more into the limelight by the insurance industry [4] due to its link with increased
mortality by actuarial studies in the twentieth century. Eknoyan, 2006 [4] further reported that by the
1930s, the medical profession made a total about-face on the desirability of excess 'flesh' and
accepted fat as a health problem after analyzing Metropolitan Life Insurance Company data in the
1920s for differential mortality by weight. Thus, by the 1920s, insurance companies were already
charging higher premiums for life insurance coverage to persons with excess body weight, based on
their actuarial data on mortality rates of obese people [53].
James, 2008 [54] reported that obesity was already classified as a disease with the formation of World
Health Organization (WHO) in 1948. Thus, obesity and its associated co-morbidities have been
recognised as diseases for over half a century. However, it is worth noting that obesity remained
neglected, probably due to a lack of political and medical will since then. It is not often realized that
the World Assembly delegations agreeing on new policies are essentially controlled by the foreign
services of the member states, and they often overturn the views of their Ministries of Health if there
are strong economic arguments from the Trade or Agriculture departments [54].
In the United States, earlier reports of the problem of obesity surfaced in 1966 by the US Department
of Health followed by the US Senate's Select Committee on Nutrition report on 'Nutrition and Health'
in 1975, warning of the alarming increase in the prevalence of 'diseases of over-abundance [53].
In June 2013, American Medical Association classified obesity as a disease [55]. Furthermore, in
November 2013, The American Heart Association, American College of Cardiology, and The Obesity
Society released guidelines that doctors consider obesity as a disease and actively treat obese
patients for weight loss [56]. The guidelines also recommended weight loss for some overweight
people, e.g., individuals with a BMI of 25 to 29.9, and one risk factor, such as hypertension or
hypertriglyceridemia.
8. CONCLUSION
We have shown that obesity has been recognized from the Paleolithic era up to the present. Obesity
as a disease was first described by Hippocrates, followed by physicians of the Greco-Roman and
Byzantine eras. Furthermore, in the 1920s, the Insurance Companies, in 1948 World Health
Organisation, and in 2013 both the American Medical Association and The American Heart
Association, American College of Cardiology, and The Obesity Society recognized obesity as a
disease.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Biomedical Research and Clinical Practice, 3(2): 1-5, 2018.
_____________________________________________________________________________________________________
1Department of Radiology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre (IKDRC), Dr. H. L.
Trivedi Institute of Transplantation Sciences (ITS), Ahmedabad, 380016, Gujarat, India.
*Corresponding author: E-mail: drkajal@yahoo.co.in;
Chapter 9
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Anastomotic Pseudoaneurysm in Post Renal
Transplantation
Kajal N. Patel1* and Shruti Mehta1
DOI: 10.9734/bpi/rdmmr/v7/4904F
ABSTRACT
Renal arterial pseudoaneurysm is a rare complication of renal transplantation that often causes a graft
loss. Approximately 10% of patients undergoing renal transplantation may suffer a medical, urological
or a vascular complication. The existence of very small series of patients with pseudoaneurysm after
renal transplantation and isolated case reports published in current literature indicates it is rare.
Controversy persists in eliciting the etiology, occurrence, indications for repair, treatment options and
prognosis. Imaging plays a major role and so that inspire us to present our modest experience with
pseudoaneurysm after renal transplant. Pseudoaneurysm can be easily detected by Ultrasonography
and color Doppler. The analysis of literature and from our series leads us to formulate some
considerations: The anastomotic pseudoaneurysm should be identified early, this condition can be
fulfilled only with periodic ultrasound monitoring in post-transplant follow up. Conservative procedures
should be considered in patients in good condition with preserved graft function and without
symptoms or signs of infection. Open surgical repair, endovascular repair and ultrasound guided
percutaneous thrombin injection are the current reported treatment options. Pseudoaneurysm can
carry a potentially devastating loss of allograft and the need for allograft nephrectomy. Early diagnosis
and timely operation might be the most important factors in the survival of patients. Clinical,
biochemical as well as radiological follow up examination confirmed successful therapeutic
management of the patient.
Keywords: Pseudoaneurysm; Renal transplantation; Ultrasound; Multislice CT scan; Imaging; Colour
Doppler.
1. BACKGROUND
Renal arterial pseudoaneurysm is a rare complication of renal transplantation that often causes a graft
loss. Kidney transplant is the best treatment for end-stage chronic renal failure. The average life of the
transplanted kidney is 10-15 years, ranging between a few months to 20-30 years. Approximately
10% of patients undergoing renal transplantation may suffer a medical, urological or a vascular
complication [1]. The main cause of loss of transplanted kidneys is the rejection, while only a small
number of grafts are lost due to surgical complications, such as urological and vascular problems.
Anastomotic pseudoaneurysm is a rare complication of renal transplantation occurring in 0.3%. The
existence of very small series of patients with pseudoaneurysm after renal transplantation and
isolated case reports published in current literature indicates it is rare. Controversy persists in eliciting
the etiology, occurrence, indications for repair, treatment options and prognosis. It is not unusual for
pseudo aneurysms exist for years before detection or develop years after transplantation or
transplantation nephrectomy. Imaging plays a major role and so that inspire us to present our modest
experience with pseudoaneurysm after renal transplant inform of the role of different imaging
modalities in detection of pseudo aneurysms and treatment options.
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2. DISCUSSION
Chronic kidney disease is a large and growing problem the worldwide. It is attributed mainly to
diabetic and hypertensive nephropathies. Other causes include glomerulonephritis, autoimmune
diseases, obstructive nephropathies, inherited diseases such as polycystic kidney disease, congenital
malformations and repeated urinary tract infections. With the advanced stage of the chronic kidney
disease, most patients will require substitute treatment such as hemodialysis or peritoneal dialysis to
survive. Renal transplantation is cost-effective and provides better long-term survival and better life
quality in comparison to hemodialysis and/or peritoneal dialysis. Vascular complications represent an
important cause of morbidity and mortality after renal transplantation. Different studies have shown a
range of 3 to 15% occurrence [2,3]. They include transplant renal artery stenosis, transplant renal
artery thrombosis, transplant renal vein thrombosis, hematomas, extra-renal false aneurysms
(pseudoaneurysm) and biopsy-induced arteriovenous fistulas and intra-renal false aneurysms.
2.1 Incidence
Anastomotic pseudoaneurysm is a rare complication of renal transplantation occurring in 0.3%. [4],
but are potentially devastating and can lead to allograft loss due to the risk of rupture.
2.2 Location
It may affect the anastomotic site between iliac and renal arteries.
2.3 Etiology
Etiology is attribute to various factors like poor surgical technique, perivascular infection, defective
suture technique, suture rupture, anastomotic leakage, vessel wall ischemia and arterial dehiscence
caused by local infection [5,6]. No experimental or clinical data suggest an immunological cause for
extra renal pseudo aneurysm in transplant patients, while there are few reported cases of intra renal
small pseudo aneurysm in association with immunologic factors such as acute or chronic rejection [7].
While anastomotic pseudoaneurysm have been reported since 1985, infectious pseudoaneurysm
have been rarely reported and were often associated with graft loss in the case reports and series
available in the literature [8]. Causes of infectious aneurysm formation are multifactorial. Post-renal
transplant patients often have multiple risk factors for opportunistic infections: intake of
immunosuppressant, end-stage renal failure and diabetes mellitus in patients with diabetic
nephropathy. Infectious pseudoaneurysm secondary to septicemia or contaminated preservation
solution in the process of graft handling have been reported.
2.4 Time of Onset
Extra renal pseudo aneurysms mostly occur in the early weeks after transplantation and are rarely
observed as a late complication [9]. Most late pseudo aneurysms are the consequence of mycotic
infection; other causes are suture rupture, anastomotic leakage, or vessel wall ischemia [10].
2.5 Signs and Symptoms
Patients with pseudoaneurysm after their renal transplant are usually asymptomatic and they are
diagnosed incidentally. Few are reported to present with the following symptoms [11].
Fever,
Anemia of unknown origin,
Compression of adjacent structures in iliac fossa,
Discomfort,
Renal dysfunction or deterioration of renal graft function
Signs of ischemia,
Thrombosis in the ipsilateral limb
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Pain
Graft loss
Lethal hemorrhage due to acute rupture
Physical examination should identify any existing tenderness, pulsatile masses, thrill or bruit. There is
no documented existing size for developing symptoms. One can expect that the size of the false
aneurysm is a direct factor to predict risk of rupture as well as other factors such as the rate of
expansion or growth, the presence of active blood flow in the false aneurysm, a weakness of the wall
and existence of trauma, or radial force on the lesion. From the review of literature, there is no
identified diameter to predict the risk of rupture of these rare lesions [12].
2.6 Predisposing Factors
Occurrence of vascular complication is more frequent in recipients of deceased donor renal
transplantation as compared to recipients of living donor renal transplantations. They are more
frequent with renal allograft with multiple renal blood vessels (more than one artery or one vein)
compared to allograft with a single artery and vein [13] but in study of 6 patients by kidney institute,
they found this complication more in live transplantation and they also found in their study that cases
of pseudoaneurysm patients has single renal artery and single renal vein only [14].
Chronic rejection of donor renal artery may play a role in the development of 45% of the observed
cases of pseudo- aneurysms complicating kidney transplantation in Bracale’s study [15].
Hyperlipidemia may act as predisposing factor. The gradual deterioration of renal function may be due
to micro emboli arising from the aneurysm and the presence of hypertension.
Among the 30 reported cases of infectious pseudoaneurysm, 76.7% yielded fungus growth in the
resected specimen, although there are also severe cases with the growth of bacteria such as
Pseudomonas, Klebsiella and Staphylococcus. The high occurrence of fungal infection could be
explained by the immunocompromised status of post-transplant patients and also the angioinvasive
nature of fungi [8].
3. ROLE OF IMAGING
Multiple imaging modalities have been used to identify pseudo aneurysm of transplanted renal artery.
Imaging modalities:
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3.1 Ultrasonography (USG) and Color Doppler
Ultrasonography: is routinely used; a pseudoaneurysm can be easily detected. On B mode ultrasound
pseudo aneurysm appears as a simple or a complex cyst adjacent to supplying artery. Concentric
layers of hematoma are occasionally seen within the pseudoaneurysm.
Color Doppler: shows intra-cystic blood flow. Color Doppler allows a differential diagnosis hematoma,
urinoma and lymphocele [Fig. 1(a) and Fig. 1(b)].
Findings: Characteristic “yin-yang” sign (typical swirling motion) with bidirectional flow at the neck of
pseudo aneurysm is seen in Doppler study. Spectral waveform demonstrates the classic to and fro
flow at neck.
Fig. 1 (a) Grey scale sonography image of graft kidney shows cystic lesion near anastomosis
(blue arrow) Fig.1 (b) Doppler image shows color filled out pouching at anastomosis confirmed
non thrombosed pseudo aneurysm
Advantages of color Doppler study are: relatively cheap, portability, readily available, inexpensive,
fast, involves no ionizing radiation or non-nephrotoxic modality and non-invasive, applied for
diagnostic and monitoring purposes early on, in the post-transplant period, establishing thus a
baseline for follow-up scanning. Duplex ultrasonography has now replaced the venography as the
most widely used diagnostic test with excellent sensitivity and specificity of 97% and 94% respectively
[3].
Disadvantage are also like: evaluation of deep (visceral) arteries is difficult and it is operator
dependent.
Color Doppler had an advantage in follow up imaging of post stenting pseudoaneurysm. The stent can
be easily visualized in ultrasonography and stent thrombosis also evaluated by color Doppler
examination [Fig. 4].
3.2 Multi slice Computed Tomography Angiography (CTA)
Multi slice Computed tomography angiography, Magnetic resonance angiography or catheter directed
conventional angiography can be used to confirm the findings of ultrasound before embarking on
treatment modality.
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Findings: Contrast enhanced Multislice CTA demonstrates a contrast material–filled sac and
communication between donor artery and pseudoaneurysm ; Wall of the pseudoaneurysm usually
smooth and well delineated except in a mycotic pseudoaneurysm, whose wall is thickened, irregular,
or ill defined. It also delineates the low-attenuation area within the pseudoaneurysm suggestive of
partial thrombosis. Intermediate or high attenuation (hemorrhage) can be identified adjacent to the
pseudoaneurysm which indicates pseudoaneurysm rupture [Fig. 2a and Fig. 2b] [Fig. 3].
Fig. 2 (a). Axial image of CT Renal Graft Angiography shows contrast filled pseudo aneurysm
at anastomosis, with perigraft hematoma and non-visualization of main renal artery
Fig. 2 (b). Sagittal Image of CT Renal Graft Angiography arterial phase show pseudo aneurysm
at anastomosis with contrast filled main renal artery
Fig. 3. Volume rendering image(VRT) of CT scan shows anastomotic pseudoaneurysm(blue
arrow), graft renal artery (white arrow) and right external iliac artery(black arrow)
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Fig. 4. Gray scale Image of Renal graft shows two echogenic line structure (Stent) in Main
anastomotic renal artery
Advantage of CT scan is it allows visualization of the lesion from all angles and provides a global
perspective on the entire vasculature, including adjacent vascular beds.
Disadvantages of the CT scan are it requires more contrast material than for angiography and
endovascular therapy cannot be performed at the time of diagnosis. So conventional angiography
carries the additional benefit of intervention.
3.3 Conventional Angiography
Conventional angiography is usually performed with intra-arterial digital subtraction technique and
dilute contrast material. Ipsilateral or contralateral femoral arterial approach is used. Image acquisition
rates should include: early rapid phase for arterial anatomy and prolonged slower phase for
parenchymal or venous anatomy.
Findings – pseudoaneurysm appear as a spherical extra vascular collection of contrast material that
opacified during arterial phase and often persistent in to late venous phase. Degree of opacification
depends on the size of its neck and amount of thrombosis within its lumen. It may exhibit
heterogeneous opacification owing to luminal thrombosis.
Advantage: Conventional angiography carries the additional benefit of intervention. Super-selective
transcatheter embolization can be used to treat small favorable false aneurysms [16]. Intravascular
graft stenting can be used for extra-renal false aneurysms with suitable anatomy [17].
Disadvantages of conventional angiography like its invasive nature, increased risk of procedure-
related complications and it does not help to accurately assess the size of a pseudoaneurysm that
contains a thrombus.
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3.4 MRI
May be used as primary modality if the complication is highly suspected or following ultrasound.
MRI is complementary to USG or CT scan in the characterization of abnormality to reach a specific
diagnosis. It provides cross sectional and vascular information without risk of ionizing radiation,
iodinated contrast or arterial catheterization. Even though without radiation risk, this method should
reserve for selected cases, mainly due to its lack of accessibility.
3.5 Scintigraphy
Can be used to detect some large pseudoaneurysm but not to resolve smaller lesion. 99m Tc DTPA
radionuclide is adequate for detection of complication. Image acquisition should begin immediately
after venous injection of isotope includes: flow phase (one image per second for 60 second) for
depiction of vascular anatomy and functional phase (one image every 30 second for 30 minutes) for
depiction of parenchymal and urinary leakage.
Findings – pseudoaneurysm appears a focal hot spot in early flow phase near iliac vessels. Because
of their location they can be confused with focal urine leaks. This two are differentiated by recognition
of early or flow phase appearance of a pseudoaneurysm versus the delayed or functional phase
appearance of a urine leak. Pseudoaneurysm also tend to wash out sooner than urinoma do.
Labeled leukocyte scintigraphy - has not yet shown its value in anastomotic PA diagnostic protocol.
4. TREATMENT
Small pseudoaneurysm can be managed conservatively, while infected or large ones require
treatment to prevent rupture.
Indications for repair of anastomotic pseudoaneurysm renal transplant recipients and therapeutic
strategies are at present controversial. If infection is not present, it is possible to manage
asymptomatic small pseudoaneurysm in a conservative manner with periodic ultrasound monitoring
[18]. Fujikata et al. describes a conservative treatment for a mycotic aneurysm with an unaltered size
and no complications in his three year follow-up study [19]. They require repair in cases where they
are symptomatic, larger than 2.5cm in size, show the presence of infection, progressive enlargement
and if there are signs of impending rupture [15].
Despite the high morbidity and mortality rates reported, most surgeons agree that the majority of
patients with pseudoaneurysm require a transplant nephrectomy due to persistent rejection or
infection or to other ensuing complications arising from a non-functioning graft.
Therapeutic options:
conventional open repair (OR),
endovascular repair (EVR) with covered stent placement to exclude
aneurysm
Ultrasound-guided percutaneous thrombin
injection (USG-PT).
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Open surgical repair includes the surgical resection of the false aneurysm and the subsequent arterial
reconstruction with patch angioplasty, reanastomosis [20] or an allograft autotrasplantation [15]. An
interposition graft or an extra anatomic reconstruction following false aneurysm resection has been
reported to lead to graft loss [21].
Endovascular repair has become a more attractive treatment option for extra-renal anastomotic
pseudo aneurysms and has gained popularity during the last decade [17]. It excludes the blood flow
into the false aneurysm by endoluminal stent deployment, therefore reducing the risk of rupture.
Certainly it requires anatomic criteria for proximal and distal landing zones. Endovascular stenting of
the external iliac artery with renal transplant artery exclusion can be considered in emergency
situations of acute rupture with adjunctive percutaneous drainage of the retroperitoneal hematoma
[22].
Ultrasound-guided percutaneous thrombin injection (USG-PT) has been reported as an efficient and
secure treatment option given the false aneurysm is accessible and not associated with infection [23].
Complications of thrombin injection are reported as rare, they include distal arterial embolization, and
anaphylaxis reaction, and generalized urticaria [24] after using bovine thrombin. Poels et al. reported
combined use of a thrombotic agent and covered stent in an end-to-end anastomosis while preserving
the transplant kidney [25].
Successful treatment of mycotic pseudoaneurysm after kidney transplantation includes radical
debridement of all infected tissue and long-term antifungal therapy. Vascular reconstruction may be
difficult. In patients who have infected tissue, the use of synthetic grafts may cause persistence of
infection, and the use of autologous or allogeneic material may be preferred.
Although EVR and USG-PT offer a less invasive approach for the exclusion of these
pseudoaneurysm, surgery is still indicated in case of infection, failure to identify the origin of
pseudoaneurysm, the presence of a large neck, when the pseudoaneurysm is not accessible for
percutaneous treatment, and in cases of unsuccessful mini-invasive procedures. But there is a need
for nephrectomy in majority of renal transplant patients with rejection, infection or other ensuing
complications arising from a non-functioning graft. Bracale et al. described their experience in the
treatment of six patients with anastomotic pseudoaneurysm [26]. Five of six patients needed a
transplant nephrectomy, as a result of irreversible rejection (three patients) or local infection (two
patients) [Fig. 5].
Fig. 5. Maximum intensity projection (MIP) image of coronal CT scan revealed
pseudoaneurysm with non contrast filled right external iliac artery and acute cutoff of proximal
and distal end.(blue arrow) Suggest thrombosis
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POINTS TO REMEMBER
The anastomotic pseudoaneurysm should be identified early, and should be monitored with
periodic ultrasound during follow up.
Blood investigations are necessary to rule out infective etiology
Conservative management should be considered in patients in good condition with smaller size,
unaltered graft function and without symptoms or signs of infection close follow up is always
needed for a long time
Infected or large ones pseudoaneurysm (>2.5 cm) require treatment to prevent rupture.
Majority of patients with pseudoaneurysm require a transplant nephrectomy due to persistent
rejection or infection or to other ensuing complications arising from a non-functioning graft.
Therapeutic options: conventional open repair (OR), endovascular repair (EVR) with covered
stent placement to exclude aneurysm, Ultrasound-guided percutaneous thrombin injection
(USG-PT).
The early pseudoaneurysm is frequently due to errors in the execution of vascular suture and
have a higher cure rate.
7. CONCLUSION
Pseudoaneurysm can be easily detected by ultrasonography and color Doppler. The analysis of
literature and from our experience leads us to formulate some considerations: The anastomotic
pseudoaneurysm should be identified early, this condition can be fulfilled only with periodic ultrasound
monitoring in post-transplant follow up. Conservative procedures should be considered in patients in
good condition with preserved graft function and without symptoms or signs of infection. Open
surgical repair, endovascular repair and ultrasound guided percutaneous thrombin injection are the
current reported treatment options. Pseudoaneurysm can carry a potentially devastating loss of
allograft and the need for allograft nephrectomy. Early diagnosis and timely operation might be the
most important factors in the survival of patients. Clinical, biochemical as well as radiological follow up
examination confirmed successful therapeutic management of the patient. Early recognition of this
entity based on a high index of suspicion and use of early diagnostic procedures is vital for its
successful management.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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13. Salehipour M, Salahi- H, Jalaeian H, Bahador A, Nikeghbalian S, Barzideh E, et al. Vascular
complication following 1500 consecutive living and cadeveric donor renal transplantation: A
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experience. Indian Journal of Applied Research. 2019;9(1):61-65.
15. Bracale UM, Carbone F, del Guercio L. Viola D, D’Armiento FP, Maurea S, et al. External Iliac
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16. Yağci AB, Parildar M, Oran I, Memiş A. Interventional radiological management of vascular
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17. Hegde UN, Rajapurkar MM, Gang SD, Lele SS. Percutaneous endovascular management of
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Biography of author(s)
Dr. Kajal N. Patel
Department of Radiology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre (IKDRC), Dr. H. L.
Trivedi Institute of Transplantation Sciences (ITS), Ahmedabad, 380016, Gujarat, India.
She is an Associate Professor of Radio diagnosis at Institute of Kidney Diseases and Research Centre, Dr H.L. Trivedi Institute
of Transplantation Sciences and Gujarat University of Transplantation Sciences, Civil Hospital, Ahmedabad, Gujarat, India. She
is a Graduate from Saurashtra University with more than 15 years wide experience in the field of Radio diagnosis. She has
contributed in the fields of Transplantation imaging and renal imaging. She has almost more than 20 publications in her field
having many research articles, including topics like anastomotic Pseudoaneurysm in renal allograft, Pseudoaneurysm of Radial
artery occurring after arterial puncture, and post renal transplantation lymphocele. She has keen interest in pre and post liver
transplantation imaging with research related to portal vein anatomical variations and hepatic regeneration after donor
hepatectomy.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Indian Journal of Applied Research, 9(1), 2019.
_____________________________________________________________________________________________________
1Department of Nursing Faculty of Health Science, Aino University, Japan.
2Division of Physiology and Metabolism, University of Hyogo, Division of Pathophysiology, Kobe Women’s University, Japan.
*Corresponding author: E-mail: m-nagai@ns-u.aino.ac.jp;
Chapter 10
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Assessing the Effects of Thermal Stimulation on
Skeletal Muscle-Derived Cell Density
Masayo Nagai1* and Hidesuke Kaji2
DOI: 10.9734/bpi/rdmmr/v7/2661E
ABSTRACT
We previously examined whether thermal stimulation can prevent atherosclerotic cardiovascular
disease (ASCVD). Studies using human skeletal muscle-derived cells (SMDC) confirmed fluctuations
in the expression of related genes. We also confirmed a slight decrease in the number of cells. It is
well known that the application of thermal stimulation to cultured cells is associated with apoptosis.
Although there have been several studies confirming the above, such as inducing apoptosis by
thermal stimulation and suppressing apoptosis, the detailed effects of thermal stimulation on
apoptosis have not been clarified. Therefore, we reexamined the effects of thermal stimulation on
human skeletal muscle cells in order to safely utilize thermal stimulation for the prevention of ASCVD
in vivo. From the experimental results thus far, we hypothesized that thermal stimulation to SMDC
induces apoptosis. This suggested that thermal stimulation should be mild to prevent ASCVD in vivo.
Keywords: Thermal stimulation; heat; fomentation; cell growth; cell division; apoptosis; skeletal
muscle-derived cells; Transcriptome.
ABBREVIATIONS
HSP : Heat shock protein
ASCVD : Atherosclerotic cardiovascular disease
SMDC : Skeletal muscle derived cells
1. INTRODUCTION
Our previous study [1] demonstrated favorable changes in plasma protein levels, such as adiponectin,
by thigh muscle fomentation in healthy people. We also reported that the thermal stimulation altered
mRNA levels to prevent atherosclerosis in human skeletal muscle-derived cells (SMDC) [2]. However,
we previously observed a 74.6% decrease in the density of SMDC cultured at 42°C for 20 hours [2].
Cell density or number is affected by many mechanisms such as cell detachment, cell growth
suppression by slower cell division, necrotic cell death, and programmed cell death (apoptosis). It has
been reported that the culture environment and the origin of cells also affect the cell density [3,4]. In
previous studies using a human neuroblastoma cell line (SH-SY5Y), heat treatment at 43C
significantly reduced cell viability [5]. In our in vitro experiment, neither cell morphological change nor
cell detachment was observed 20 hours after the start of thermal stimulation. The number of cells
seeded at the start of subculture was considered to be comparable. We examined [6] whether thermal
stimulation affects the level of mRNA associated with cell density or the number of SMDC. In that
study, direct factors regulating cell density were related to cell proliferation or cell death, including
apoptosis, and cell detachment or attachment. Microarray analysis of SMDC cultured under these
conditions demonstrated changes in the expression of genes related to cell density such as apoptosis,
cell growth inhibition, and cell detachment.
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We are conducting research to safely utilize the thermal stimulus effects in the prevention of
atherosclerotic cardiovascular disease (ASCVD). It is important to confirm safety when utilizing
thermal stimulation of muscle for the purpose of preventing ASCVD in medical and nursing practice.
2. EFFECTS OF THERMAL STIMULATION ON APOPTOSIS
The effects of thermal stimulation on apoptosis have been reported in multiple animals. In humans, it
is known that cell apoptosis is induced by thermal stimulation at 43°C or higher. Apoptosis is induced
by thermal stimulation above 42.5°C, and cytotoxicity is rarely observed below that in cancer cells,
which are more vulnerable to heat than normal cells [7,8]. In SH-SY5Y, thermal stress induces
apoptosis due to an imbalance between endoplasmic reticulum stress and intracellular calcium ion
homeostasis [5].
It has also been reported that thermal stimulation below 42.5°C causes minimal damage to cells and
hardly induces cell death [9]. Even in vivo, a heating temperature of 40 ± 2°C is considered to be safe
with a low risk of low-temperature burns [10]. In human umbilical vascular endothelial cells (HUVECs),
heat stress pretreatment at 43C reduced LPS-induced Bcl-2 associated apoptosis by attenuating p38
activation [11].
As described above, the effects of heat stress on apoptosis have been reported, but the underlying
mechanisms have not been clarified.
3. EFFECTS OF THERMAL STIMULATION ON GENE EXPRESSION RELATED TO
SMDC DENSITY
3.1 Outline of our Previous Study
Methods for cell culture and gene expression analysis were previously reported [2,6]. We used normal
human SMDC (SkMC, Lonza, Japan). SMDC are human germ cells derived from the quadriceps
femoris. Thermal stimulation was applied due to the difference in the culture temperature of SMDC
(37C group, 42C group). Differences in mRNA expression between the 37C group and the 42C
group were analyzed by microarray.
Table 1. Cell density-related mRNA expression changed by heat stimulation in SMDC,
reproduced with a slight modification from reference [4]
Gene symbol
Gene title
Fold
change
Function
Changes to promote apoptosis or inhibit cell growth
Upregulated
THAP2
THAP domain containing, apoptosis
associated protein 2
3.63
apoptosis
PDCD6
programmed cell death 6
3.306
programmed cell death
* CDC14B
cell division cycle 14B
2.865
regulation of p53
BCL2L13
BCL2-like 13 (apoptosis facilitator)
2.244
apoptosis
LOC728613
programmed cell death 6 pseudogene
2.189
apoptosis
CASP4
caspase 4, apoptosis-related cysteine
peptidase
2.132
apoptosis
FAS
Fas cell surface death receptor
2.028
programmed cell death
Changes to inhibit apoptosis
Upregulated
NOL3
nucleolar protein 3 (apoptosis repressor
with CARD domain)
4.518
anti-apoptosis
CIAPIN1
cytokine induced apoptosis inhibitor 1
2.28
anti-apoptosis
NAIF1
nuclear apoptosis inducing factor1
2.03
anti-apoptosis
Downregulated
PAWR
PRKC, apoptosis, WT1, regulator
0.474
apoptosis
* cell growth inhibition-related gene
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Thermal stimulation of SMDC resulted in a significant increase in the expression of 1,072 genes and
significant inhibition of the expression of 1,123 genes [2]. Among them, significant changes were
confirmed in 10 genes related to apoptosis, 1 gene related to cell division, and 1 gene related to cell
adhesion (Table 1).
Gene ontology (GO) is a conceptual arrangement of features, such as gene functions, for the purpose
of cross-species information utilization [12]. GO analysis was performed using a probe list in which
gene expression significantly increased or decreased. Therefore, our study suggested that the genes
with significant expression fluctuations acted as a group of genes to promote apoptosis. They were
considered to promote apoptosis as a biological system rather than individually. In addition, the
analysis targets were limited to genes with GO terms. GO terms are not given to all genes and one
gene may have multiple GO terms. Many of the functions of genes included in microarray probes
have not been clarified. It is also important to confirm individual gene expression in order to
investigate whether genes whose expression increased or decreased are associated with apoptosis.
GO analysis was performed on 1,072 genes whose gene expression more than doubled in the 42C
group compared with the 37C control group. As a result, the functions of 152 genes were significantly
(p <0.001) consistent with the GO term list (Table 2).
Table 2. GO analysis upregulated by heat stimulation in SMDC, reproduced from reference [4]
Ontology
GO ACCESSION
GO term
Corrected
p-value
Biological
GO: 0042981
regulation of apoptotic process
0.020
process
GO: 0010941
regulation of cell death
0.020
GO: 0010942
positive regulation of cell death
0.026
GO: 0043067| GO:
0043070
regulation of programmed cell death
0.028
GO: 0008626
granzyme-mediated apoptotic signaling
pathway
0.035
GO: 0043068| GO:
0043071
positive regulation of programmed cell
death
0.045
corrected P-value :The probability that the significantly varied expression probe would match the GO-classified
gene list was calculated (p <0.001)
Genes carry out their functions by interacting with molecules to form networks. Pathway analysis
analyzes relationships between a series of biomolecules that work together for a function.
Relationship analysis has not been performed for individual gene expression analysis or GO analysis.
Pathway analysis includes relationships between genes [13]. Pathway analysis in our study
suggested that multiple genes functioned in collaboration with multiple factors in the regulation of
apoptosis and cell proliferation. In an in vivo study, increased activity of the apoptotic pathway in
skeletal muscle was associated with sepsis, disuse syndrome, cancer-induced skeletal muscle
atrophy, and age-related sarcopenia [14]. Moreover, studies on changes in gene expression after
burns [15] have been conducted and changes in the expression of apoptosis-related genes were
confirmed. In addition, in previous studies [15] that assessed gene expression after severe burns, GO
terms, such as leukocyte aggregation, T cell aggregation, and lymphocyte activation, were included,
but this was not confirmed in our study. Severe burns include processes related to inflammation /
immune system and cell activity, which are thought to be related to post-burn pathological processes
[15]. A previous study [16] that examined gene expression in elderly burn patients reported that the
expression of immune system signaling pathways was suppressed during the acute post-burn phase
based on pathway analysis. In our study, it is possible that no damage, such as burns, occurred to the
cells.
3.2 Factors that Reduce the Number of SMDC due to Thermal Stimulation
Based on the above results, we investigated the factors that reduced the number of SMDC by thermal
stimulation at 42C.
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The individual genes causing increased apoptosis were THAP2 (THAP domain-containing, apoptosis-
related protein 2), PDCD6 (programmed cell death 6), BCL2L13 (BCL2-like 13), LOC728613
(programmed cell death 6 pseudogene), CASP4 (caspase 4), and FAS (Fas cell surface death
receptor). Their expression increased after heat stimulation, thereby promoting apoptosis and
suppressing cell proliferation. The upregulation of CDC14B (cell division cycle 14B: regulator of anti-
oncogene p53) was also noted. On the other hand, 3 anti-apoptotic genes, NOL3 (nucleolar protein 3),
CIAPIN1 (cytokine-induced apoptosis inhibitor 1) and NAIF1 (nuclear apoptosis inducing factor 1),
were upregulated and 1 gene related to apoptosis, PAWR (PRKC, apoptosis, WT1, regulator), was
downregulated, as shown in the middle panel of Table 1.
NOL3 encodes an anti-apoptotic protein that down-regulates the enzyme activity of caspase 2,
caspase 8, and tumor protein p53 [17]. In addition, the expression of CIAPIN1, a factor that
suppresses cytokine-induced apoptosis [17], increased. On the other hand, increased expression of
CASP4, an apoptosis-related cysteine peptidase that plays important roles in apoptosis, cell migration,
and inflammatory responses, was confirmed [17].
Increased expression of PDCD6 was also confirmed. The PDCD6 gene product is involved in T cell
receptor, Fas, and glucocorticoid-induced programmed cell death [17]. Increased expression of Fas
cell surface death receptor (FAS) was also observed. Fas is a cell surface receptor that transmits an
apoptosis-inducing signal into the cell. Therefore, it is possible that thermal stimulation affected SMDC
number, but changes in apoptotic and anti-apoptotic factors have been confirmed. Further verification
in vivo is needed to determine whether apoptosis was induced by thermal stimulation.
In GO analysis, significantly upregulated genes with 6 GO terms were associated with cell
proliferation and apoptosis. The GO terms related to increased apoptosis were “regulation of apoptotic
process”, “regulation of programmed cell death”, “granzyme-mediated apoptotic signaling pathway”,
and “positive regulation of programmed cell death”. Cell adhesion function also affects the number of
cells, but no significant changes in mRNA expression related to cell adhesion were detected by GO
analysis [6].
Table 3. Cell density-related pathways changed by heat stimulation in SMDC, reproduced from
reference [4]
Pathway
p-value
Matched
Entities
Pathway
Entities
Function
Pathways that promote apoptosis
Upregulated
TNF a Signaling
Pathway_WP231_72093
3.08E-04
8
87
Apoptosis, chronic
inflammation
Type II interferon signaling
(IFNG)_WP619_71168
7.69E-04
5
37
Apoptosis
Pathways that promote cell growth
Upregulated
MAPK Signaling
Pathway_WP382_72103
7.13E-06
14
168
Regulation of cell
proliferation and
differentiation
Oncostatin M Signaling
Pathway_WP2374_72050
9.27E-03
5
65
Cell proliferation
Downregulated
TGF b Signaling
Pathway_WP560_68944
1.02E-03
6
55
Cell growth inhibition
Pathways that promote cell adhesion or detachment
Upregulated
Integrin-mediated Cell
Adhesion_WP185_71391
3.56E-03
7
99
Cell adhesion
Downregulated
Integrin-mediated Cell
Adhesion_WP185_71391
5.46E-03
7
99
Cell adhesion
Pathways causing increased apoptosis were the TNFα signaling pathway and type II interferon
signaling. The upregulated apoptosis-related genes varied according to the method of analysis. As
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shown in the middle panel of Table 3, heat stimulation of SMDC upregulated two pathways that are
involved in cell proliferation, 1) “MAPK Signaling Pathway” and 2) “Oncostatin M Signaling Pathway”.
Heat stimulation of SMDC downregulated one pathway that is involved in cell growth inhibition, “TGFβ
Signaling Pathway”. Moreover, heat stimulation of SMDC both upregulated and downregulated
“Integrin mediated Cell Adhesion”, as shown in the lower panel of Table 3.
There are indirect factors regulating cell density such as heat shock proteins (HSPs). Expression of
HSPs increased 11-fold in SMDC after heat stimulation, as reported previously [2]. Increased
expression of HSP72 by thermal stimulation suppresses muscle atrophy, and promotes protein
synthesis and muscle hypertrophy [18]. HSP70 suppresses the apoptotic pathway via its chaperone
function [19]. In this study, increased expression of HSP70 by thermal stimulation that may have
suppressed apoptosis. Furthermore, a previous report suggested that the HSP70 family inhibits the
activation of multiple MAP kinases, including JNK, to block apoptosis [20]. However, the relationship
between the induction of HSP70 expression and the acquisition of resistance of cells to heat has not
been clarified [8]. It is necessary to confirm whether the effective induction of HSP70 protects cells
from damage and promotes skeletal muscle function. HSPs are also associated with unfolded protein
response (UPR). However, the expression of UPR stress markers activating transcription factor 6
(ATF6) and HSPA5 was reduced in this study. Thermal stimulation was considered to have improved
the chaperone function of HSPs and activated the enzymes involved in folding, and it is possible that
the endoplasmic reticulum stress caused by the thermal stimulation was alleviated. Thus, the
possibility of apoptosis due to endoplasmic reticulum stress is low. However, the expression of
apoptosis-related factors may have been induced by thermal stimulation. Monitoring the serum
HSP70 concentration in vivo may be useful for elucidating these mechanisms.
Many genes negatively and positively regulate cell density by heat stimulation. Taken together with
our previous studies, the promotion of direct apoptosis-related genes may play a major role in
reducing cell density.
4. FOR FUTURE STUDIES
Although we previously reported that heating SMDC at 42°C for 20 hours altered mRNA expression
and aided in preventing atherosclerosis, our previous study suggested that the slight reduction of
SMDC involved several genes, especially those promoting apoptosis.
The practical application of hot compresses on muscle to prevent atherosclerosis, particularly in
patients with sarcopenia, requires further validation of the safe temperature and duration. In addition,
proteins, such as HSPs, that are considered to be strongly associated with apoptosis have been
reported to be associated with inflammatory diseases. It is also necessary to pay attention to the
relationship between atherosclerosis and chronic inflammation. The in vivo environment is
complicated and verification in the living body is important.
5. CONCLUSION
The thermal effect may be effectively used to prevent ASCVD.
In that case, it is important to ensure safety. We need to continue to verify and strive for safe and
effective ASCVD prevention.
ACKNOWLEDGEMENTS
This study was supported by Grant-in-Aid for Scientific-Research from JSPS KAKENHI Grant Number
JP25870930, JK00860 and JP20K23147.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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Biography of author(s)
Dr. Masayo Nagai, RN, PHN, Ph.D.
Department of Nursing Faculty of Health Science, Aino University, Japan.
She obtained MSN. Degree from University of Hyogo Graduate School of Nursing, and Ph.D. degree from University of Hyogo
Graduate School of Nursing. She served as a Nurse in Osaka University Hospital, Assistant Professor in Division of Physiology
and Metabolism, University of Hyogo, Japan, Assistant Professor in BAIKA women’s University, Japan, Associate Professor in
AINO University, Japan. She has conducted research on prevention of lifestyle diseases of local residents. She has some
Academic Society Membership: Member of the Japan Nursing Science Society, Member of Co-Medical Function Society
Member, and Member of Japan Society of Rural and Remote Area Nursing.
Prof. Hidesuke Kaji M.D., Ph.D.
Division of Physiology and Metabolism, University of Hyogo, Division of Pathophysiology, Kobe Women’s University, Japan.
He is a Professor in Kobe Women’s University, Emeritus Professor in University of Hyogo. He obtained M.D. degree from Kobe
University School of Medicine in 1978, and Ph.D. degree from Kobe University Graduate School of Medicine in 1985. He
served as Clinical Fellow in Kobe University and satellite hospitals, Research Associate in University of Rochester, Division of
Endocrine Pharmacology, Chief Physician in National Hyogo Central Hospital, Division of Internal Medicine, Associate
Professor in Kobe University, Division of Internal Medicine (Endocrinology and Metabolism), Professor in University of Hyogo,
Division of Physiology and Metabolism. He is a Certified member of the Japanese Society of Internal Medicine, Councilor,
Supervisor, Member of the Japan Endocrine Society, Distinguished Councilor, Specialist and Supervisor of Endocrinology and
Metabolism in Internal Medicine, Member of the Japan Neuroendocrine Society, Distinguished Councilor, Member of the Japan
Diabetes Society, Member of Endocrine Society (USA). His Research theme: Basic and clinical research in normal and
abnormal mechanism of release and action of hypothalamic-pituitary and thyroid hormone, and Basic and clinical research in
metabolic syndrome including dyslipidemia, diabetes, hypertension, visceral obesity and atherosclerosis.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Journal of Advances in Medicine and Medical Research, 33(5): 73-81, 2021.
Reviewers’ Information
(1) Angélica Berenice Coyoy Salgado, Instituto Mexicano del Seguro Social, Mexico.
(2) Ming-Qiang Han, Xingtai people’s Hospital,Xingtai,Hebei,China.
_____________________________________________________________________________________________________
1Department of Biochemistry, LLRM Medical College, Meerut (U.P.), India.
2Department of Pharmacology, LLRM Medical College, Meerut (U.P.), India.
3Dental Surgeon, C.H.C. Siyana, Bulandshahr, (U.P.), India.
*Corresponding author: E-mail: drpinkivkm@yahoo.com;
Chapter 11
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
α-tocopherol: A Ticket to Prevent Antitubercular
Drugs Induced Hepatotoxicity
Rajiv Nehra1, Pinki Vishwakarma2*, Manju Nehra3 and Shashank Tyagi1
DOI: 10.9734/bpi/rdmmr/v7/13924D
ABSTRACT
Background: Mycobacterium tuberculosis, the bacteria that causes tuberculosis, is infamous for
developing resistance to monotherapy. To prevent the emergence of resistance, patients are given a
mixture of antitubercular medications for months to years, which can cause side effects. One of the
most prevalent negative effects of antitubercular medicines is hepatotoxicity.
Aims: This study was aimed to explore the hepatoprotective potential of α-tocopherol against
experimentally induced hepatotoxicity in albino rabbits.
Methods: This experimental study was carried out on 30 rabbits of either sex. They were divided into
three groups comprising 10 animals each. Hepatotoxicity is induced experimentally in rabbits following
a standard protocol. Group I received normal saline (10 ml/kg bw). Rabbits in group II were treated
with first line antitubercular drugs isoniazid (5 mg/kg bw), rifampicin (20 mg/kg bw) and pyrazinamide
(25 mg/kg bw) concurrently. Group III received α- tocopherol 200 mg/kg bw along with group II drugs.
All drugs were administered by oral route for 90 days. On last day of experiment blood samples were
taken to investigate the plasma levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP)
and serum total bilirubin.
Results: Serum levels of ALT were found to be markedly elevated upon oral administration of
antitubercular drugs for 90 days. A statistically significant reduction in ALT levels was noticed when α-
Tocopherol was given in doses of 200mg/kg bw along with antitubercular drugs for same duration.
Similar results were obtained with serum ALP & serum total bilirubin.
Conclusions: α-tocopherol (200 mg/kg bw, oral) was found to have hepatoprotective effect against
antitubercular drugs induced hepatotoxicity in albino rabbits.
Keywords: Antitubercular drugs; Hepatotoxicity; α-tocopherol; antioxidant.
1. INTRODUCTION
India has the highest burden of tubercular patients worldwide. As per WHO statistics nearly two
million people develop active tuberculosis per year and about 1000 people die from tuberculosis
everyday [1].
Isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (ETH) are first line oral
antitubercular drugs. The single use of any first line drug can lead to the rapid development of drug
resistant tuberculosis that is very difficult to treat. Therefore first line antitubercular drugs are used in
combination as per WHO recommendation [2].
Hepatotoxicity is the most well known toxic effect with antitubercular drugs. Any one or more of INH,
RIF or PZN could be causative especially when these drugs are used as combination therapy as per
standard protocol [3]. Most of the hepatotoxic reactions are dose-related; some are, however, caused
by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity,
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α-tocopherol: A Ticket to Prevent Antitubercular Drugs Induced Hepatotoxicity
101
especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other
principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as
well as chronic hepatitis B and C infections [4-5]. Drug-induced hepatic dysfunction usually occurs
within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical
(including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to
improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis
chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-
hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic
dysfunction [5]. It has been reported that the generation of free radicals is associated with toxic effect
of antitubercular drugs [6]. This study was aimed to investigate the possible effect of α- tocopherol
(antioxidant) in protecting hepatotoxicity of first line oral antitubercular drugs in rabbits.
2. METHODS
This study was conducted in Department of Biochemistry, Muzaffarnagar Medical College,
Muzaffarnagar as well as in Department of Pharmacology, LLRM Medical college, Meerut, Uttar
Pradesh, India from March 2008 to September 2009.
2.1 Animals
Albino rabbits of either sex weighing 1-3 Kg were procured from central animal house of the institute
and were housed individually in cages, in air conditioned environment. They were provided with food
and water ad libitum. Study was begun following an acclimatization period of 7 to 10 days.
2.2 Drugs
Isoniazid and rifampicin (powder dosage form) gifted by Lupin Research lab Ltd. α-tocopherol (Vit E)
was gifted by Franco India Pharmaceuticals Ltd. Pyrazinamide and other used chemicals were
provided by Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, India.
2.3 Doses and Route of Administration
Each drug was administrated in three different doses in the early stage of experiment, to select the
optimum dose that was found as INH 5mg/Kg bw, RIF 20mg/Kg bw, PZN 25mg/Kg bw.
Selected optimum doses of first line oral antitubercular drugs were administrated concurrently to
match the pattern of administrated drugs in tubercular patients. Ethambutol was excluded from the
study because it is not hepatotoxic [7]. Route of administration was oral.
2.4 Study Design
Following approval from Institutional animal ethics committee the study was carried out from March
2008 to September 2009. Thirty albino rabbits of either sex were used and were divided into three
groups with 10 animals in each group. They were treated with drug for three months. Doses were
administrated per Kg body weight, by oral route, as following.
Group I (control group)- Normal saline (10ml/Kg bw) [8].
Group II- INH (5mg/Kg bw) + RIF (20mg/Kg bw) + PYZ (25mg/kg bw)
Group III-INH (5mg/Kg bw) + RIF (20mg/Kg bw) + PYZ (25mg/kg bw) + Vit. E (200mg /Kg bw)
Blood sample were taken before drug administration at day 1 and then at weekly interval till the end
of study.
Serum was separated from blood sample by centrifugation at 2500 rpm and stored at refrigerated
temperature till analysis (2 to 4 weeks) was done. Serum was assayed for the levels of all
biochemical parameters.
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Serum levels of ALT, ALP and total bilirubin were measured by using commercially available kits.
2.5 Statistical Analysis
Results were presented as mean and standard deviation of mean. Statistical significance was
determined at the P<0.05, 0.01, 0.001. Intra group comparisons were made for the levels of
biomarkers with control and statistically evaluated by student “t” test.
3. RESULTS
The mean serum AST level of the control group was 29.10±3.30 IU/L before initiating administration
of normal saline in doses of 10mg/Kg bw. No significant changes in this value were observed till the
end of the experiment. Similarly the serum level of ALP and Total bilirubin remained constant as
120.10±7.21 IU/L and 0.15±0.02 mg/dl respectively from the day 0 to day 90. Thus administration of
normal saline by oral route did not show any change during the experiment.
Oral administration of a combination of INH 5mg/Kg bw, RIF 20 mg/Kg bw and PYZ 25mg/kg bw
resulted in a significant rise in serum AST level from 28.60±3.38 IU/L at day one to 56.80±7.00 IU/L
at day 90 in comparison to control group (P<0.001) (Table 1, Fig. 1A).
Fig. 1A. Levels of ALT and ALP following administration of a combination of INH 5+RIF 20+
PYZ 25 mg/kg bw
Fig. 1B. Serum bilirubin levels following administration of a combination of INH 5+RIF 20 +
PYZ 25 mg/kg bw
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Fig. 2A. Levels of ALT and ALP following administration of α tocopherol (200mg/kg bw) and
combin ation of INH 5+RIF 20 + PYZ 25 mg/kg bw
Fig. 2B. Serum bilirubin level following administration of α tocopherol (200mg/kg bw) and
combination of INH 5+RIF 20+PYZ 25 mg/kg bw
Treatment with α-tocopherol along with INH+RIF+PYZ administration significantly reduced Serum
AST level from 56.80±7.00 IU/L to 20.00±3.89 IU/L at day 90(P<0.001) (Table 2, Fig. 2A).
There was an increase in serum ALP in the INH+RIF+PYZ treated rabbits. The respective values in
group I and group II were 120.10±7.21 IU/L and 183.00±7.79 IU/L (Table 1, Fig. 1A). Administration
of α-tocopherol along with INH+RIF+PYZ significantly reduced serum ALP level from183.00±7.79
IU/L to 112.00±6.60 IU/L. The difference was found statistically significant (p<0.05) (Table 2, Fig. 2A).
The serum total bilirubin was 0.15±0.02mg/dl in group I. It was found significantly increased to
1.70±0.61 mg/dl at day 90 (p<0.001) in INH+RIF+PYZ treated group (Table 1, Fig. 1B).
Administration of α-tocopherol along with INH+RIF+PYZ significantly reduced total bilirubin from
1.70±0.61mg/dl to 0.10±0.03mg /dl at day 90. (Table 2, Fig. 2B).
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Table 1. Levels of ALT, ALP and serum bilirubin following administration of a combination of INH 5+RIF 20 + PYZ 25 mg/kg bw.
Biochemical
parameter
INH 5+RIF 20 + PYZ 25 mg/Kg Body Wt.
Control
Day 1
Day 15
Day 30
Day 45
Day 60
Day 75
Day 90
S. ALT (IU/lt)
29.10
3.30
28.60
3.38
30.70
3.97
34.60*
5.10
36.90**
6.01
40.00***
6.17
46.60***
5.70
56.80***
7.00
S. ALP (IU/lt)
120.1
7.21
124.10
7.24
131.7**
7.00
148.0***
6.83
162.0***
7.70
164.0***
8.11
179.0***
7.60
183.0***
7.79
S. bilirubin (mg/dl)
0.15
0.02
0.16***
0.02
0.67***
0.04
1.31***
0.10
1.70***
0.09
1.63***
0.07
1.60***
0.05
1.70***
0.61
Values are expressed as their mean ± SD; * P<0.05; ** P<0.01;***P<0.001
Table 2. Levels of ALT, ALP and serum bilirubin following administration of α-tocopherol (200mg/kg bw) and combination of INH 5+RIF 20 +
PYZ 25 mg/Kg bw
Biochemical
parameter
INH 5+RIF 20 + PYZ 25 + α Tocopherol 200mg/Kg Body Wt.
Control
Day 1
Day 15
Day 30
Day 45
Day 60
Day 75
Day 90
S. ALT (IU/lt)
29.10
3.30
28.30
3.23
30.60
3.10
34.80*
3.71
30.00
3.51
28.00
4.00
24.00**
3.91
22.00***
3.89
S. ALP (IU/lt)
120.1
7.21
122.0
8.30
124.0
8.10
127.0
7.80
127.0
8.10
122.0
7.86
116.0
6.91
112.0*
6.60
S. Bilirubin (mg/dl)
0.15
0.02
0.16
0.02
0.15
0.01
0.16
0.02
0.14
0.03
0.12**
0.02
0.12**
0.02
0.10***
0.03
Values are expressed as their mean ± SD; * P<0.05; ** P<0.01; ***P<0.001
Recent Developments in Medicine and Medical Research Vol. 7
α-tocopherol: A Ticket to Prevent Antitubercular Drugs Induced Hepatotoxicity
105
4. DISCUSSION
Rabbit is a reliable, reproducible clinically relevant animal model of antitubercular drug induced
toxicity [9] Sarich TC et al reported rabbit a good and sensitive model of hepatotoxicity. The pattern of
hepatotoxicity produced in rabbits resembles that of human [10]. In our study treatment was given
orally, as oral route is the preferred route of administration of anti tubercular drugs. Monotherapy with
antitubercular drugs can lead to rapid development of resistance resulting in multi drug resistance
tuberculosis that is very difficult to treat. Therefore combination of anti-tubercular drugs was used in
our study [2]. The best known toxic effect of first line oral anti tubercular drugs is hepatotoxicity [11].
Incidence is increased when these drugs are used in combination. INH, RIF, PYZ are the first line anti
tubercular drugs having hepatotoxic potential [12]. Therefore this combination was used in our study
to induced hepatotoxicity in rabbits. This fact is also reported by an earlier study by Durand F et al.
[13]. This study demonstrated that INH and PYZ are major hepatotoxic antitubercular drugs. The
remaining two drugs (RIF and ETM) are rarely or not hepatotoxic. However, RIF, is a powerful
enzyme inducer may enhance the hepatotoxicity of INH [14].
All anti tubercular drugs treated rabbit showed elevated levels of serum hepatic biomarkers of
hepatotoxicity ALT, ALP & total bilirubin. These findings support previous studies reported by Singhal
KC et al. [15].
There are inadequate data regarding hepatoprotective effect of α-tocophherol in hepatotoxicity
induced by anti tubercular drugs. So far, there are only few studies which investigated the
effectiveness of α-tocopherol in INH, RIF and PYZ induced hepatotoxicity in experimental animals. A
study by Skakun et al showed hepatoprotective potential of α- tocopherol on INH, RIF and PYZ
induced hepatotoxicity in rats. The results of our study also support the finding of study by Skakun et
al. [16].
Although the mechanism behind the hepatoprotective effect of α- tocopherol is not known.
Electrophilic intermediates produced during metabolism of anti tubercular drugs are highly reactive
free radicals. These free radicals may lead to oxidative stress resulting in cell injury or cell death by
various mechanisms as lipid per oxidation [17].
One possible mechanism for hepatoprotective effect of α- tocopherol may be its antioxidant property.
α-topopherol was found to inhibit lipid peroxidation in hepatocytes caused by agents like carbon
tetrachloride and halothane [17-18]. Thus α-tocopherol may act as antioxidant as reported by Martine
ZC et al. in their study that stated protective effect of α-tocopherol in halothane induced hepatotoxicity
in rats [19]. Another study by Saraswathy SD et al. also reported that treatment with antioxidant
preparation such as Liv.100 offers protection against INH induced hepatotoxicity in rats by reducing
lipid per oxidation and restoring the anti oxidant defense system [20].
5. CONCLUSION
Thus it may be concluded that α-tocopherol has hepatoprotective potential against INH, RIF and PYZ
induced hepatotoxicity in rabbits. Further studies on large sample size for longer duration are needed
to explore hepatoprotective effect of α-tocopherol.
ETHICAL APPROVAL
The study was approved by the Institutional Ethics Committee
COMPETING INTERESTS
Authors have declared that no competing interests exist.
Recent Developments in Medicine and Medical Research Vol. 7
α-tocopherol: A Ticket to Prevent Antitubercular Drugs Induced Hepatotoxicity
106
REFERENCES
1. Tripathi KD. Antitubercular drugs. In: KD Tripathi editor. Essentials of medical
pharmacology.7th ed. New Delhi: Jaypee publication;2013. Pg 765.
2. Tripathi KD. Antitubercular drugs. In: KD Tripathi editor. Essentials of medical pharmacology.
7th ed.New Delhi: Jaypee publication;2013. Pg 773.
3. Garg PK, Tandon RK. Antitubercular drug induced hepatotoxicity. Sharma SK editor.
Tuberculosis.1st ed. New Delhi: Jaypee publication, 2001. pg 500- 506.
4. Kothekar MA, Ubaid RS, Jaju JB, Mateenuddin M. Effect of the antioxidants alpha-tocopherol
acetate and sodium selenite on hepatotoxicity induced by antitubercular drugs in rats. Indian
journal of physiology and pharmacology. 2004 Jan 1;48(1):119-22.
5. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology. 2006
Nov;11(6):699-707.
6. Chowdhury A, Santra A, Kundu S, Mukherjee A, Pandit A, Chaudhuri S. Induction of oxidative
stress in antitubercular drug induced hepatotoxicity. Indian Journal Gastroenterol.
2001;20(3):97-100.
7. Tripathi KD. Antitubercular drugs. In: KD Tripathi editor. Essentials of medical pharmacology.
7th ed. New Delhi: Jaypee publication;2013. Pg 769.
8. Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D et al. A good practice guide
to the administration of substances and removal of blood including routes and volumes, Journal
of applied Toxicology. 2001;21;15-23.
9. Thomas BM, Woney T, Zeitz W. Isoniazid metabolism in rabbits and the effect of rifampicin
pretreatment. Res Commmu in chem Path and Pharmacol .1981;33(2):235-7.
10. Sairch TC, Zhou T, Adams SP, Bain AI, Wall RA, Wright JM. A model of Isoniazid induced
hepatotoxicity in rabbits. Journal of pharmacol toxicol methods. 1995;34(2):109-16.
11. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet. 2003;362:887-99.
12. Girlig DJ. The hepatotoxicity of antituberculosis regimens containing Isoniazid, Rifampicin and
Pyizinamide. Tubercle. 1978;59(1):13-32.
13. Durand F, Jebrak G, Pessayre D Fournier M, Bernuau J. Hepatotoxicity of antitubercular
treatments. Rationale for monitoring liver status. Drug safe.1996;15(6):394-405.
14. Shakya R, Rao SB, Shrestha B. Incidence of hepatotoxicity due to Antitubercular medicine and
assessment of risk factors. Ann Pharmacother. 2004;38:1074-9.
15. Singhal KC, Grover JK, Moideen R, Kamini V. Incidence of adverse reactions to antitubercular
drugs. Indian J Pharmacol.1990;5:1413-5.
16. Skakun NP, Slivka Iul. Effectiveness of tocopherol and anti hypoxic agents in liver damage
caused by antitubercular agents. Probl Tuberk. 1991;(3):57-9.
17. Trush MA, Mimnaugh EG, Gram TE. Activation of pharmacologically active agents to radical
intermediates .Implications for the role of free radicals in drug action and toxicity. Biochem
pharmacol. 1982;31(21):3335-46.
18. Calva M, Campos-Apaez A, Rosales-Vega E, Mourelle M. Vitamin E improves membrane lipid
alterations induced by CCl4 intoxication. J Appl Toxicol. 1984;4:270-2.
19. Karakilcik AZ, Hayat A, Zerin M, Cay M. Effects of intraperitonially injected selenium and
vitamin E in rats anesthetized with halothane. J Trace Elem Med Biol. 2003;17(1):33-8.
20. Saraswathy SD, Suja V, Prema G, Shyamala DC. Effect of Liv.100 against antitubercular drugs
(isoniazid, rifampicin and pyrazinamide) induced hepatotoxicity in rats. Indian J Pharmacol.
1998;30:233-8.
Recent Developments in Medicine and Medical Research Vol. 7
α-tocopherol: A Ticket to Prevent Antitubercular Drugs Induced Hepatotoxicity
107
Biography of author(s)
Dr. Rajiv Nehra
Department of Biochemistry, LLRM Medical College, Meerut (U.P.), India.
He is currently working as a Professor and Head Department of Biochemistry, Govt Medical College, U.P, India. He has
teaching and research experience of more than 15 years. Previously he worked as Associate Professor and Head at LLRM
Medical college, Meerut (U.P). He presented various papers in National conferences. He has 15 Publications in National and
International Journals. He also attended several conferences, Symposia and CME’s. He also guided M.D thesis as Co-
supervisors of various departments. He received various awards for his achievement in Biochemistry research like William
Harvey Research award, foreign investigator award by the Liver week, S. Korea etc. He is also honoured with Fellowship of
Medical Research Council (FMRC).
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
International Journal of Research in Medical Sciences, 4(4):1158-1162, 2016.
_____________________________________________________________________________________________________
1Nephrology Consultant in Arar Hospital, MOH Nephrology Administration, Mansoura military hospital- nephrology department,
12 Hedaya st. Mubarek City, Mansoura, Daqahlia, Egypt.
2Teshrin University Nephrology specialist in Arar Hospital, Egypt.
3Rheumatology and Rehabilitation Mansoura University, Egypt.
4Nephrology and Internal Medicine. Nephrology and Dialysis Unit (MNDU), Faculty of Medicine, Mansoura University,
Mansoura, Egypt.
*Corresponding author: E-mail: dnps2016@gmail.com;
Chapter 12
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Determination of Intravenous L- Carnitine in HD
Patients and Some of Its Benefits
Abir Farouk Megahed1*, Ghassoub Mustafa Hles2, Amany S. Elbahnasawy3
and Nagy Sayed-Ahmed4
DOI: 10.9734/bpi/rdmmr/v7/2670E
ABSTRACT
L-carnitine is an essential cofactor in fatty acid and energy metabolism and has become of interest in
end-stage renal disease and dialysis patients. Chronic kidney disease (CKD) patients could be
predisposed to carnitine deficiency due too many factors, however, serum carnitine concentrations
tend to decrease more at longer dialysis duration. L-Carnitine has been used as adjuvant therapy in
HD for many years L- Carnitine has been used inconsistently with an argument in many HD Units and
was generally free of serious side effects. Therefore, we recorded the effect of intravenous L-
Carnitine in HD patients complaining of muscle fatigue and weakness. This is a clinical and laboratory
observation at Arar general hospital in Kingdom Saudi Arabia (KSA) and included eleven patients on
maintenance HD. The observation was performed for more than 30 months starting from November
2017 until Feb 2020. All patients had been complaining of muscle fatigue and weakness
manifestations. The patients started to receive management in the form of intravenous injection of L-
carnitine ampoule (1000 mg) post HD session three times/week for eighteen months up to two years.
At the start of the year 2020, Because of the inaccessibility of the L-carnitine, all patients discontinue
its usage compulsory. The eleven patients involved in the observation received L-carnitine ampoule
each HD session and all of them had improved as regards their complaints of muscle fatigue and
weakness either totally or partly. After discontinuation of the drug; the patients started to complain
once more from muscle fatigue and weakness as before the start of management except for one
patient who worsened furthermore. Four of the observed patients were complaining of intradialytic
hypotension which disappeared with the use of L- carnitine ampoule and reappeared again after the
stop of L- carnitine.
Conclusion: The intravenous L-carnitine ampoule of 1000 mg post HD three times/week could be
valuable in HD patients with special manifestations comprising intra-dialytic hypotension and muscle
weakness or fatigue.
Keywords: L- Carnitine Administration; Hemodialysis Patients; muscle fatigue; intradialytic
hypotension
1. INTRODDUCTION
L-carnitine is an essential cofactor in fatty acid and energy metabolism and has become of interest in
end-stage renal disease and dialysis patients. Chronic kidney disease (CKD) patients could be
predisposed to carnitine deficiency due to many factors including protein-restricted diet, decreased L-
carnitine production because of impaired kidney function, and increased carnitine loss during dialysis,
however, serum carnitine concentrations tend to decrease more at longer dialysis duration [1,2].
Ahmad, 2001, added that Hemodialysis (HD) patients often have lowserum concentrations of free L-
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Intravenous L- Carnitine in HD Patients and Some of Its Benefits
109
carnitine and decreased skeletal muscle stores [3]. Abnormal carnitine metabolism in dialysis patients
could be associated with some clinical problems. Studies have shown that L-carnitine
supplementation in HD patients improves several complications seen in dialysis patients, including
limitation of exercise capacity, increased intradialytic hypotension, and muscle symptoms [3,4]. L-
Carnitine has been used as adjuvant therapy in HD for many years. However, there is controversy
whether L-carnitine supplementation is beneficial [5]. L- Carnitine has been used inconsistently with
an argument in many HD Units and was generally free of serious side effects.
We recorded the effect of intravenous L- carnitine in HD patients complaining of muscle fatigue and
weakness. This is a clinical and laboratory observation at Arar general hospital in Kingdom Saudi
Arabia (KSA) and included eleven patients on maintenance HD. The observation performed for more
than 30 months starting from November 2017 until Feb 2020. All patients had been complaining of
muscle fatigue and weakness manifestations. Additionally, they cannot get out from the sitting
position easily or with aid. The patients started to receive management in the form of intravenous
injection of L-carnitine ampoule (1000 mg) post HD session three times/week for eighteen months up
to two years. At the start of the year 2020, Because of the unavailability of the drug (L- carnitine), all
patients stopped its use obligatory. All patients’ reviews were evaluated by two treating physicians
(Megahed A F and Hles G M). They prescribed the management and followed the patients'
complaints before, during the use of L-carnitine, and after the obligatory stoppage of the drug.
Observations of the two treating physicians were recorded. After the collection of the data, they were
analyzed using the statistical package of social science (SPSS,IBM) software version 24. Categorical
data were expressed as numbers and percentages. Scale data were expressed as means ± SD and
medians.
The current observation included eleven HD patients of mean age of 56.91(6.964) years. Males
constituted five (45%) of the total sample. The mean dialysis duration was 59.82(54.175)
months. Tables 1 shows the baseline demographic and clinical and laboratory data of the included
sample.
Table 1. Demographic data and clinical and laboratory data of the observed patients
Demographic data of the observed patients
n
%
Gender
Female /Male
6/5
54.5/45.5
Country
KSA
8
72.0
Non-Saudi
3
28.0
Smoking
Non-smoker
9
81.8
Smoker
1
9.1
Ex-smoker
1
9.1
Diabetes mellitus
Yes
7/11
63.6
HTN
Yes
11/11
100.0
Ischemic heart disease
Yes
3/11
27.3
Serology
Negative
7
63.6
Positive HCV-Ab
3
27.3
Positive HBsAg
1
9.1
Clinical and laboratory data of the observed patients
n
Mean
Std. Deviation
Median
Age
11
56.91
6.964
58.00
Duration of HD (in months)
11
59.82
54.175
46.00
Body Weight
11
75.39
17.463
70.00
Average UF
11
2.95
1.340
3.25
Diastolic blood pressure
11
83.45
7.313
80.00
Systolic blood pressure
11
155.82
15.132
160.00
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Intravenous L- Carnitine in HD Patients and Some of Its Benefits
110
Possible Aetiology of CKD
DM
1
9.1
HTN
9
81.8
DM & HTN
1
9.1
WBC Pre study
10
7.07
1.539
6.93
Hemoglobin Pre study
10
10.39
1.292
10.20
Platelet Pre study
10
250.80
148.037
213.50
Glucose Pre study (mg/dl)
10
217.01
105.911
207.54
Blood. Urea Pre study (mg/dl)
10
130.59
32.734
126.90
Creatinine Pre study (mg/dl)
10
8.67
3.383
7.96
Uric acid Pre study (mg/dl)
9
5.59
1.414
5.87
Albumin Pre study..
10
3.27
0.429
3.41
ALT Pre study
9
22.22
15.458
17.00
AST Pre study
6
41.33
63.933
11.00
GGT Pre study
10
73.99
111.054
34.00
Cholesterol Pre study (mg/dl)
9
148.87
32.258
146.68
Triglyceride Pre study (mg/dl)
10
137.71
127.508
84.08
Calcium Pre study (mg/dl)
9
8.64
0.864
8.84
Phosphorus Pre study (mg/dl)
9
4.76
1.363
4.46
Serum Sodium Pre study(ml
9
135.00
2.828
135.00
eq/L)
Serum potassium Pre study(ml
9
5.04
0.976
4.80
eq/L)
Transferrin. Saturation(%)
10
24.047
13.3217
18.64
The eleven patients included in the observation received L-carnitine ampoule each HD session and
all of them had improved as regards their complaints of muscle fatigue and weakness either totally
or partially. Seven of them improved totally, can get up from bed without aid and walk and descend
stairs without aid, while the remaining improved partially. One patient shifted to another HD unit and
lost follow-up. After discontinuation of the drug; the ten patients started to complain again about
muscle fatigue and weakness as before the start of management except for one patient who
deteriorated furthermore. Four of the observed patients were complaining of intradialytic
hypotension which disappeared with the use of L- carnitine ampoule and recurred again after the
stop of L- carnitine.
In the current observation, the use of intravenous L –carnitine post HD sessions is associated with
subjective improvement in muscle function, this is supported by many studies that considered L-
carnitine is very essential in HD patients. Routine administration of L-carnitine to all dialysis patients
is still not recommended; however, a trial of L-carnitine administration can be useful in symptomatic
patients with certain clinical features. These include intradialytic muscle cramps and hypotension,
asthenia, and muscle weakness [3,4]. Significant benefits of L-carnitine supplementation in patients
with better serum albumin advocate that this therapy should not be restricted to patients with the
worst nutritional and overall status [6]. Iwasaki and his associates, (2020) reported that baseline
carnitine concentrations were low among Japanese dialysis patients, especially among patients who
received dialysis for more than four years [7]. However, L-carnitine administrations may help reduce
muscle spasms in selected patients. Additionally, Sugiyama and his colleagues (2021) deduced that
Reducing L-carnitine administration for six months significantly decreased both plasma and red blood
corpuscles carnitine levels [8].
2. CONCLUSION
The intravenous L-carnitine ampoule of 1000 mg post HD three times/week could be useful in
symptomatic HD patients with certain clinical features including intra-dialytic hypotension and muscle
weakness or fatigue. Large prospective observational studies are warranted to validate these findings.
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Intravenous L- Carnitine in HD Patients and Some of Its Benefits
111
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
1. Guarnieri G, Situlin R, Biolo G, Carnitine metabolism in uremia. Am. J. Kidney Dis.
2001;38:S63–S67.
2. Mochizuki T, Takahashi M, Abe R, Oishi T, Shiga N, Kaneko M, et al. Carnitine metabolism
and its relation to nutritional parameters in patients with peritoneal dialysis. J Jpn. Soc. Dial.
Ther. 2002;35:165-170.
3. Ahmad S. L-carnitine in dialysis patients. Semin Dial. 2001;14(3):209-17.
4. Lorenzo A. Calò, Ugo Vertoll, Paul A. Davis, Vincenzo SAVICA L carnitine in hemodialysis
patients Hemodialysis International. 2012;16:428–434.
5. Yang S, Xiao L, Song P, Xu X, Liu F, Sun L. Effect of L-carnitine therapy on patients in
maintenance hemodialysis: a systematic review and meta-analysis. J Nephrol. 201427(3):317-
29.
6. Katalinic L, Krtalic Br, Jelakovic B, Basic- Jukic N. The Unexpected Effects of L- Carnitine
Supplementation on Lipid Metabolism in Hemodialysis Patients Kidney. Blood Press Res.
2018;43(4):1113-1120.
7. Iwasaki MK, Io H, Muto M, Ichikawa S, Wakabayashi K, Kanda R, et al. Effects of L-Carnitine
Supplementation in Patients Receiving Haemodialysis or Peritoneal Dialysis. Nutrients.
2020;12(11):3371.
8. Sugiyama M, Hazama T, Nakano K, Urae K, Moriyama T, Ariyoshi T, Kurokawa Y, Kodama G,
Wada Y, Yano J, Otsubo Y. Effects of Reducing L-Carnitine Supplementation on Carnitine
Kinetics and Cardiac Function in Hemodialysis Patients: A Multicenter, Single-Blind, Placebo-
Controlled, Randomized Clinical Trial. Nutrients. 2021;13(6):1900.
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Intravenous L- Carnitine in HD Patients and Some of Its Benefits
112
Biography of author(s)
Dr. Abir Farouk Megahed
Nephrology Consultant in Arar Hospital, MOH Nephrology Administration, Mansoura military hospital- nephrology department,
12 Hedaya st. Mubarek City, Mansoura, Daqahlia, Egypt.
She was born on 1st September 1966, in Egypt. She is a Visiting Consultant and Head of Nephrology Department in King
Salman Specialized Hospital, Hail, Saudi Arabia. She completed MBBCh, Mansoura University, 1989, Master Degree of
Internal Medicine, Mansoura University, 1996, and MD in Internal Medicine, Menoufia University, 2009. She has Egyptian
Fellowship of Nephrology, 2003. She is a Nephrology consultant in MOH and Visiting consultant in Mansoura military hospital,
Coordinator and Supervisor of HD units in MOH, Management of training Nephrology programs for Nephrology doctors and
nurses in MOH. She has 21 Published Papers in the National and International Journals.
Prof. Nagy Sayed-Ahmed
Nephrology and Internal Medicine. Nephrology and Dialysis Unit (MNDU), Faculty of Medicine, Mansoura University, Mansoura,
Egypt.
He was born in Mansoura Egypt on 19th February, 1959. He is a Professor of internal medicine and nephrology, Mansoura
Nephrology and Dialysis Unit (MNDU), Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt. He completed
MBBCh, Mansoura University, 1983, Master Degree of Internal Medicine, Mansoura University, 1989, and MD in Internal
Medicine, Mansoura, 1994. He is currently a Member of Nephrology Department of Mansoura university hospital, Currently
Chief tutor of Nephrology MD degree in Mansoura University. He supervised many original articles, MD, and MSc thesis in
different Nephrology aspects.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Asian Journal of Medicine and Health, 19(7): 92-95, 2021.
Reviewers’ Information
(1) Ali Mohamed Gado, Tanta University, Egypt.
(2) Mona Sayed Ghaly, Suez Canal University, Egypt.
_____________________________________________________________________________________________________
1Department of Oral and Maxillofacial Pathology and Oral Microbiology, Indira Gandhi Institute of Dental Sciences, Sri Balaji
Vidyapeeth University, Pillayarkuppam, Puducherry, India.
*Corresponding author: E-mail: vidyan@igids.ac.in;
Chapter 13
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Case Report of Odontoma – Mixed Odontogenic
Tumor
S. Vidyalakshmi1*
DOI: 10.9734/bpi/rdmmr/v7/4665F
ABSTRACT
Paul Broca coined the term Odontoma in 1869, defining it as a tumour formed by overgrowth of
complete dental tissue. Odontomas account for approximately 22% of all odontogenic tumours of the
jaws. We present two cases in which children aged 9 to 12 years old visited our OPD with the chief
complaint of missing teeth. Clinical, radiographic, and histopathological examinations revealed the
presence of a compound odontoma, which was surgically removed.
Objective: Benign mixed odontogenic tumor early diagnosis of odontomas ensure better prognosis.
Keywords: Odontoma; compound odontoma; mixed odontogenic tumor; hamartomatous lesion.
1. INTRODUCTION
Mixed odontogenic neoplasm is re termed as benign epithelial and mesenchymal odontogenic tumors
and Odontoma in 2017 WHO classification and further reclassified Odontoma as the 3rd benign mixed
tumor following ameloblastic fibroma and primordial odontogenic tumor. Odontoma originates from
epithelial and ectomesenchymal component. They are generally small but occasionally grow to large
sizes [1,2]. Most authors accept that odontoma represents a Hamartomatous malformation rather than
a true neoplasm [3]. The recent WHO classification of odontogenic tumors have included the
neoplastic entities of ameloblastic fibro odontoma and ameloblastic fibro dentinoma as developing
odontomas under odontoma and not any more to be considered as separate entities [4]. Odontoma is
called as composite odontoma, since it is composed of more than one type of tissue such as enamel,
dentin, variable amounts of cementum and pulpal tissue [5,6]. Aetiology of odontoma is unknown.
Local trauma/infection can cause odontoma. Males show a slight higher predilection when compared
to females [3,7]. The mean age of incidence is around 14 years and most prevalent age of diagnosis
is around 2nd decade of life [8]. Maxilla shows greater predilection than mandible at the ratio of 3:1 [3].
In general odontomas are asymptomatic, occasionally presents with signs and symptoms related to
their surrounding structures, such as unerupted / impacted teeth, retained deciduous teeth, swelling
and evidence of infection.
70% of Odontomas associated with impacted tooth and they are the most prevalent (22%) lesions of
the jaws. Radiologically, they show 3 varied stages ranging from well defined radiolucency lacking
calcification to partial calcification and the last stage with radiopaque masses surrounded by
radiolucent areas [9].
Odontoma can be classified into three variants clinically: Central (intraosseous) odontoma, peripheral
(extra osseous) odontoma and erupted odontoma. Intraosseous odontoma is further sub-classified
into compound and complex odontoma. The compound type is more prevalent in maxillary anteriors
(61%) and complex in (59%) [3]. Compound odontoma characteristically comprises multiple, small
tooth like structures whereas complex odontoma presents as a conglomerate mass of dentin and
enamel [8].
Recent Developments in Medicine and Medical Research Vol. 7
Case Report of Odontoma – Mixed Odontogenic Tumor
114
2. CASE REPORT – 1
A 9-year-old female came with the complaint of missing upper right second tooth. On intra oral
examination a diffuse swelling was seen in the region of 12 which was firm to hard in consistency.
Intra oral periapical radiograph in 12 revealed a radiopaque mass which was Obstructing the eruption
of 12 [Fig. 1a]. Macroscopic examination revealed a small primary tooth like structure which was hard
in consistency [Fig. 1b]. Microscopic examination of the ground section of the specimen revealed well
organized enamel and dentin like structures with no evidence of root [Fig. 1c]. The mass was
surgically removed and 2 was orthodontically moved to the occlusal position.
Fig. 1a. Radiograph showing radiopaque mass in 12 region
Fig. 1b. Macroscopic feature showing small tooth like structure
Fig. 1c. Well organized enamel and dentin like structures with no evidence of root
2.1 Case Report – 2
A 11-year-old male came with the complaint of missing anterior tooth. On intraoral examination a firm
swelling was noticed in maxillary anterior region in the region of 11, but it was not associated with any
pain. Upon radiographic investigation, OPG revealed a radiopaque mass obstructing the eruption
pathway of the impacted 11[Fig. 2a]. The mass is removed and patient referred to orthodontic
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Case Report of Odontoma – Mixed Odontogenic Tumor
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alignment. Macroscopy revealed hard tissue bits resembling teeth with crown and root like portions.
Small tooth like structures were found fused as a mass also. [Fig. 2b]. Macroscopic examination of the
ground section revealed a thin hypo plastic enamel and dentin like areas, a completely formed root
with cementum like structure. Fusion of three tooth like structures were evident [Fig. 2c].
3. DISCUSSION
The world health organization (WHO) defined the odontoma as ‘a malformation in which all the dental
tissues are represented, individual tissues being mainly formed but occurring in more or less
disorderly pattern’. It is the most commonly occurring benign odontogenic tumor (32-40%) and the
term ‘Odontoma’ was coined in the year 1869 by Paul Broca [3]. Odontoma is considered to be a
mixed tumor having both epithelial and ectomesenchymal component. Now, it is considered as a
developmental anomaly or Hamartomatous lesion, rather than true neoplasm. Odontomas present
themselves solitarily and also associated with impacted tooth and other odontogenic cysts and
neoplasms, for which the identification and removal of the lesion is urged. [1,3,5]. Etiology of
odontomas still remains unknown, however some studies have focused on the remnants of dental
lamina as the major etiological factor. Odontoma may arise due to complete functional discrepancy of
ameloblasts and odontoblasts during formation of enamel and dentin leading to an irregular
arrangement. It might be Congenital or due to an altered gene or postnatal genetic intervention of
odontogenesis [10]. Genetic incongruities like Gardner’s syndrome, Hermann’s syndrome and local
trauma, infectious or inflammatory processes, have been accredited to the development of odontomas
[1].
Fig. 2a. Radiopaque mass in the region of 11, obstructing the eruption pathway of 11.
Impaction of 11 is also evident
Fig. 2b. Macroscopic feature showing a hard tissue bits resembling teeth.
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Case Report of Odontoma – Mixed Odontogenic Tumor
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Fig. 2c. Photomicrograph of ground sectioned specimen showing fusion of teeth like
structures containing well organized thin hypoplastic enamel, dentin cementum with
incomplete root formation (4X)
Table 1. Showing comparison of features of 2 presented cases with the literature evidence
Criteria
Case -1
Case -2
Compound odontoma –
Literature Review
Age/sex
9/f
11/f
Childhood/adolescence (below
20 yrs) M:F=1:1
Site
12
11
Maxillary anterior region(73%)
Clinical
presentation
Painless swelling with
missing 12
Painless swelling with
missing 11
Painless ,non aggressive
lesion,often associated with
unerupted /impacted tooth
Radiological
features
Radiopaque mass
impacted 12
Radiopaque mass impacted
11
Radiopaque mass of multiple
small calcified structures with
an anatomical similarity to
normal teeth, usually
surrounded by radiolucent
zone.
Microscopical
features
Crown with well
organized enamel and
dentin like structures-
No evidence of root.
Thin hypoplasic enamel
,dentin and cementum like
structures- fusion of 3 teeth
like structures evident
Thin hypoplastic
enamel,mature tubular dentin
and cementum resembling
tooth like structure
Treatment
Enucleation
Enucleation
Conservative surgical
enucleation
Prognosis &
follow up
No recurrence – 5
months
No recurrence – 5 months
Excellent prognosis with no
recurrence.
WHO classified odontoma into three variants namely, central, peripheral and erupted. Central or
intraosseous variant is further sub classified into compound and complex .Compound odontoma
presents as malformations in which dental tissues are well organized in orderly pattern whereas in
complex odontoma, it displays calcified structures resembling tooth like structures. Complex
odontoma is a malformation in which all dental tissues are well formed but occurring in less orderly
pattern without any anatomical resemblance to a tooth [3,8].
Compound odontomas are painless benign lesion with limited growth potential compared to complex
odontomas. It usually occurs in children and young adult below the age range of 20 years with equal
sex predilection. Maxillary anterior region is most frequently involved site.
Very few cases are also reported in association with primary dentition also.Radiographically, it is
characterized by a radiopaque mass of different sizes, with variable amount of enamel, dentin,
Recent Developments in Medicine and Medical Research Vol. 7
Case Report of Odontoma – Mixed Odontogenic Tumor
117
cementum and pulp and they resemble malformed or supernumerary teeth. The lesion is usually
circumscribed by a narrow, radiolucent rim which corresponds to the fibrous capsule [1,11,12].
Compound odontoma comprises of multiple structures such as enamel, dentin, cementum and even
pulp chamber which resembles small tooth like structure, associated with this presence loose fibrous
matrix were also present. Under decalcification, enamel that capped the teeth like structure were lost
and leaves ample amount of enamel matrix [8].
Conservative surgical excision of odontomas considered to be a treatment of choice [11]. Which also
raises the query of need for classification of odontomas into compound and complex since the
treatment is the same though they vary in clinical presentation [13]. Since odontomas are often
associated with unerupted impacted teeth there could be a possibility of tooth eruption after surgical
excision of the lesion. There is no recurrence reported till date, however the lesion may recur if it is
incompletely removed at its early soft tissue stage [3]. Odontomas involving the maxillary antrum may
lead to various complications such as orbital infections, epidural and subdural emphysema,
meningitis, cavernous sinus thrombosis, brain abscess and death [14]. This literature elaborates on
two cases that reported to our OPD, with a complaint of missing upper anterior teeth. Both the cases
upon examination and investigations were found to be compound odontoma.
Our cases were in accordance with the literature with respect to age, radiographic findings, and
clinical presentation. The macroscopic and microscopic features revealed structures resembling
enamel, dentin and cementum. The lesions were enucleated conservatively and followed up. No
recurrence was noticed during the follow up period.
Fewer odontomas reported in younger children in association with primary dentition was
histopathologically observed to contain ameloblastic follicles in the stroma which is resembling
ameloblastic fibroma and ameloblastoma. Hence care must be taken during histopathological
examination to view the specimen in total and also to ensure appropriate follow up for any recurrence
in such cases [15]. Primordial odontogenic tumor is recently added in 2017 WHO classification of
odontogenic tumors should be considered in the differential diagnosis of Odontoma in the maxillary
region associated with impacted tooth in primary dentition [4].
4. CONCLUSION
Odontomas are the commonest tumor of all the odontogenic tumors. Adequate knowledge of the
clinical subtypes and lesions associated will render arriving at accurate methods of resolving the
cases.
COMPETING INTERESTS
Author has declared that no competing interests exist.
REFERENCES
1. Bordini J Jr, Contar CM, Sarot JR, Fernandes A, Machado MA. Multiple compound odontomas
in the jaw: Case report and analysis of the literature. J Oral Maxillo fac Surg. 2008;66(12):2617–
20.
2. Siwach P,Joy T,Tupkari J,Thakur A.Controversies in Odontogenic tumors: Review.Sultan
Qaboos Univ med J. 2017;17(3):e268-e276.
3. Rajendran R, Sivapathasundharam B. Shafer’s Textbook of Oral Pathology: 7th ed. India:
Elsevier; 2012.
4. Mortazavi H, Baharvand M. Jaw lesions associated with impacted tooth: A radiographic
diagnostic guide. Imaging science in dentistry. 2016;46(3):147-57.
5. Reichart PA, Philipsen HP. Odontogenic tumours and Allied lesions. London: Quintessence
Publishing Co Ltd; 2004;150–53.
6. Cuesta SA, Albiol JG, Aytes LB, Escoda CG. Review of 61 cases of odontoma. Presentation of
an erupted complex odontoma. Med Oral. 2003;8(5):366-73.
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7. Gujjar PK, Sahni P, Pereira T, Zingade J. Multiple Compound Odontomas in the Jaws: A Rare
Case Report. Journal of Clinical and Diagnostic Research. 2015;9(12):ZD05-ZD06.
8. Neville BW, Damm DD, Allen CM, Bouquot J. Oral and maxillofacial pathology. 3rd ed. St.
Louis, Missouri: Saunders Elsevier; 2009.
9. Godoy H, Reichart PA, Philipsen HP, Godoy F. Primordial Odontogenic Tumor: Report of a
Case with 10 Years Follow-Up. SVOA Dentistry. 2021;2(4):126-30.
10. Serra-Serra G, Berini-Aytés L, Gay-Escoda C. Erupted odontomas: A report of three cases
review of the literature. Med Oral Pathol Oral Cir Bucal. 2009;14(6):E299–303.
11. Erdogan, Ztunc H, Evlice B, Altug HA, Günhan. Compound odontoma involving the four
quadrants of the jaws: a case report and review of the literature. Quientessence Int.
2014;45(4):341–44.
12. Ajike SO, Adekeye EO. Multiple compound odontomas in the facial bones: A case report. Int J
Oral Maxillofac Surg. 2000;29 (6):443–44.
13. Wright JM, Vered M. Update from the 4th edition of the World Health Organization classification
of head and neck tumours: odontogenic and maxillofacial bone tumors. Head and neck
pathology. 2017;11(1):68-77.
14. Guledgud MV, Degala S, Patil K, Keshari D. Multiple extensive complex odontomas of the jaws.
Int J Dent Sci Res. 2014;2(6):128–32.
15. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization
Classification of Head and Neck tumours: Odontogenic and maxillofacial bone tumours.
Virchows Archiv. 2018;472(3):331-9.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Journal of Scientific Dentistry, 7(1), 2017.
_____________________________________________________________________________________________________
1The Royal Bournemouth Hospital, Dorset, UK.
2Centre for Postgraduate Medical Research and Education, Bournemouth University, Dorset, UK.
*Corresponding author: E-mail: drscallen@aol.com;
Chapter 14
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Determination of a Possible Benefit of 4-
Aminoquinoline Drugs to Reset Post-Acute
Inflammation in Old Age
Stephen Allen1,2* and Divya Tiwari1,2
DOI: 10.9734/bpi/rdmmr/v7/4559F
ABSTRACT
Persisting systemic inflammation of low amplitude is frequently found in elderly people and is a
contributary factor to several components of the frailty phenotype, particularly sarcopenia, low mood
and higher levels of dependency on others for essential activities, as well as higher all-cause
mortality. Older patients with such “inflammaging” have raised baseline concentrations of several pro -
inflammatory cytokines in peripheral blood, such as tumor necrosis factor alpha and interleukin-1
beta, and chronically raised C-reactive protein. There is a clear need to identify interventions,
including drugs, that can ameliorate such inflammation by helping to re-set the innate immune system
to a less inflamed baseline. Several classes of drugs have such properties. The purpose of this
chapter is to provide a summary of the background science of the relationship between ageing,
inflammation and frailty, then described the established role of methyl-xanthines, particularly
theophylline, as immune modulating drugs, then proceeding to propose a case for the use of 4-
aminoquinolines, such as chloroquine, in a similar role. The probable mechanisms of anti-
inflammatory action for those classes of drugs are compared, leading to a suggestion that formal
clinical trials should be conducted of chloroquine as an adjunctive immune modulator for
“inflammaging” and persisting post-acute inflammation in old age.
Keywords: Systemic inflammation; ageing; frailty; sarcopenia; immune modulation; theophylline;
chloroquine.
1. INTRODUCTION
A strong imperative is emerging to search for pharmacological agents that can effectively modify the
consequences of persisting low amplitude systemic inflammation, particularly in aged people in whom
it has been shown to be causally associated with a pre-frail or overtly frail condition, and is a probable
direct etiological factor in the development of sarcopenia [1,2]. This is especially so for the many
patients who are physically or mentally unable to perform exercise of sufficient regularity, work-rate
and duration to benefit from the anti-inflammatory effects of aerobic exercise [2,3]. This is a familiar
clinical phenotype in geriatric medicine and represents a major challenge to clinicians, health service
planners and economists. Our proposition is that opportunities should be taken to identify
pharmacological and non-pharmacological interventions that can help to reduce the burden of frailty
and preserve function. To that end, a case can be made for taking a fresh look at a number of drugs,
many of which are in common use for other purposes, that have been shown to modulate
inflammatory cellular and biochemical responses, largely by resetting immune networks toward a less
inflamed baseline state. To date, these effects have been arguably explored most avidly for methyl-
xanthines and statins [4-7]. In this paper the authors will summarize the prevailing evidence for 4-
aminoquinolines (4AQs), mainly chloroquine and hydroxychloroquine, that have been shown to have
immune modulating effects similar to methyl-xanthines, though apparently through different
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mechanisms. We draw on that evidence to propose a need for properly conducted clinical trials of
4AQs to ascertain any measurable clinical benefits.
2. BACKGROUND
2.1 Ageing of the Innate Immune System
Innate immunity in older people is fundamentally the same as that in younger adults but does exhibit
some different characteristics, particularly with respect to baseline settings and response amplitudes.
For example, commonly measured biochemical markers of inflammation, such as interleukin-1 beta
(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) at baseline between acute
inflammatory episodes have been shown to be often 2-4 -fold higher in the peripheral plasma of aged
subjects, and to become increasingly so with advancing age, most steeply in people older than 80
years, when compared to young and middle-aged adults [1,8,9]. In one high quality study of healthy
individuals across the adult age range there was a mean baseline venous plasma TNFα concentration
of 0.6 pg/ml in adults below the age of 30 years compared to a mean of 1.5 pg/ml in those above the
age of 70 years [10]. This is one of the manifestations of the clinical state frequently referred to as
“inflammaging”, a term that is now widely used in clinical geriatric medicine and by researchers
focusing on the immunology of ageing [1]. In many individual patients this state can be attributed to
clinically obvious co-morbid chronic inflammatory diseases such as rheumatoid arthritis (RA) or
chronic obstructive pulmonary disease (COPD) [9]. Similar raised plasma levels of the biochemical
indicators of inflammation, particularly TNFα and IL-1 have been reported in elderly people with
other conditions that appear to shift the innate immune web towards a relatively pro-inflammatory
setting; common examples are central obesity, atheromatous arterial disease, and type 2 diabetes
[11-13]. Further, a sustained low-level rise in plasma pro-inflammatory markers has been found in
people with Alzheimer’s disease (AD), and in association with a sedentary lifestyle, chronic renal
disease and osteoarthritis [11,14-16]. For reasons that are uncertain, some but not all well elderly
people have raised baseline plasma inflammatory markers that appear to have no identifiable
pathological cause, and age itself appears to be accompanied by an up-regulated baseline
inflammatory state [17,18]. Taking C-reactive protein (CRP), a non-specific marker of inflammation, as
an example, healthy young adult participants were found to have mean venous blood CRP levels of
0.9 mcg/ml compared to 3.0 mcg/ml in healthy people over the age of 65 [17]. Baseline peripheral
blood IL-6 and IL-1β also appear to be significantly correlated with age [19]. These observations have
relevance for clinical practice and pathophysiological research because persisting low-amplitude
inflammation, as measured by such blood markers, is associated with higher all-cause mortality, lower
muscle strength as assessed by handgrip and quadriceps femoris performance, impaired instrumental
function, thereby affecting activities of daily living, and lower subjective wellbeing, mood scores and
self-reported health status [20,21]. The observed plasma levels of inflammatory markers, such as
CRP, IL-1β, IL-6 and TNFα vary between studies, depending on assay methods, but overall the
adverse outcomes considered were broadly associated with 1.5 to 3-fold elevation above those found
in healthy age-matched controls. Another factor of importance to clinical geriatric medical practice that
is relevant to the argument we are positing in this paper is the persisting pro-inflammatory state that
often does not resolve, or does so slowly and incompletely, after an acute inflammatory event such as
pneumonia or septicemia. This clearly has implications for the rate and completeness of clinical
recovery and the return to pre-event mobility and instrumental function, and therefore offers a clear
and clinically important target for research into effective drug interventions [22-29].
It is likely that disease progression in a number of chronic pathological states is to some extent driven
by persisting inflammation and not just indicated by the presence of raised inflammatory markers [25].
It appears that a complex interactive relationship exists between cause and effect. An illustrative
example is the endothelial inflammation found in atheromatous disease which has been extensively
researched and is frequently cited as being typical of the inter-relationship between inflammation,
age-related changes and pathological mechanisms [26]. In many elderly people, the inflammatory
response to an acute stimulus, such as infection or injury, settles back to baseline more gradually
than it does in younger adults. The rises in plasma TNFα, IL-1β and IL-6 last longer and the
corresponding rise in the anti-inflammatory cytokine interleukin-10 (IL-10) occurs later and is of lower
amplitude. This effect of ageing on innate immune responses has been most clearly shown for
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pneumococcal and Gram-negative endotoxin antigens [27,28], in which cases an approximately
doubling of the time taken to return to pre-stimulus baseline levels in elderly subjects, after
comparable pro-inflammatory peak levels. This observation strongly suggests that regulatory anti-
inflammatory function is impaired, with a consequent delay in re-establishing a baseline surveillance
state of the innate immune system. It is a plausible argument that this altered mechanism is a likely
reason for the slower post-acute functional recovery and persisting low-level inflammation often seen
in older patients after acute inflammatory illnesses [2]. The evidence for cytokines having a central
role in age-associated inflammation is certainly well established.
2.2 Sustained Inflammation and Frailty
Systemic inflammation is closely, and probably causally, associated with some clinically important
features of frailty, including sarcopenia, cachexia and low mood [2]. The molecular mechanisms are
inevitably complex, incompletely understood and likely to be dependent on the patho-physiological
context in individuals. Various components of the innate and adaptive immune systems, notably
chemokines, the catecholamine-cortisol axis, complement reactions, interferons, immune cells and
other somatic cells communicate with and influence each other in a non-linear manner best pictured
as a network or web. A full account is outside the scope of this paper, but the authors have published
detailed descriptive reviews elsewhere [2-4]. Effective drug treatments for the subtle dys-immune
state described above are therefore likely to be those that cause a corrective multi-component shift in
the innate immune network, a process often termed immune modulation, and consequently ameliorate
the inflammatory burden that contributes to frailty.
2.3 Drugs that Modulate Systemic Inflammation: Particularly Theophylline
Drugs in several pharmacological classes have been shown to dampen systemic inflammation
through a range of complex mechanisms that are only partially understood. The list includes, but is
not limited to, statins, methyl-xanthines, salicylates, 4AQs, beta-adrenoreceptor blockers,
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS), metformin and mono-clonal
antibodies (MCAs) [2]. Though many of these are licensed for use as anti-inflammatory agents, some
are not despite having received considerable attention to explore immune modulating properties and
therapeutic potential. For example, theophylline, a methyl-xanthine drug used as a broncho-dilator in
patients with asthma and COPD, was noted to improve certain outcomes in patients with COPD, for
example improved walking performance, even when there was little or no measurable change in
spirometry or arterial blood gas tensions. Further, this occurred at plasma levels well below (<10
mg/L) those likely to cause toxic effects [30]. Follow up studies found that the anti-inflammatory
properties of theophylline acted not only locally on airways but also systemically [31,32]. Despite a
series of studies, the set of mechanisms through which theophylline modulates innate immune
reactions remain incomplete. Further, the patterns and sequences of reactions that constitute the
innate immune web and are likely to vary from episode to episode, within and between individuals,
and with the prevailing pathophysiological context. Importantly however, theophylline has consistently
been found to reduce post-acute TNFα and IL-1β, and increase IL-10, by around 25-50 per cent.
Similarly, in vivo testing of comparable concentrations of pentoxifylline, another methyl-xanthine,
caused a progressive fall in the release of pro-inflammatory IL-1β, IL-6, IL-8 and TNFα of between 20
and 80 percent by peripheral venous blood monocytes over 4 days [32]. This effect appears to be
mediated by activation of histone deacetylase-dependent gene switches to set a more anti-
inflammatory phenotype [31-33]. These properties are apparently due to theophylline-induced re-
direction of the immune web toward an anti-inflammatory state in macrophages and other immune
cells. Such cells have been shown to possess several dose-dependent gene switches that up- and
down-regulate various cytokines. This is therefore a plausible explanation for the observation that
patients with COPD treated with the addition of theophylline to a standard regimen had lower baseline
CRP levels and better functional scores compared with control subjects. It also appears that
theophylline at normative therapeutic doses reduces inflammation without compromising an
appropriate inflammatory response to infection. In a critical care context, it has been shown that a
reduction in mortality occurs in patients with severe sepsis treated with theophylline. These effects
can be viewed as the clinical manifestations of immune “modulation” [5,7,34-43].
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3. PROPOSITION
3.1 A Possible Role for 4AQs
Chloroquine and other 4AQs analogues are in established use as anti-inflammatory drugs, mainly in
the field of rheumatology for the management of conditions such as rheumatoid arthritis and systemic
lupus erythematosus. The anti-inflammatory properties of 4AQs were discovered as a beneficial side
effect when chloroquine was in widespread deployment as an anti-malarial drug. Subsequent
research established the efficacy of 4AQs in a range of disorders and some progress has been made
to identify the mechanisms of action. Early research suggested that the principal anti-inflammatory
action was mediated by the changes in macrophage and other monocyte intra-lysosomal pH, and
consequent effects on antigen proteolysis and enzymatic activation, as chloroquine and its analogues
are concentrated in lysosomes [44]. The accumulation of chloroquine in lysosomes appears to be
irreversible and elevates lysosomal pH by trapping of H+ ions in association with chloroquine
molecules. Hydroxychloroquine, also a lysosomotropic amine, has a similar effect on cellular function.
By that apparent mechanism, chloroquine and its analogues interfere with lysosomal pH, which in turn
inhibits phagocytosis, antigen processing and proteolysis and, thereby indirectly, chemotaxis, antigen
presentation and the phenotypic expression of inflammation. Further research showed that
chloroquine and its analogues reduce the release, and probably the production, of the pro-
inflammatory cytokines TNFα, IL-1β and IL-6 by monocytes in vitro, and in vivo during treatment of
patients with inflammatory conditions [45]. However, confirmatory in vitro studies have shown that it is
likely that the chloroquine-induced reduction of production by monocytes is due to slower conversion
of TNF precursors to the active molecule, whereas the reduced production of IL-1β and IL-6 appears
to be caused by a pH-dependent inhibition of cytokine release from cells consequent mainly upon
reduced molecular stability but possibly due to acid-base effects on gene transcription [45,46]. These
effects appear to be mediated by alterations in antigen processing, as described above, and by an
acid-base sensitive reduction in messenger-ribonucleic acid (mRNA) involved in IL-1β and IL-6
transcription [46], rather than through an epigenetic gene-switching mechanism. It appears, therefore,
that the biochemical mechanisms of the immune modulating properties of 4AQs (for example
chloroquine) and methyl-xanthines (for example theophylline) are different.
4. NEXT STEPS
4.1 The Need for Research
We have, in previous papers, contended that a case can be made for well conducted studies of the
use of low-dose theophylline to modulate persisting inflammation, when it is inappropriately prolonged
after stimuli such as sepsis, particularly in pre-frail or overtly frail elderly patients [2,4] We also
advocate similar carefully designed trials of 4AQs, especially chloroquine and hydroxychloroquine. A
role for the use of 4AQs might consequently be established in the reduction of post-acute and chronic
inflammation in an attempt to ameliorate the progression from pre-frailty to established frailty, either
as a sole treatment or as an adjunct to use of, for example, methyl-xanthines. On a topical point, the
finding that hydroxychloroquine has no beneficial effect in patients with Covid-19, neither as
prophylactic drug [47] nor as a treatment to reduce mortality in established cases [48], does not
indicate that there would be no benefit in patients with post-acute persisting low-amplitude systemic
inflammation. While most individuals with post-acute persisting inflammation have hitherto suffered
from common illnesses such as influenza, bacterial pneumonia and urinary tract infection, the
emergence of the SARS-CoV-2 virus has provided a further source of inflammatory stimulus, and
indeed it is probable that systemic inflammation contributes to the syndrome of “long covid” in
survivors of Covid-19 [49]. Further, though no benefit of 4AQs in the preventative and acute phases of
Covid-19 was found in trials, there has yet to be a conclusive trial in post-Covid syndrome [50].
Therefore, the principal targets for further research should be specifically: 1) to conduct placebo-
controlled trials of anti-inflammatory doses of chloroquine or hydroxychloroquine, given orally, as
short-term (4-6-weeks) adjunctive treatment in elderly patients recovering from sepsis or trauma. 2) to
establish whether chronic low-grade inflammation, as measured by peripheral blood biochemical
markers such as TNFα and IL-1β can be modified by such treatment, and functional outcomes
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improved. 3) include as defined outcomes measures of mortality, mobility scores, functional scores,
return to independent living, measurements of muscle strength and other indices of
sarcopenia, cognition, mood, wellbeing scores, and duration of hospital treatment.
5. CONCLUSION
It is concluded that the probable mechanisms of anti-inflammatory action for those classes of drugs
are compared, leading to a suggestion that formal clinical trials should be conducted of chloroquine as
an adjunctive immune modulator for “inflammaging” and persisting post-acute inflammation in old age.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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Biography of author(s)
Stephen Allen
The Royal Bournemouth Hospital, Dorset, UK and Centre for Postgraduate Medical Research and Education, Bournemouth
University, Dorset, UK.
Research and Academic Experience: An NHS consultant physician in Internal Medicine and Geriatric Medicine. Involved in
clinical and laboratory research for 45 years in affiliation with several UK universities, and with collaborators in Hong Kong,
Singapore and Lusaka.
Extensively involved in UK postgraduate medical education and training through various committees at the Royal College of
Physicians. External examiner, at various times, for the Universities of Leeds, Cardiff, Salford and the Chinese University of
Hong Kong.
Research Area: Pneumonia, COPD, inhaler technique, ageing respiratory physiology, systemic inflammation, autonomic
dysfunction.
Number of Published papers: 180
Special Award: NHS Clinical Excellence Gold Award
Divya Tiwari
The Royal Bournemouth Hospital, Dorset, UK and Centre for Postgraduate Medical Research and Education, Bournemouth
University, Dorset, UK.
Research and Academic Experience: An NHS consultant physician in Internal Medicine and Geriatric Medicine. Involved in
clinical and laboratory research for 20 years in affiliation with Bournemouth University, and with collaborators in India and the
USA.
Extensively involved in UK postgraduate medical education and training through various committees at the Royal College of
Physicians and British Geriatrics Society.
Research Area: Old-age neurology, inflammation, clinical quality improvement, medical statistics, clinical outcomes.
Number of Published papers: 25
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
SM Gerontol Geriatr Res, 3(1):1020, 2019.
_____________________________________________________________________________________________________
1Max Lab, Nijjar Path Care, Amritsar, India.
2Dr. Om Prakash Eye Hospital, Amritsar, India.
*Corresponding author: E-mail: maninderkr24@gmail.com;
Chapter 15
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Study on Nocardia in Psoas Abscess: A Rare Case
Presentation
Maninder Kaur1* and Aruna Aggarwal2
DOI: 10.9734/bpi/rdmmr/v7/4500F
ABSTRACT
We report a case of primary psoas abscess caused by Nocardia in an immunocompetent patient who
presented with low back ache with pain radiating to both legs. The objective of the study is to
summarize the clinical characteristics of this rare presentation in order to improve the knowledge of
Nocardia which can help in making diagnosis of Nocardiosis in clinical cases. Unless suspected, the
diagnosis can be easily missed resulting in increased morbidity and mortality. A suspicion of
nocardiosis was made based on gram staining and modified acid fast staining of material obtained by
ultrasound guided aspiration. The patient showed remarkable recovery after treatment with co-
trimoxasole. Quick identification by simple gram staining and modified acid fast staining helped in
timely diagnosis and treatment of the patient.
Keywords: Immunocompetent; modified acid fast staining; psoas abscess; Nocardia.
1. INTRODUCTION
Infections caused by Nocardia species are infrequent but challenging to the clinicians. Although
Nocardiosis is a global disease but it has significant prevalence in tropical countries of the world. They
cause a variety of diseases in both the normal and immunocompromised patients [1]. In a state like
Punjab where agriculture is the main occupation of the majority of the population, infections by soil
saprophytes must always be considered.
The hallmark of Nocardiosis is abscess formation and chronic progression irrespective of anatomical
barriers with a tendency to recur or relapse despite adequate treatment [2]. Psoas abscess is an
infrequent entity described in medical literature. It is a collection of pus in the iliopsoas muscle
compartment, also called “Psoitis”. It was first described by Mynter in 1881 [3].
Psoas abscess is classified as primary and secondary. The aetiology of primary psoas abscess is not
well known. The primary type is caused by haematogenous dissemination of bacteria or spread
through lymphatics, the source of which is usually occult. This type is seen in about 30% cases and
especially in immunocompromised patients such as diabetics and alcoholics. Secondary type occurs
as a result of local extension of infective process and is responsible for about 70% of psoas abscess
[4]. Staphylococcus aureus is the causative agent in over 88% of patients with primary iliopsoas
abscess. Secondary iliopsoas abscess is caused by Streptococcus species (4.9%) and E. coli (2.8%).
Mycobacterium tuberculosis is also not uncommon in the developing countries [5].
2. CASE REPORT
A 60 years old female patient was admitted to Sri Guru Ram Das Institute of Medical Sciences and
Research, Amritsar, in November 2012, with a history of severe low back ache for last 15 days. The
pain was also radiating to both legs and more to the right one. Pain was so severe that the patient
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Study on Nocardia in Psoas Abscess: A Rare Case Presentation
128
was unable to stand on her legs. There was no history of hypertension, diabetes mellitus and asthma.
On local examination, a swelling was present on lower back region.
Laboratory investigation showed haemoglobin of 8.9, WBC count of 16000 with neutrophilic
leukocytosis (86% neutrophils, 10% lymphocytes, 1% monocytes, 3% eosinophils). Erythrocyte
sedimentation rate was 136mm/Hg and Mantaux test was negative. Renal function and liver function
tests were within normal limits. Ultrasound guided FNAC was performed and the aspirate was sent to
microbiology and pathology Departments. Cytology report showed mainly neutrophils with a necrotic
background. Gram stained smear from the aspirate showed presence of slender, weakly gram
positive, branching filamentous bacilli. Modified ZN (1% sulphuric acid as decolourizer) stained smear
showed numerous acid fast branching filamentous organisms morphologically resembling Nocardia
species (Fig. 1). Based on findings of gram stain, modified ZN stain and cytology, a provisional
diagnosis of Nocardial infection was made. The micro-organism was later confirmed as Nocardia
species by its growth on LJ medium (Fig. 2). Accordingly the patient was started on high dose of
intravenous cotrimoxazole.
Fig. 1. Modified Ziehl Neelsen stained smear showing thin branching filamentous acid fast
bacilli
Recent Developments in Medicine and Medical Research Vol. 7
Study on Nocardia in Psoas Abscess: A Rare Case Presentation
129
Fig. 2. Growth of Nocardia on LJ medium
Meanwhile MRI imaging of the lumbosacral region of the patient was done which showed multifocal
abscess involving paravertebral, psoas, posterior paraspinal, presacral and right gluteal abscess
without significant vertebral marrow oedema. CT scan of thorax and abdomen did not reveal any other
focus of infection. These findings pointed towards a primary psoas abscess by Nocardia species in an
immunocompetent patient which is a rare possibility.
Being multiloculated, therapeutic aspiration could not be performed. So the patient was continued on
parenteral therapy for one month after which some improvement was noticed. She was discharged
after six weeks on oral treatment but the patient was lost to follow up.
3. DISCUSSION
Nocardia species are ubiquitous in the environment as saprophytic components in water, soil, dust,
decaying vegetation and faecal matter [6]. Nocardia usually is an opportunistic pathogen with majority
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Study on Nocardia in Psoas Abscess: A Rare Case Presentation
130
of infections occurring in patients with immunosuppressive conditions. However, upto one third of
patients with nocardiosis, however, are immunocompetent [7]. In this case the patient is
immunocompetent without any associated illness and the source of infection could not be traced.
The clinical forms include pulmonary involvement, skin or soft tissue infection and disseminated forms
with brain and pulmonary lesion. Primary nocardial infection includes pulmonary and cutaneous
and/or subcutaneous lesion. Disseminated disease is defined by the identification of nocardial
infection in two or more organs. Less frequent clinical presentations include peritonitis, epididymo-
orchitis, iliopsoas and perirectal abscesses, pericarditis, endocarditis, septic arthritis and osteomyelitis
[1]. Nocardia as the causative agent for a primary psoas abscess, as reported in this paper is an
uncommon finding reported only in few studies [8]. The tendency for the initial pulmonary focus of
nocardiosis to clear spontaneously may obscure the source of subsequent metastatic infection and
thus make it appear that primary nocardial infection is taking place [9].
Clinical and radiological features are not pathognomic for nocardial infection, thus smear and culture
remains the principal mode of diagnosis [10]. Microscopy involves Gram stain and modified acid fast
staining of specimen. Gram stain is extremely important because the organism is usually missed with
routine acid fast staining and culture may require prolonged incubation before appearance of typical
colonies. Nocardia species appear as beaded gram positive, thin, branching, filamentous organism. In
modified acid fast stain they usually appear as partially acid fast filamentous bacilli [10].
Recently, molecular tools have been added to improve the diagnosis of Nocardia infection because
they need shorter time to diagnose such rare infections . The gold standard for Nocardia species
identification is molecular biology with amplification and sequencing of one or two genes among rrs,
hsp65, secA1 and SodA [11]. MALDI-TOF MS is increasingly being used for identifying Nocardia
species, but still the role of simple gram stain and modified acid fast staining cannot be under-
estimated for diagnosis [12].
Successful therapy requires the use of antimicrobials in combination with appropriate surgical
drainage. Sulphonamides have been the antibiotics of choice either alone or in combination with other
antimicrobials [6]. Susceptibility testing should especially be considered in refractory cases [10].
Therapeutic aspiration is generally inadequate in patients with thick walled multiloculated abscesses,
which contain free flowing pus including patients with mycetoma.
In a tuberculosis endemic country like India, nocardiosis is often misdiagnosed as tuberculosis. Lack
of laboratory support or failure to communicate the clinical suspicion of Nocardiosis to the
microbiology laboratory could be other reasons for the under diagnosis of this condition. This case
exemplifies the need to know the clinico- epidemiological profile of nocardial diseases and the
importance of correct microbiological diagnosis for the appropriate treatment of the condition.
4. CONCLUSION
Although Nocardia is rarely reported as a cause of psoas abscess, its timely diagnosis with simple
microscopy and high index of clinical suspicion can aid in appropriate management of the patient.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
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2. Sullivan DC, Chapman SW. Bacteria that masquerade as fungi: Actinomycosis/nocardia. Proc
Am Thorac Soc. 2010;7(3):216-21.
3. Mynter H. Acute psoitis. Buffalo Med Surg J. 1881;21:202-10.
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Study on Nocardia in Psoas Abscess: A Rare Case Presentation
131
4. Adelekan MO, Taiwo SS, Onile BA. A review of psoas abscess. Afr J of clin Exp microbiol.
2004;5:55-63.
5. Ricci MA, Rose FB, Meyer KK. Pyogenic psoas abcess. Worldwide variations in etiology. World
J Surg. 1986;10:834-43.
6. Brown JM, McNeil MM. Nocardia, rhodococcus, gordonia, actinomadura, streptomyces, and
other arobic actinomycetes. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH,
editors. Manual of clinical Microbiology, 8th ed. Washington, D.C: American Society for
Microbiology. 2003:502-31.
7. Beaman BL, Burnside J, Edwards B,Caurey W. Nocardial infections in the United State. 1972-
1974. J Infect Dis. 1976;134(3):286-89.
8. Saubolle MA, Sussland D. Nocardiosis: Review of clinical and laboratory experience. J Clin
Microbiol. 2003;41:4497-501
9. Lerner PI. Nocardiosis.ClinInfect Dis. 1996;22:891-905.
10. Saubolle MA, Sussland D. Nocardiosis: Review of clinical and laboratory experience. J Clin
Microbiol. 2003;41:4497-501.
11. Margalit I, Lebeaux D, Tishler O, Goldberg E, Bishara J, Yahav D, Coussement J. How do I
manage nocardiosis? Clin Microbiol Infect. 2021;27(4):550-558.
DOI: 10.1016/j.cmi.2020.12.019. Epub 2021 Jan 5. PMID: 33418019.
12. Body BA, Beard MA, Slechta ES, Hanson KE, Barker AP, Babady E, et al. Evaluation of the
Vitek MS v3.0 matrix-assisted laser desorption ionization-time of flight mass spectrometry
system for identification of Mycobacterium and Nocardia species. J Clin Microbiol. 2018;56:
e00237.
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Biography of author(s)
Maninder Kaur
Max Lab, Nijjar Path care, Amritsar, India.
Research and Academic Experience: 5 years of experience in Research and Academics during tenure in Government
Medical College, Amritsar and Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar.
Research Area: Medical Microbiology.
Number of published papers: 10 Research papers publications in National and International journals
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
J of Gastro Infs., 3(1), 2013.
_____________________________________________________________________________________________________
1Department of Anatomy, Rajiv Gandhi Institute of Medical Sciences (RIMS), Ongole, Prakasam District, Andhra Pradesh,
India.
2Kamineni Academy of Medical Sciences & R.C, L. B. Nagar, Hyderabad, Telangana, India.
*Corresponding author: E-mail: v.usharani53@yahoo.com;
Chapter 16
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Determination of Foetal cases of Sirenomelia
Sequence with Their Embryological Correlations
Usha Rani Vanagondi1*, S. Saritha2, Jwalaram Kumar Chaluvadi1,
Gayathri Pandurangam2 and D. Nagajyothi2
DOI: 10.9734/bpi/rdmmr/v7/1809C
ABSTRACT
A thorough investigation of a congenital anomaly “Sirenomelia” of the foetus is a rare malformation
that makes life impossible. This is a very rare occurrence, and hearing such cases is heartbreaking.
The sequence was named after the mythical Greek sirens and was first described by Rocheus in
1542 and Palfyn in 1953. Sirenomelia sequence is also known as Mermaid Syndrome because it has
two fused lower limbs that resemble a mermaid's tail, according to Greek mythology. Sirenomelia was
previously thought to be an extreme case of Caudal Regression Syndrome (CRS); however, CRS is
now thought to be caused by a lower spinal trunk ending anomaly (Frog-like). It includes a wide range
of anomalies, such as partial or complete agenesis of the thoraco-lumbosacral spine and pelvic
deformities. Sirenomelia may be caused by blastogenesis abnormalities affecting multiple midline
primordial structures during the final stages of Gastrulation at the caudal eminence. This causes
insufficient migration and differentiation of mesoderm, which is responsible for a variety of defects in
the caudal region, and it also affects blood distribution to the fetus's caudal region. In the literature,
approximately 300 cases have been reported, with a male: female ratio of 3:1. Typically, these infants
do not survive more than 24 hours. Even after surgery, only a small percentage of patients survive.
Aim: The aim of this study is Comprehensive study of Foetal cases of Sirenomelia Sequence with
emphasis on prenatal diagnosis and Pathological features of sirenomelia. An ultrasound scan may be
useful in detecting this anomaly early in pregnancy. In the face of a poor prognosis, earlier intrauterine
diagnosis allows for less traumatic therapeutic abortion, minimising pregnancy termination at
advanced gestation.
Observation & Results: We found two cases of the Sirenomelia sequence. The first patient was a
25-year-old primigravida who was admitted to the hospital at 24 weeks of pregnancy. Prenatal
ultrasound revealed severe Oligohydramnios and fusion of the lower limbs, indicating Sirenomelia; the
pregnancy was terminated. The second case involved a 25-year-old primigravida who gave birth to a
stillborn full-term baby whose gender could not be determined. The specimen was obtained from a
private nursing home and was identified as Sirenomelia.Both cases had no relevant history of
consanguineous marriage, tobacco smoking, or drug use, among other things. Both foetuses were
taken to the anatomy dissection hall for a thorough autopsy. This paper reported the findings, along
with a brief assessment of the literature, discussion of etiopathogenesis, and embryological
correlation.
Keywords: Sirenomelia; Caudal Regression Syndrome (CRS); vascular steal theory and
Teratogenesis.
1. INTRODUCTION
The sirenomelia sequence is more prevalent in males, with a 2.7:1 sex ratio [1]. There is no link
between sirenomelia and chromosomal aneuploidy. Sirenomelia sequence, also known as Symelia or
Mermaid syndrome, is a rare lethal congenital anomaly marked by fusion, rotation, hypotrophy or
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Determination of Foetal cases of Sirenomelia Sequence with Their Embryological Correlations
134
atrophy of the lower limbs, a single umbilical artery, and severe urogenital anomalies resulting in
oligohydramnios. Because of the resultant oligohydramnios, these infants more often have potter’s
facies and pulmonary hypoplasia. Prognosis is very poor because the condition involves various
major anomalies, including bilateral renal agenesis, absence of both internal and external genitalia,
with agenesis or hypoplasia of diverse organs and Monopedia [2]. This rare malformation sequence
characterized by fusion of the lower limbs, the spectrum of lower limb anomalies ranges from simple
fusion of soft tissues to the presence of single rudimentary limb [3]. There is no consistent data for
the incidence of Sirenomelia. It is estimated to be between 1.1-4.2 cases per 100,000 births [4] and
reported as 0.8 to 4.2 in 100,000 births [5]. Most of cases are sporadic and have very little chance of
recurring in next pregnancy. The aim is stressed on fact a compulsory antenatal ultrasound
scanning for fetal anomalies are necessary for prompt diagnosis. Recent advances in the
understanding of axial mesoderm patterning during early embryonic development suggest that
sirenomelia represents the most severe end of the caudal regression spectrum. Third-trimester
ultrasonographic diagnosis is usually impaired by severe oligohydramnios related to bilateral renal
agenesis, whereas during the early second trimester the amount of amniotic fluid may be sufficient to
allow diagnosis. Early antenatal sonographic diagnosis is important in view of the dismal prognosis,
and allows for earlier, less traumatic termination of pregnancy [6].
2. TWO CASE REPORTS
2.1 First Case Report
A 25 year old female with 24- 25 weeks of gestation was admitted to the hospital and on ultra sound
scan was diagnosed to have oligohydramnios and lack of fetal movements. No h/o diabetes or any
teratogenic affects. The fetus demonstrated with fusion of lower limbs. The diagnosis of Sirenomelia
was made. At the level of kidneys, bilateral enlarged polycystic structure was identified and other
multiple interesting anomalies were seen. Because of incompatibility with postnatal life, pregnancy
was terminated with the consent of the parents. Detailed fetal autopsy was done in anatomy
dissection hall and findings were presented in the report. Since there were fused lower limbs seen,
the fetus was subjected to radiological examination. The affected fetus presented with fused lower
limbs and sacral agenesis.
2.1.1 Gross External Features. (Foetus A –Figs. 1 &2)
1. Upper limb length was normal measured about: 10 cm and there was discoloration of right
upper limb.
2. Lower limbs were fused & forming single lower limb whose length was about 7.5 cm.
3. The thighs and legs were fused with ill-defined muscles. The two feet were attached at the
ankle joint and rotated laterally, abducted and everted
4. The external genitalia was absent and it was represented as small flap and absence of anal
orifice (Imperforate anus)
2.1.2 Internal Features
On dissection placenta, heart was unremarkable and brain with absence of sulci.
1. Abdominal anomalies: The abdominal cavity includes multiple anomalies. It had a small liver with
agenesis of gallbladder, annular pancreas around duodenum. The stomach and spleen were normal.
The intestines were malrotated with small intestine on the right and large intestine on left side. The
blind end of sigmoid colon opens into the cloaca and there was an atresia of anorectal canal. (Foetus
A; Fig. 3).
2. Urogenital anomalies include bilateral polycystic kidneys, two ureters opening in the cloaca.
The bladder and urethra were absent. There was small gonad on the left side of the abdomen. Cloaca
receives the two openings of the ureters and sigmoid colon. (Foetus A; Fig. 4)
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Determination of Foetal cases of Sirenomelia Sequence with Their Embryological Correlations
135
3. Vascular anomalies: Abdominal aorta continuous as superior mesenteric artery (SMA) the steal
vessel which continuous as single umbilical artery or aberrant umbilical artery (SUA). Further there
was caudal tapering of abdominal aorta as hypoplastic aorta and it ended at the pelvic brim.
The inferior mesenteric artery (IMA) arose from abdominal aorta above the origin of superior MA.
(Foetus A; Fig. 5).
4. Radiology findings: (Foetus -A; Fig-6):
1. Upper Limb Bones Normal
2. Lower Limb Bones: Hip Bones, Femora, Tibiae, Fibulae were present and were normal & feet
rotated with Sacral agenesis.
5. Umbilical cord showing single Umbilical artery and vein with microscopic images (Foetus -A; Fig.
7).
6. Microscopic picture of single gonad (primitive) (Foetus -A; Fig. 8).
7. CT scan- (Foetus A, Fig. 8): Brain showing absence of Sulci, parenchymal hypodensity,
Hypodense cortical sinus secondary to stasis of blood
2.1.3 Impression
Soft tissue fusion in the region of thigh, leg up to the ankle region. Both feet are separated and rotated
lateral. It was diagnosed as mild mermaid syndrome, with sacral agenesis and fusion restricted to skin
and soft tissue
2.2 Second Case Report
Second case was also 25 years old primigravida gave birth to still born full term baby, sex could not
be identified .The specimen was collected from private nursing home and the diagnosis was of
Sirenomelia. No h/o diabetes or any teratogenic affects. The full term fetus small for gestational age
and of undetermined sex was born by spontaneous vaginal delivery. The infant was demonstrated
with fusion of lower extremities and showed absence of external genitalia. Detailed fetal autopsy was
done in anatomy dissection hall and findings were presented in the report. Since there was a fused
lower limb seen, the fetus was subjected to radiological examination
2.2.1 External features: (Foetus B; Figs. 1& 2)
1. The eyes are amphibian-like and the ears are floppy and low set.
2. The Upper extremity normal with abnormal fingers.
3. Only one left lower limb and it was not completely formed.
4. Absence of external genitalia and No urethra and anal openings.
2.2.2 Internal features
Fetal autopsy was done and following features were observed.
The Placenta no remarkable findings and Brain with absence of sulci.
1. Thorax: The heart and thymus were normal and lungs were hypoplastic. (Foetus B; Fig. 3)
2. Abdominal cavity showed multiple anomalies. The Gut rotation was complete. The Stomach,
small intestine, liver and spleen were normal. The Caecum and Ascending colon distended with
meconium and Rectum ended blindly. (Foetus B; Fig. 4)
3. Urogenital anomalies: There was complete renal agenesis, No kidneys, Ureters and Bladder.
Gonad (single) was seen in inguinal canal of right side. (Foetus B; Fig. 5)
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4 Vascular anomalies: Blood vessels of abdomen. (Foetus B; Figs. 6& 7)
Abdominal Aorta has no division of Common Iliac arteries and complete absence of External &
Internal iliac arteries. There was a small branch from abdominal aorta entering into the left lower limb.
Superior& Inferior mesenteric arteries were ill defined A single umbilical artery was present, which
was in direct continuity with the abdominal aorta.
5. Umbilical cord showing single Umbilical artery and vein (Foetus B; Fig. 8)
6. Microscopic structure of Testis & Epididymis (Foetus B; Fig. 9)
7. Microscopic structure of Thymus (Foetus B; Fig. 10)
8. X-ray findings: (Foetus B; Figs. 11 & 2)
Vertebral anomalies: Clefting seen in T3, T5 and T6, Scoliosis – convexity to left Spina bifida at
lumbar level. Distal sacral segment not seen.
Partial agenesis of sacrum present.
Limb defects:
Right hand: Polydactyly and Syndactyly of right thumb
Lower limbs: Single left lower limb was present, no fusion.
One femur, one tibia, no fibula
No tarsal bones & only small (little toe) metatarsal present
2.2.3 Diagnosis: SIRENOMELIA
9. CT scan Brain: Sulci absent, parenchymal hypodensity.
Hypodense cortical sinus secondary to stasis of blood
Limbs: One left lower limb with femur, tibia and no fibula.
3. IMPRESSION: SIRENOMELIA
Foetus - A
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4. DISCUSSION
Sirenomelia or the Mermaid syndrome is a rare congenital dysmorphic syndrome of the lower body
segments and with fusion of the lower limbs. The first reported case of mermaid syndrome was in the
16th century. The etiology of Sirenomelia is unclear though it is well known that the embryological
injury occurs between 28 and 32 days of intra uterine life. Sirenomelia was formerly thought to be an
extreme case of Caudal Regression Syndrome (CRS); however, it was reclassified to be considered a
separate condition. Sirenomelia is a lethal condition characterized by fusion of lower limbs, single
umbilical artery and severe malformations of lower GIT and Urogenital systems associated with renal
agenesis (Mermaid Tail). On the contrary CRS is also rare disorder associated with two umbilical
arteries and non fusion of lower limbs. It is characterized by various degrees of developmental failure
involving legs, lumbar, sacral and coccygeal vertebra, spine including sacral agenesis and
corresponding segments of spinal cord are also involved due to defect in neuralisation followed by
motor and sensory deficits. The defects predominantly involving the lower portion of the body, mainly
in lower spine end of fetus (frog like). Sirenomelia is associated with Oligohydramnios and Caudal
Regression Syndrome is associated with polyhydramnios and strongly associated with maternal
diabetes and therefore they are two different entities. Sirenomelia is thought to result from “Vasc ular
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Steal Syndrome”. Diversion of blood flow away from the caudal portion of the embryo through the
abdominal umbilical artery/“vascular steal” has been proposed as the primary mechanism leading to
Sirenomelia. The presence of single umbilical artery & associated with renal agenesis and fusion of
lower limbs, not compatible with life. In contrast, CRS is hypothesized to arise from primary deficiency
of caudal mesoderm. A teratogenic event during the gastrulation stage, the 3rd gestational week, may
interfere with the formation of notochord, resulting in abnormal development of the caudal structures.
The presence of two umbilical arteries, non lethal renal anomalies and divided lower limbs, CRS
relatively compatible with life.
4.1 Vascular Malformations
Heifetezet et al. 1984 & Stevenson et al. reported that the vascular abnormalities in Sirenomelia.
They explained diversion of blood away from the caudal region of the embryo through the abdominal
umbilical artery "A vascular steal” has been leading etiological factor to Sirenomelia. Human umbilical
cord normally has two umbilical arteries carrying deoxygenated blood from the fetus to placenta &
single umbilical vein carrying oxygenated blood to the fetus. However invariably Sirenomelia fetuses
exhibit a single umbilical artery [7, 8]. Heifetezet et al. 1984 & Stevenson et al.. considered the
presence of single umbilical artery (SUA) of vitalline origin as characteristic and pathognomonic of
Sirenomelia and forms differential diagnosis of other malformations such as caudal dysgenesis or
CRS. This SUA branches from the abdominal aorta at a quite high in the abdomen, thereafter the
Aorta narrows and lacks number of branches supplying kidneys, large intestine & genitalia. SUA
steals the blood from the structures below it- Vascular steal [9]. Recent studies have shown that
vascular disruption precedes caudal dysgenesis in the mouse [10].
Three pathogenic theories have been proposed to explain this malformation (Stevenson et al.) [8, 9,
10].
1. A pressure theory (Oligohydramnios and intrauterine force acts on the tail of the embryo may
impede normal rotation of limb buds).
2. Primary failure in the development of caudal somities that leads to defective development of
lower parts of the embryo.
3. A lack of nutritional support of the caudal region of the embryo. (Vascular steal theory)
The present study both Sirenomelia fetuses had single umbilical Artery (SUA) associated with severe
Oligohydramnios leading to ill defined or agenesis caudal organs.
4.2 Hind Limb Fusion Types
The classification of Sirenomelia infants on presence or absence of bones within the lower limb was
made by Stocker and Heifetz [11] in 1987 into 7 types. Stocker’s more detail classification into 7 Sub
types according to the fused bones.
Type – I : Paired femora, Tibiae and Fibulae.
Type – II : Paired femora, Tibiae & single fused fibula.
Type – III: Paired femora, Tibiae & absent fibula.
Type – IV: Partially fused femora, tibiae & single fibula.
Type – V: Partially fused femora, tibiae & absent fibulae.
Type – VI: A single femur & Tibia absent fibulae.
Type – VII: A single femur and absent Tibiae and fibulae
Type I to Type VII mainly according to presence of skeletal elements in the thigh & leg. Type I is
mildest form, all bones in the fused limbs are present& fusion affecting only soft tissues. In Type VII is
most severe form, only single bone is present. In Type VI has single femur, Tibia & absent fibulae.
Our first index case was 24 weeks fetus belongs Type I & Second index case was full term still born
fetus belongs Type VI. Both the fetuses multiple internal anomalies and associated with sacral
agenesis.
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Sarpong and Heading [12] classified the Sirenomelia syndrome into three types which is known as
Sirtoris’s classification.
SIRTORIS’S classification into 3 types according to the Number of feet [12].
1. Sympus Apus [Absence of feet, only one tibia and one femur.]
2. Sympus Unipus [Presence of only one foot, two femora, two tibiae, two fibulae]
3. Sympus Dipus [Presence of both feet and two fused legs] fused appearance is of a flipper or
fins. Accordingly the present report the clinical and anatomical features consistent with
Sirenomelia dipus & apus. Fetus A belongs to Sympus dipus with malrotated feet and
associated with multiple internal anomalies &Fetus B belongs to, Sympus apus ill formed foot
also associated with multiple internal anomalies Visceral malformations.
Lutz et al. [3] stated that all human Sirenomelia fetuses are characterized by fusion of lower limbs
with sacral agenesis and other anomalies like imperforate anus, colonic atresia and rectal atresia,
renal agenesis and absent bladder. Usual gonads are present and external genitalia absent.
Duhamel et al. in [13] also mentioned described the spectrum of visceral anomalies of the mermaid
syndrome. He described imperforate anus, absence of genitalia (expect for gonads) renal agenesis,
gastrointestinal anomalies including vascular anomalies like aberrant single umbilical artery. This
anomaly is a manifestation of the mermaid syndrome.
The present two cases had all the above features mentioned by Lutz et al. and Duhamel et al.
except for no renal agenesis in Fetus A and it presented with polycystic kidneys and ureters opening
in to cloaca. Cloaca also receives the blind sigmoid colon and Fetus B was associated with renal and
urinary bladder agenesis.
Kallen et al. [14] & Goodlow et al. [15] stated that malformation of urinary tract is consistently
associated with genital anomalies affecting external genitalia which were either absent or represented
as indistinct tag of tissue whereas gonads may be present.
In the current study both the fetuses malformations of urinary system, external genitalia represented
as indistinct tag of tissue in Foetus A & Foetus B had no external genitalia. Both the fetuses had
single gonad in the abdomen.
In 1980 Gardner and Breuer [16] proposed a theory of a neural tube over distension in the caudal
area may lead to a roof plate expansion of the tube leading to lateral rotation of mesoderm by 1800 .
This results in fusion of the lower limb buds followed by closing off the midline primitive gut and
urethra.
In present study the second fetus Spina bifida in lumbar region with absence of sulci in the Brain and
Foetus A also had absence of sulci in the Brain with no spinal defects.
4.3 Other Malformations Associated with Sirenomelia
According to Stocker and Heifetz [11] in 1987 & Kjaer et al. [17] other important commonly observed
anomalies in mermaid syndrome are lumbosacral & pelvic anomalies including sacral agenesis and
hemivertebrae with also corresponding anomalies of central nervous system. Our both fetuses
showed sacral & coccygeal agenesis and Foetus B also had Spina bifida in lumbar region and
Scoliosis with left side convexity.
Maternal teratogenesis associated with Sirenomelia has been described with maternal diabetes,
cocaine or snuff exposure. In the monozygotic twins; the incidence is 150 times greater than in
singleton [18,19].
Maternal diabetes is considered as causative environmental factor for Caudal Regression Syndrome
(Caudal dysgenesis) because 10-15% of affected children have diabetic mothers. However this
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association remains controversial for Sirenomelia because 0.5-3.7% of reported cases has diabetic
mothers [11,20,21].
Al-Haggar et al reported a fetus of sirenomelia sequence with Potters syndrome which showed
oligohydramnios and symelia apus. The Infant showed absent urinary tract and external genitalia, the
legs were fused by skin and had separate bones like in foetus A of our study .The mother had a
history of gestational diabetes mellitus [2].
Valezona et al observed two sirenomelic fetuses that were at the 19th and 16th gestational week
respectively. In the former, transvaginal ultrasound revealed severe oligohydramnios and internal
abortion, whereas bilateral renal agenesis, absence of a normally tapered lumbosacral spine, and a
single, dysmorphic lower limb were detected in the latter. In both cases, X-rays and autoptic
examination allowed categorization on the basis of the skeletal deformity. Subtotal sacrococcygeal
agenesis was present in both cases. Agenesis of the urinary apparatus and external genitalia and
anorectal atresia were also found as seen feotus B of present study [6].
Currently there is no serum marker to diagnose Sirenomelia. Prenatal ultrasonography as early as 13
weeks of pregnancy can detect gross structural anomalies. So if diagnosed earlier the alternative of
termination of pregnancy can be safely advised to the mother. Similarly proper control of blood
glucose level in a diabetic mother may prevent the occurrence of Sirenomelia [22]. Absence of
chromosomal abnormalities and familial inheritance has been noted in almost all cases. Karyotyping
of parents was normal as reported by number of researchers. This was done in the parents of both
the fetuses and found normal. The evidences have shown that Sirenomelia associated with
Oligohydromnias 0.5-3.7% of reported cases have diabetic mothers and Caudal regression Syndrome
associated with polyhydromnias 10-15% of affected children have diabetic mothers. and therefore
they are two different entities [23].
Diversion of blood flow away from the caudal portion of the embryo through the abdominal umbilical
artery/“vascular steal” has been proposed as the primary mechanism leading to Sirenomelia. In
contrast, CRS is hypothesized to arise from a primary defect of the caudal
Mesoderm [24, 25,26].
New reproductive technologies like Intra Cytoplasmic Sperm Injection(ICSI) was described to be
associated with Sirenomelia [27].
To conclude the precise etiology of the present two cases were labeled as rare variant of Sirenomelia
and not Caudal regression syndrome of unknown etiology. Both the fetuses presented with Single
umbilical artery & renal anomalies which not compatible with life. However etiology, still remains
unknown as both the mothers were non diabetic and not exposed to any teratogenic agents probably
Vascular steal theory holds good.
5. CONCLUSIONS
The prognosis of Sirenomelia or mermaid syndrome represents a rare and fatal congenital
malformation that is incompatible with life. Survival is extremely rare due to multiple agenesis or
hypoplastic viscera associated with fused lower limbs. Early ultrasound in the first trimester may be
useful in antenatal detection of this anomaly. In view of the bad prognosis earlier intra-uterine
diagnosis allows less traumatic therapeutic abortion. Although in our both the Sirenomelia fetuses, the
mothers did not have any evidence of any exposure to teratogenic factors, the couples should be
counselled about early screening in subsequent pregnancy.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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12. Sarpong, Headings V. Sirenomelia accompanying exposure of embryo to cocaine. South. Med.
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Mastriocovo. P. Robert E. The cyclops and mermaid: Epiemiological study of two types of renal
formation. J. Med. Genet. 1992;29:30-35.
15. Goodlow OG, Sibley RI, Allen BG, Kamanda WS, Gullatee AC, Rayfield WC. Sirenmelia:
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16. Gardner NJ, Breuer AC. Anomalies of heart, spleen, kidneys, gut and limbs may result from an
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25. Aslan H, Yanik H, Celikaslan N, Yildirim G, Ceylan Y. Prenatal diagnosis of Caudal regression
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Biography of author(s)
Usha Rani Vanagondi
Department of Anatomy, Rajiv Gandhi Institute of Medical Sciences (RIMS), Ongole, Prakasam District, Andhra Pradesh, India.
Number of Published papers: 5 papers published in various journals
S. Saritha
Kamineni Academy of Medical Sciences & R.C, L. B. Nagar, Hyderabad, Telangana, India.
Research and Academic Experience:
Vast Teaching Experience in Anatomy since 1988.
Passed MS Anatomy in 1988 & Stood First from Osmania university (TEACHING EXPERINCE: 35 YEARS)
Research Area: STUDY IN FETAL & CADAVERIC ANAMOLIES
Number of Published papers: PUBLISHED 49 PAPERS IN NATIONAL (INDIAN) & INTERNATIONAL
Any other remarkable point(s):
Publications of Text and Power point slides (DVD) January 2018
1.Histology Text and Power point Presentation (DVD) January 2018
2.Embryology Text and Power point Presentation (DVD) January 2018
By CBS Publication & Distributors Pvt Ltd (New Delhi
Dr. Gayathri Pandurangam
Kamineni Academy of Medical Sciences & R.C, L. B. Nagar, Hyderabad, Telangana, India.
Research and Academic Experience: Assistant professor of Anatomy with 6 years of Teaching experience.
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Foetal cases of Sirenomelia Sequence with Their Embryological Correlations
146
Research Area: Fetal & Cadaveric Study of Anomalies.
Number of Published papers: Published over 11 papers in national & international journals.
Special Award: University topper in Anatomy in 2015
Any other remarkable point(s): Member of regional society of Anatomists, Andhra Pradesh and Telangana.
Dr. D. Nagajyothi
Kamineni Academy of Medical Sciences & R.C, L. B. Nagar, Hyderabad, Telangana, India.
Research and Academic Experience: Teaching experience in Anatomy since 2014.
Research Area: Interested in studying Embryological Anatomy
Number of Published papers: Published 5papers in National & International
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
JMSCR, 4(4): 10074-10084, 2016.
_____________________________________________________________________________________________________
1Department of Veterans Affairs, Knoxville Outpatient Clinic, 8033 Ray Mears Blvd., Knoxville, TN 37919, USA.
2Endocrinology Consultants of East Tennessee, 1450 Dowell Springs Blvd., Suite 300, Knoxville, TN 37909, USA.
*Corresponding author: E-mail: Edwin.Jones2@va.gov;
Chapter 17
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Functional Improvement in -Islet Cells,
Hepatocytes and Cardiomyocytes with Decreasing
Deuterium from Low Carbohydrate Intake in a Type-
II Diabetic
Edwin C. Jones1* and Cortney L. Jardet2
DOI: 10.9734/bpi/rdmmr/v7/4920F
ABSTRACT
A 59-year-old patient with an 18-year history of type II diabetes showed remarkable improvements in
glucose tolerance tests and improved fasting hepatic glucose production with systemic deuterium
depletion. Deuterium, which is known to reduce the effectiveness of ATP synthesis nanomotors, is
most likely to blame for systemic variations in insulin and hepatic glucose production in the pancreas
and liver, respectively. Low carbohydrate (keto) diets with deuterium-depleted water can cause
systemic deuterium depletion.
Keywords: ATP; ATPase nanomotor;
-islet cell, deuterium; deuterium-depletion; deuterium-depleted
water; glucose tolerance; HBa1c; type-II diabetes.
ABBREVIATIONS
CBC: complete blood count; CHO: carbohydrates; CMP: comprehensive metabolic panel; D:
deuterium; DDW: deuterium-depleted water; DM: diabetes mellitus; DM-II: type-II diabetes mellitus;
1H: protium hydrogen isotope; 2H: deuterium hydrogen isotope; HBa1c: hemoglobin a1c; SNP: single-
nucleotide polymorphism;
1/2 : half-life.
1. INTRODUCTION
Deuterium 2H is a naturally occurring heavy hydrogen isotope, with one 2H deuterium atom for every
6400 1H protium atoms on the earth. The efficiency of cellular ATP generation is reduced when these
deuterium atoms interact with the ATP synthase in live organisms [1-3]. Deuterium-depletion is the
process of lowering the deuterium:protium ratio below 1:6400. Data are presented that suggest
deuterium-depletion via the consumption of a low carbohydrate diet was the mechanism responsible
for the elimination for the need for 130 units of exogenous insulin in a type-II diabetic patient
previously published [4]. During this period, the patient's c-peptide improved, indicating that the
dysfunctional -islet cells were being regenerated [4]. During this period of improvement, the patient
was said to have used a cyclical ketogenic diet, a strenuous exercise programme, and oral
GABA/probiotic supplementation. Over the past three years, further research was conducted to
elucidate the mechanism leading to these dramatic improvements to glycemic control. A study from
Ackermann et al. was published shortly after the original report showing that GABA does not appear
to induce pancreatic - to -islet cell differentiation [5]. Another study showed that diabetic patients
who choose low carbohydrate diets over low calorie diets have better glycemic control over their
counterparts [6] and this is believed to be due to lower deuterium 2H exposure. This is because plants
store the deuterium in their storage sugars and starches [7-8].
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-Islet Cells, Hepatocytes and Cardiomyocytes with Decreasing Deuterium from Low Carbohydrate
Intake in a Type-II Diabetic
148
Recently, animal studies have been published showing improvements to diabetes in rats with
deuterium depletion [9-11]. Numerous publications over the last 20 years have been devoted to the
study of the role of deuterium in natural (150 ppm) or reduced content in the human body. It has been
shown that deuterium-depleted water (DDW) exhibits antidotal properties with individual and
combined effects on the dosage of pharmaceutical substances and auxiliary substances [10,12-14].
Studies in humans are more limited; however, one recent study in 30 volunteers who consumed 1.5L
of 104 ppm deuterium-depleted water for 90 days showed improvement to the peripheral glucose
disposal in 15 of those individuals [15]. No toxic effects from the deuterium depletion process were
observed in any of the CBC or CMP lab values [15].
In this case report, glucose tolerance improvements, hepatic glucose production rate changes, and
HBa1c improvements are presented that reveal systematic metabolic changes with deuterium depletion
utilizing deuterium-depleted water (DDW) after the initial improvements seen from the introduction of a
low carbohydrate diet.
2. RESULTS
2.1 Genetic Risk Factors for DM-II
Diabetes mellitus is a metabolic disorder effecting over 100 million people worldwide. This metabolic
disorder has both genetic and environmental risk factors. In this case report, the patient took a
23andme DNA test (https://www.23andme.com/) in September 2016 which tested for 960,614 SNP
markers. Using the NIH Genome Data Viewer (https://www.ncbi.nlm.nih.gov/genome/gdv/), three SNP
markers that increase the risk for the development of Diabetes Mellitus, Type II were identified from
this list of markers. These are summarized in Table 1. The patient’s genotype, odds of developing
DM-II, and description of each gene are included in the table. These genes predict decreased insulin
secretion and increased hepatic insulin production. Furthermore, one gene predicts functional
hypoglycemia early in life followed by an increase risk in DM-II later in life.
Table 1. Genetic markers identified in the patient that are known to increase the risk of
developing Type II Diabetes Mellitus
Gene
SNP
Chromosome
Patient
Genotype
DM-II
Odds
Description
TCF7L2
rs7903146
10q25.2-q25.3
TT
1.59x
Transcription factor 7-like 2 (92% predictor
for DM-II)
IGF2BP2
rs4402960
3q27.2
TT
1.2x
Insulin like growth factor 2 mRNA binding
protein 2
KCNJ11
rs5219
11p15.1
TT
1.17x
Potassium voltage-gated channel subfamily J
member 11 found on -islet cells.
TCF7L2 genotype TT and IGF2BP2 genotype TT are both strong predictors for decreased insulin
secretion and increased hepatic glucose production. KCNJ11 genotype TT is known to increase the
risk of hypoglycemia early in life and DM-II later in life.
2.2 Improved Glycemic Control with a Low Carbohydrate Diet
The patient was treated with insulin between the ages of 52 and 55 during which time he started
recording detailed food intake logs. Fig. 1 illustrates daily carbohydrate (CHO) intakes in grams per 24
hours. In these data, one-half the fiber intakes were subtracted from the total carbohydrates which is
standard practice in predicting exogenous insulin requirements. The solid curve indicates the three-
week running average of daily carbohydrate intakes. These data were needed to maintain optimal
control of his glucose values especially during the time he required short acting insulin aspart.
Shortly after initiating a low carbohydrate diet with weekly ketogenic cycling, described elsewhere, [4]
the patient’s need for exogenous insulin slowly decreased disappearing completely by age of 55.29
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years. The patient’s c-peptide had increased by 350% during this same time period indicating a
regeneration in his -islet cell functioning [4]. In 2002 it was shown that pancreatic ductal cells could
differentiate into -cell in response to glucagon-like peptide-1 [16]. An important question that now
arose was whether or not the lower carbohydrate diet induced -islet cell differentiation by virtue of a
deuterium depletion process [7-8]. A lower deuterium:protium ratio would be expected to increase
cellular ATP production efficiency [1-3] which in turn could induce the improvements to internal
biochemical processes needed for the -islet cell differentiation.
Fig. 1. Daily carbohydrate consumption as a function of age dating back to age 52 when the
patient was initially started on short acting insulin aspart. By age 55.29 years, the patient no
longer required any insulin therapy. The solid curve is a three-week running average
carbohydrate intakes. The ideal carbohydrate intake based on lean body appearance was
estimated to be around 130 grams per day. The age where the keto cycling diet (low CHO) and
deuterium-depleted water (DDW) were started are indicated
2.3 Glucose Tolerance Improvement with Deuterium Depletion
To investigate this hypothesis, deuterium depleted water (DDW) was added to the low carbohydrate
diet of the patient at the age of 57.5. Further improvements to his glucose tolerance tests were
immediately observed as shown in Fig. 2. A hair sample that was originally collected for trace mineral
analysis was later tested for deuterium content which estimated his systemic deuterium to be 143
ppm at the age of 55.3 before the possible link between deuterium and -islet cell function was
suspected. Three additional glucose tolerance tests were collected at the ages of 57.4, 57.6 and 57.9
years immediately after collecting breath deuterium levels. All of the hair and breath deuterium tests
were analyzed by the Center of Deuterium Depletion (https://www.ddcenters.com) using mass
spectroscopy. Tap water was the primary water consumed before age 57.5 years and deuterium-
depleted water of various deuterium contents after age of 57.5 years. The deuterium level in the tap
water at the time of these deuterium studies was also measured with mass spectroscopy to be 149.8
ppm.
These data indicate the most significant improvement to the -islet cell functioning occurred between
age of 51 and 55 when the patient transitioned between insulin dependent DM-II and non-insulin
dependent DM-II [4]. Further -islet cell improvements occurred after deuterium-depletion water was
added to the low carbohydrate diet lowering the breath deuterium to a low of 119.9 ppm. Breath
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deuterium is believed to be a very close estimate of the blood plasma deuterium level [17] which is
already known to decrease the efficiency of ATP production in animals [1-3].
Fig. 2. Glucose tolerance tests following the administration of 50 grams dextrose (d-glucose)
at the ages of 17.3, 51.3, 55.3, 57.4, 57.6, and 57.9 years. The patient was diagnosed with
functional hypoglycemia at age 17, insulin dependent DM-II at age 51, and non-insulin
dependent DM-II at age 55. After age 55, the glucose tolerance tests show a gradual
improvement to -islet cell functioning in response to decreasing systemic deuterium 2H levels
2.4 Skeletal Fat Changes with Sleep
The patient is physically active with him hiking in the mountains nearly every weekend and spending
an hour of weight lifting five days during the week to reduce his skeletal fat. At the age of 53, he
began recording his total time slept using a timer to determine if there was an ideal amount of sleep
needed to further reduce skeletal fat. The skeletal fat was measured daily using a full body electronic
Omron HBF-514c scale described in more detail below. A decrease in skeletal fat not only improves
overall physical appearance but also helps in optimizing glycemic control. Previous researchers did
report a decrease in insulin sensitivity in type-1 diabetics with partial sleep restriction [18].
Skeletal fat measurements were made immediately after awakening from sleep when the water
distribution is more evenly distributed throughout the body [19]. Fig. 3 plots the skeletal fat readings
every morning over a five-year period plotted against the total time recorded for sleep. The data do
show clear decreases in skeletal fat with longer sleep durations but optimal sleep times are difficult to
achieve due to career/family obligations. These recorded sleep times would later prove useful in
determining the hepatic rate of glucose production.
2.5 Change in Hepatic Glucose Production with Deuterium Depletion
Hepatic glucose production rates were estimated for each of the breath deuterium levels recorded at
ages 57. 4, 57.6, and 57.9 years. The deuterium depletion level in the water consumed was held
constant for 6 weeks following each of the glucose tolerance tests shown in Fig. 2. Over a period of 6
weeks the patient’s fasting glucose upon awakening was plotted as a function of total recorded sleep
duration. The patient’s TCF7L2 genotype TT and IGF2BP2 genotype TT both predict increased
hepatic glucose production which are reflected as positive slopes in the best linear fits shown in Fig.
4. As the breath deuterium levels decrease, the slopes were found to increase indicating an increased
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rate of hepatic glucose production strongly suggesting a more efficient metabolism within the
hepatocytes with decreasing deuterium level.
Fig. 3. Skeletal fat (%) immediately upon awakening from sleep plotted as a function of hours
of total sleep duration. These data were recorded over a period of five full years (ages 53-58).
The curve shows the trend decreasing by roughly 0.201% skeletal fat per hour of sleep. The
dotted curves are the 95% confidence intervals. The upper confidence interval suggests an
optimal sleep period of 10 hours per night
Fig. 4. Fasting glucose values immediately after awakening vs total sleep duration. These were
recorded for 6 weeks for each breath deuterium level and color coded according to the breath
deuterium level. The slopes in the trend lines extrapolated to the y-axis yield the hepatic
glucose production rates. These slopes increased with the lowering of systemic breath
deuterium levels
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3. DISCUSSION
3.1 ATP Production Efficiency Estimated from Fasting Glucose Data
At this time there is no known method for directly measuring the deuterium level inside the
mitochondria matrix where the majority of our ATP production occurs. Fortunately, deuterium levels
can be measured in other body fluids including the liquid condensation of exhaled air which is
believed to be close to our blood plasma deuterium level [17]. Saliva deuterium level testing is also
available which is believed to the best estimate of the deuterium level inside our cellular cytoplasm
[17]. All of these deuterium levels are influenced by the deuterium levels that we are exposed to from
both food and water consumption.
Glycolysis is a sequence of ten enzyme catalyzed reactions that occurs in the cytoplasm where
deuterium rich hydrogens in glucose are stripped to produce pyruvate which then moves into the
mitochondria. There deuterium depleted “metabolic” water molecules are added back into the
structure via nine enzymatic steps called the Krebs Cycle. These “metabolic” water molecules are
produced inside the mitochondria from the oxidation of fatty acids that are believed to be depleted of
deuterium relative to glucose [17,20]. In sum, there is a total of 6 NADH and 2 FADH2 that are
produced inside the mitochondria matrix and these provide the deuterium depleted hydrogens needed
to efficiently drive the ATPase nanomotors [20]. Any contamination of the mitochondria matrix by
deuterium isotopes seriously reduce the efficiency of the ATPase nanomotors in producing cellular
ATP [1-3].
An estimate of hepatic ATP production efficiency in our patient can be estimated from the slopes in
the fasting glucoses vs total sleep duration trends taken from Fig. 4. As the patient lowered his breath
deuterium by consuming low deuterium content water, hepatic glucose production during sleep
increased. These data are shown in Fig. 5 which also shows ocean deuterium level and typical breath
deuterium levels seen in North America before deuterium depleted water is consumed [17].
Improvements in his overall glycemic control occurred with these hepatic glucose outputs due to
simultaneously improvements to his -islet cell functioning (Fig. 2).
Fig. 5. The hepatic glucose production rates derived from the slopes in fasting glucose vs
total sleep taken from Fig. 4. Higher hepatic glucose production was seen with lower
deuterium levels suggesting higher ATPase efficiency. Vienna Standard Mean Ocean Water,
155.76 ppm, and typical breath deuterium levels reported before deuterium depletion in North
American diets are labelled
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3.2 Skeletal Fat Turnover with Hiking
The patient is physically active averaging 19.3km of mountainous hiking on the weekends and five
hours of weight lifting during the week. Following each hike, it was previously reported that he would
remain in a post-exercise ketosis state for 2-3 days [4]. Changes in skeletal fat for each hike taken
from a five-year period, ages 53-58, are plotted in Fig. 6. A linear regression to these data reveals an
average drop of 0.045% skeletal fat per each km hiked. Following each repetitive hike, the patient
would maintain a low carbohydrate diet (Fig. 1) with a diet high in grass-fed animal or wild caught fish
protein. It is believed this repeated skeletal fat turnover over time allowed for the replacement of
skeletal fat with a reduced deuterium content. This low deuterium content skeletal fat is necessary for
the production of low deuterium “metabolic” water found in the mitochondria matrix [20].
Fig. 6. Change in the patient’s skeletal fat over a 24-hour period on hiking days. The patient’s
average hiking distance was 19.3 km and these data collected over a five-year period (age 53–
58 years). The trend line in these data reveal a loss of 0.045% skeletal fat for each km hiked in
mountains. The dotted lines represent the 95% confidence intervals. The one point at 47km
was from a two-day trip with a loss of 4% skeletal fat over a 48-hour period. These data were
recorded in the mornings of the hikes and the morning after the hikes when water distribution
is more uniform [19]
3.3 HBa1c versus Age and Environmental Deuterium Exposure
The hallmark lab for assessing glycemic control is the Hemoglobin a1c. The Hemoglobin a1c values
dating back to the original diagnosis of Diabetes Mellitus II are shown in Fig. 7. These data have been
color coded depending on the deuterium level recently tested from the water supplies from each
location where the patient lived. These drinking water deuterium levels ranged from a low of 143.0
ppm at 2,700 meter elevation at a western US mountain range to a high of 149.8 ppm in the
southeastern US. Once he added deuterium depleted water to his diet, his average water intake is
estimated to have dropped to around 130 ppm after age 58.
These data reveal that the most significant reduction in HBa1c occurred after the low carbohydrate diet
was incorporated into the patient’s lifestyle. The initiation of deuterium depleted water led to a dditional
improvements to these already improved HBa1c’s suggesting that the importance in deuterium
depletion is governed by the following hierarchy.
2H sources in the body: CHO Intake > Drinking Water > Fat/Protein Intake
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Fig. 7. Hemoglobin a1c levels as a function of age. The colors indicate the deuterium 2H levels
measured from the local water at the patient’s residence - green and blue from a western US
mountain range and the other colors from the southeastern US. The 130 ppm is the estimated
deuterium level after the patient began consuming deuterium-depleted water (DDW) after age
58. The brown and black symbols represent the time period where the patient consumed a low
carbohydrate (CHO) diet. The open circles indicate a high consumption of grass-fed Elk and
Bison from the northern plain states (>50 grams of daily protein) and open squares indicate
consumption of wild caught Alaska Sockeye Salmon (>50 grams of daily protein). Both are
reported to be low-deuterium containing foods [7-8]. The lowest HBa1c measured at 5.6%
occurred with the regular consumption of grass-fed Elk and Bison plus the 130 ppm
deuterium-depleted water.
3.4 Resting Heart Rates versus Age and Environmental Deuterium Exposure
Recorded resting heart rates, Fig. 8, taken from old electrocardiograms recorded prior to age 53 and
recorded vital signs recorded monthly after age 53 show a significant decrease in resting heart rate
(BR) after the low carbohydrate (keto) diet was adopted into the patient’s lifestyle. These data further
support this deuterium depletion hierarchy. Heart rates decreased by approximately 20 bpm with the
initiation of the low carbohydrate diet. The later addition of deuterium depleted water (DDW) at age
57.5 lowered the resting heart rate by 4 bpm. These data clearly show the effect of keto cycling is
more pronounced than the addition of DDW. It is important to point out that no medication changes
were made at the time the keto cycling diet was adopted when these heart rates decreased.
Furthermore, there are also no relationships between the patient’s weight and these corresponding
decreases in pulse. These heart rate data are very important and suggest that changes in heart
contraction strength are significantly changed by the lowering of systemic deuterium levels in the
body. Lower resting heart rates are also observed in above average longevity [21]. Systolic (SBP) and
diastolic (DBP) blood pressures are also indicated in Fig. 8 but no overt relationships are identified
between blood pressure and changes in systemic deuterium.
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Fig. 8. Resting heart rate (HR) and systolic/diastolic blood pressures (SBP/DBP) versus age.
The patient had a resting heart rate between 70 and 90 beats per minute (bpm) prior to
adopting the keto cycling diet. This heart rate dropped to 50 to 68 bpm after the keto cycling
diet was initiated. A 74% ejection fraction (EF) measured with gated SPECT at age 57 indicates
good contractility of the cardiac muscle which is consistent with no significant drop in blood
pressure following the drop in heart rate. The addition of deuterium depleted water (DDW) at
age 57.5 years appears to have lowered the resting pulse by an additional 4 bpm indicating
that the keto diet had the most influence on the resting heart rate. The patient’s weight in kg
are indicated and these show that the decreasing heart rates are not due to changes in weight
since the patient weighed more in the cluster of data beyond age 53 than prior to age 35.
Furthermore, there were no changes in medications near the time the keto cycling diet was
initiated. The data are also color coded according to the level of deuterium in the patient’s
drinking water
Fig. 9. Resting heart rate (HR) averaged over 30 day intervals (red) are compared to the daily
carbohydrate intakes (blue). These data are fit to LOWESS smoothing splines and are shown
as red/blue solid curves. The similarities of the peaks reinforce that food intake do contribute
to the changes seen in the resting heart rates. The ages where the keto cycling diet was
initiated and the deuterium depleted water (DDW) was added to the diet are indicated
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Finally, the resting heart rates can be plotted against the daily carbohydrate data from Fig. 1. The
averaged monthly resting heart rates (red) are compared to the daily carbohydrate consumption (blue)
to reveal some similarity. These data are shown in Fig. 9. These findings again indicate that diet plays
a significant role in the resting heart rates likely due to the efficiency of rapidly producing ATP with
decreasing deuterium [1-3].
3.5 Cellular Energy Production
The deuterium:protium ratio in foods determined with mass spectroscopy at the Center of Deuterium
Depletion are measurably higher in plant storage sugars than fats [7,17]. The center has measured
wheat flour deuterium level at 150 ppm, sucrose (table sugar) at 146 ppm, butter at 124 ppm, and
pork (bacon) at 118 ppm [7,17]. To allow for better visualization on how these different deuterium
levels impact the cellular ATP production inside the mitochondria, the basic equations of cellular
energy metabolism are summarized below where the hydrogens that contain higher levels of
deuterium are bolded, i.e. H, and those with lower levels of deuterium are underlined and italicized,
i.e. H.
Glycolysis (cytoplasm):
C6H12O6 (glucose) + 2 NAD+ + 2 ADP + 2 Pi 2 C3H4O3 (pyruvate) + 2 NADH + 2 H+ + 2 ATP
TCA cycle (mitochondria):
2 C3H4O3 (pyruvate) + 6 O2 6 NADH + 2 FADH2 + 2 ATP + 6 CO2
One cycle of -oxidation of fatty acids (mitochondria):
Cn-acyl-CoA + FAD + NAD+ + H2O + CoA Cn-2-acyl-CoA + FADH2 + NADH + H+ + acetyl-CoA
The deuterium:protium ratio of the hydrogens that drive the ATP synthetase nanomotors are governed
by the ratio of deuterium obtained by the relative contribution of the glycolysis of glucose to the -
oxidation from fatty acids. If the ATP synthetase nanomotors run near 100% efficiency, the total
production 30-32 of ATP per glucose molecule is widely published in biochemistry textbooks.
Oxidative phosphorylation (inner mitochondria membrane):
6 NADH & 2 FADH2 H+ pump along e- transport chain ATP synthase nanomotor
30-32 ADP + 30-32 Pi net gain of 30-32 ATP + 30-32 H2O ,
where ADP = adenosine diphosphate, ATP = adenosine triphosphate, Pi = phosphate, FAD = flavin
adenine dinucleotide, and NAD = nicotinamide adenine dinucleotide.
Finally, it is also useful to point out that the entry of deuterium depleted water into the mitochondria is
likely occurring with the hydrolysis of ATP during various cellular processes as shown.
Hydrolysis of ATP (cellular energy supply):
ATP + H2O ADP + Pi + energy ADP + Pi transported back to mitochondria
The patient’s saliva tested 0.5% to 2.8% above the measured breath deuterium levels strongly
suggesting that the low carbohydrate diet had already decreased the cytoplasm to plasma deuterium
level ratio by the time these deuterium tests were conducted. By the time the patient did any
deuterium testing he had already been on a low carbohydrate intake to two years when the hair
sample was collected and for four full years when the breath/saliva samples were collected. According
to the Center of Deuterium Depletion, saliva deuterium levels typically run between 4.5% to 7.5%
higher than breath deuterium levels in most individuals [17].
An interesting find from the patient’s food logs was a high intake of grass-fed Bison and Elk during the
time his -islet cell function improved eliminating his need for exogenous insulin. The c-peptide used
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in making this assessment were previously reported elsewhere [4]. These meats were obtained from
Elk Marketing Council (https://www.healthyelkmeat.com) who obtained these grass-fed meats from
the Northern Plains of North America. His food logs indicated an average protein intake of 57 grams a
day from these sources between the ages of 53 - 54 years and 58 - 59 years. Between the age of 57
and 58, his food logs revealed a high protein (>50 grams daily) from wild caught Alaska Sockeye
Salmon. The HBa1c’s that correspond to these high intakes of grass-fed Bison and Elk and Alaska
Sockeye Salmon are shown as open symbols in Fig. 7. These are clearly lower than the surrounding
HBa1c values and in the same range as the HBa1c’s recorded after the addition of deuterium-depleted
water to his diet. Furthermore, this grass-fed Bison and Elk were later added back to the diet at age
58.3 years after this connection was uncovered. Since the patient has consumed both deuterium-
depleted water (1.0L of 25ppm daily) along with these grass-fed meats, his HBa1c has dropped to the
lowest value of 5.6% which is the lowest ever recorded for this patient since the diagnosis of DM-II.
4. MATERIALS AND METHODS
4.1 Deuterium Depletion
Once it was realized that deuterium might be playing a significant role in the environmental
contribution to Type-II diabetes, a deuterium depletion case study was designed utilizing the
consumption of deuterium-depleted water (DDW) to lower the patient’s systemic deuterium level while
assessing glycemic control. Deuterium-depleted water was obtained in advance from two sources: 1.
Preventa America (https://www.preventa.us) and 2. ELW (https://ExtraLightWater.com). The
65ppm±5ppm water used in the case report was obtained from the first source while the
25ppm±5ppm water used in the case report was obtained from the second source. Ample supplies
were obtained in advance to avoid any disruptions during the data acquisition. The rated deuterium
levels by these suppliers were also independently confirmed by the Center for Deuterium Depletion
(https://www.ddcenters.com) using mass spectroscopy.
Table 2. Average daily carbohydrate (CHO) consumption, water source deuterium level 2H, and
systemic deuterium 2H (if known) at the time of each glucose tolerance test. The source of
systemic deuterium determination is noted
Age (years)
Diagnosis
Avg Daily CHO
Water Source 2H ‼
Systemic 2H
17.3
Functional hypoglycemia
~ 300 grams
Tap (149.8 ppm)
unknown
51.3
Insulin Dependent DM-II
~ 350 grams
Tap (149.8 ppm)
unknown
55.3
Non-Insulin Dependent
DM-II
120 grams †
Tap (149.8 ppm)
143 ppm (hair)
57.4
Non-Insulin Dependent
DM-II
140 grams
Tap (149.8 ppm) ‡
145.2 ppm (breath)
146.8 ppm (saliva)
57.6
Non-Insulin Dependent
DM-II
140 grams
1.3 L 65ppm DDW
daily x 50 days ‡
130.2 ppm (breath)
130.7 ppm (saliva)
57.9
Non-Insulin Dependent
DM-II
140 grams
1.5 L 25ppm DDW
daily x 50 days ‡
119.9 ppm (breath)
123.4 ppm (saliva)
†, Food logs revealed the patient was eating an average of 57 grams of protein from grass fed Elk and Bison
sources from the Northern Plains. These meats are considered a low deuterium food source [7,8]
‡, These daily DDW intakes were continued for an additional 6 weeks following each glucose tolerance test
during which time the fasting glucose vs sleep correlations were recorded.
‼, The patient is estimated to consume 6.0 L of water daily based on the drop in breath deuterium with the
amount of deuterium-depleted water consumed for each test.
Tap water from all the locations where the patient resided from childhood to adulthood was also
collected and deuterium levels measured by the Center for Deuterium Depletion
(https://www.ddcenters.com) using mass spectroscopy. Furthermore, a hair sample remaining from an
earlier collection for trace mineral analysis at age 55.3 was also analyzed by the Center for Deuterium
Depletion to obtain an additional estimate of the systemic deuterium level at a date two years earlier.
Breath deuterium levels were run on three occasions after the age of 57 just prior to three separate
glucose tolerance tests. A summary of these systemic deuterium levels vs age when glucose
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tolerance tests were made is shown in Table 2. This table also gives the patient’s age, diagnosis,
average daily carbohydrate (CHO) consumption, water source deuterium 2H level, and measured
systemic deuterium 2H level if known.
Deuterium depletion by the consumption of deuterium-depleted water (DDW) was carried out for five
half-lives prior to each glucose tolerance test. Since the half-life 1/2 of deuterium in the human body
was previously determined by Harvard researchers to be 10 days, [22] the steady state deuterium
level was estimated to be reached by 50 days. Following the test, the level of deuterium depletion was
maintained for an additional 6 weeks while the morning fasting glucose readings were recorded
against the total time slept. These data were later used to calculate the rate of glucose production by
the liver as shown in this article.
All glucose tolerance tests were run in the mornings immediately after awakening from sleep while the
patient was resting quietly. The patient was also physically active during the ages of these glucose
tolerance tests with him hiking an average of 19.3 km per week for each test. At the age of 55 and 57
he was also engaged in a 5 hour per week of weight lifting in addition to this hiking. Consistent activity
levels were maintained during these tests to minimize variability in the glucose tolerance tests as a
result of changes in physical activity.
4.2 Skeletal Fat Measurements
A rf current between the feet and hands. The technique is generally considered to be accurate to
within 5% [19]. Readings are also made immediately after awakening when water distribution is more
uniform [19]. Skeletal fat was determined with a full body electronic Omron HBF-514c scale. This
system determines the skeletal fat with a bioelectrical impedance method by applying a 50 kHz 500.
5. CONCLUSIONS
The metabolic effects of deuterium depletion have recently been studied in lung [23], rare childhood
[24], renal cell [25] and colorectal cancers [26]. Human based deuterium depletion studies in Diabetes
Mellitus are very limited with one recent study showing improvement to the glycemic control in 50% of
the subjects; however, the diets in these subjects were not controlled [15]. The current case report
showed systematic improvements in the glucose tolerance response to dextrose challenges with
deuterium depletion in a well-controlled and well characterized DM-II patient. The underlying medical
biochemistry on how deuterium hampers ATP production within the mitochondria promoting the
development of disease are described in detail elsewhere [27,28]. This new field in medicine, called
Deutenomics, has recently expanded to include deuterium metabolic imaging (DMI) of glioblastoma
multiforme brain tumors in rats and humans [29].
As Type II Diabetes Mellitus is a common metabolic disorder affecting millions worldwide, simple,
metabolically well positioned and well tolerated treatments are desired. This disorder is directly
influenced by both genetic and environmental components. This article presents a well-controlled
case that reveals deuterium level as an important factor to the environmental component of glycemic
control. As systemic deuterium levels rise the efficiency of ATPase within the mitochondria matrix
decreases leading to corresponding decreases in insulin production in the -islet cells and changes in
glucose production by the liver. These metabolic changes likely occur in all tissues. Ideally, a double-
blind placebo-controlled trial in a large group of patients could prove useful in confirming these
findings. Finally, it does appear that deuterium depletion does play an important adjunctive role in the
improvement of glycemic control; however, it is not a complete cure since genetics continues to play a
role in these metabolic disorders. Fortunately, this patient is now managing his diabetes with HBa1c in
the normal range.
CONSENT
A written informed consent was obtained from the patient for publication of this report.
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AUTHOR’S CONTRIBUTIONS
Analysis of the deuterium depletion data, ECJ; endocrinology guidance, CLJ. Both authors have read
and agreed to the published version of the manuscript.
FUNDING
There are no financial interests to disclose regarding any aspect of this case report nor was the
research done using Department of Veterans Affairs time or resources.
ACKNOWLEDGEMENTS
Research began on this subject while employed by Vanderbilt University Medical Center and
completed while employed by the Department of Veterans Affairs, and was a privately funded
research separate from these organizations funding and time. The authors thank László Boros, Gábor
Somlyai, Stephen K. Souther, James E. Phelps, David K. Christen, Curtis Sexton, Andrew Sexton,
and Robert Hierholzer for informative discussions.
CONFLICTS OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the
impartiality of the research reported.
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Biography of author(s)
Edwin C. Jones
Department of Veterans Affairs, Knoxville Outpatient Clinic, 8033 Ray Mears Blvd., Knoxville, TN 37919, USA.
Research and Academic Experience:
University of Tennessee- Knoxville, Tennessee Ph.D., Physics, Dec 1992
Research Associate at the Oak Ridge National Laboratory, Oak Ridge, Tennessee, Jan 1993-Aug 1996. Conducted research in
high-temperature superconductivity, cryogenic engineering and fusion energy.
Meharry Medical College- Nashville, Tennessee M.D., May 2000
Vanderbilt University Medical Center-Nashville, Tennessee Completed residency training June 2004.
Private Medical Practice in California 2004-2005
Physician at the Dept of Veteran’s Affairs, 2005-present
Research Area: Investigating the beneficial effects of ketogenic diets and deuterium depletion on the human body. Currently
studying the effect of deuterium on cardiac functioning.
Number of Published papers: 33
Special Award: Thirteen papers in physics ranked as high impact (top 2% of literature citations).
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Medical Research Archives, 9(6): 2-19, 2021.
_____________________________________________________________________________________________________
1Department of Anaesthesia, Critical care and Pain, Homi Bhabha Cancer Hospital and Research Cente, Punjab, India.
2Department of Anaesthesia, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
3Department of Anaesthesia, Government Medical College & Hospital, Chandigarh, India.
*Corresponding author: E-mail: sofiapatial@gmail.com;
Chapter 18
Print ISBN: 978-93-5547-030-0, eBook ISBN: 978-93-5547-052-2
Determination of Tramadol as an Adjuvant to
Ropivacaine in Utrasound Guided Erector Spinae
Plane Block for Postoperative Analgesia after
Sternotomy
Sofia Jaswal1, Rashi Sarna2, Richa Saroa3 and Sanjeev Palta3*
DOI: 10.9734/bpi/rdmmr/v7/4581F
ABSTRACT
The erector spinae plane (ESP) block, which is guided by ultrasound, is beneficial for controlling
postoperative pain in thoracoabdominal procedures. The duration of the block can be extended with
the increasing usage of adjuvants in local anesthetics. In this case we used tramadol as an adjuvant
to ropivacaine for single shot bilateral ultrasound guided ESP block, to provide effective analgesia in a
patient undergoing surgery for resection of anterior mediastinal teratoma through midline sternotomy.
The resection of a mediastinal teratoma in a 21-year-old female patient was planned through a
median sternotomy. She was put under general anaesthesia using standard medications. The patient
was given a bilateral ultrasound guided ESP block with 10 ml of injection ropivacaine 0.2 percent and
50 mg tramadol at T5 level on each side at the end of surgery. For the first 24 hours, visual analogue
scores (VAS) were in the range of 2-3, and for the next 24 hours, they were in the range of 1. For the
first 48 hours after surgery, the patient did not require any analgesics and was pain-free. The use of
an ultrasound-guided ESP block can effectively control severe sternotomy postoperative pain.
Tramadol can also be used as an adjuvant to extend the duration of the block for up to 48 hours.
Keywords: Ultrasound guided; Erector spinae plane (ESP); block Tramadol.
1. INTRODUCTION
For access to anterior mediastinal tissues, a median sternotomy is performed.The sternotomy incision
is linked to significant postoperative pain [1]. Adequate analgesia promotes patient comfort and aids in
the prevention of respiratory problems such as hypoventilation, retained secretions owing to cough
suppression, and infection of the respiratory tract [2]. Various modalities have been used for the
control of postoperative pain in patients undergoing sternotomy including thoracic epidural, thoracic
paravertebral block, erector spinal plane block and patient controlled analgesia (PCA) with
intravenous opioids [3]. Regional blocks are preferred over opioids due to the lack of significant
adverse effects associated with opioid use, such as respiratory depression, sedation, nausea, and
vomiting. Moreover, use of ultrasound in regional blocks have made the procedure simpler, more
accurate and safe for the patient as the drug is being injected under direct visualization [4].
In ultrasound guided erector spinae plane (ESP) block local anesthetic is deposited in the plane
between erector spinae muscle and the transverse processes [5,6]. Bilateral ESP block provides
adequate coverage for the midline incision [7] and it is a feasible and attractive analgesic strategy in
midline sternotomy [8]. It is associated with minimum side effects because the site of injection is away
from the major blood vessels, pleura and neuraxis, and with the application of ultrasound its use may
be considered safe even in the presence of coagulopathy [9].
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Determination of Tramadol as an Adjuvant to Ropivacaine in Utrasound Guided Erector Spinae Plane Block for Postoperative
Analgesia after Sternotomy
164
Various adjuvants have been used with local anaesthetics in different nerve blocks because they
prolong the duration of sensory-motor block due to their synergistic effect. In this patient, we used
tramadol as an adjuvant to ropivacaine for ESP block.
We report the use of tramadol as an adjuvant to ropivacaine for single shot bilateral ultrasound guided
ESP block, to provide effective analgesia in a patient undergoing surgery for resection of anterior
mediastinal teratoma through midline sternotomy. To the best of our knowledge this is the first
reported case where tramadol has been used as an adjuvant to local anaesthetics in ESP block for
midline sternotomy.
2. CASE REPORT
A 21 year old, female patient weighing 36 kg presented to our hospital with the chief complaints of
chronic cough and shortness of breath for 3 years. Cough was non productive initially but for last 6
months, it was productive with scanty whitish sputum with increase in frequency on lying down.
Patient complained of insidious onset, progressively increasing shortness of breath (NYHA III). There
was history of low grade fever on and off with no diurnal variations. Patient had already received two
courses of antitubercular treatment (ATT) before presenting to hospital. There was no history of
trauma, hemoptysis, chest pain, palpitations, loss of weight or loss of appetite. Patient had no other co
morbidities. On examination, heart rate was 90/minute, BP was 102/60 mm Hg and respiratory rate
was 20/minute. On auscultation of chest, bilateral vesicular sounds were present with decreased air
entry in bilateral upper lobes. Rest of the systems were normal on examination. Blood routine
investigations were within normal limits. Chest X-Ray showed right mid-zone opacity. Contrast
enhanced CT scan showed a mediastinal mass along right heart border with fat, fluid and calcification,
suggestive of likely teratoma. In view of scattered air space opacities and nodules, possibility of co-
existing infection was also considered. Carcinoembryonic antigen (CEA) was 3.09 ng/ml (normal
value 0.05-2.5 ng/ml) and alfa fetoprotein (aFP) was within normal limits. Patient was planned for
resection of teratoma through sternotomy. She was kept nil per orally 6 hours before the surgery and
was given premedication with tablet alprazolam 0.25 mg on the night before and morning of surgery.
On the day of surgery, patient was taken to the operation theatre and standard monitors were
attached. Two 16 G cannula were secured and intravenous drip with normal saline was started.
Patient was premedicated with injection midazolam 1 mg i.v. and injection morphine 6mg i.v. Induction
was done with injection propofol 100 mg and vecuronium 4 mg and patient was intubated with 7.5 mm
internal diameter single lumen tube which was fixed at 21 cm. Intraarterial 20 G cannula was inserted
in right radial artery and intraoperative invasive blood pressure monitoring was done. Mechanical
ventilation was started and anaesthesia was maintained with nitrous oxide and Isoflurane. Intravenous
paracetamol 800 mg was given intaoperatively. Patient was hemodynamically stable throughout the
surgery. It was planned to give ultrasound guided ESP block postoperatively before extubation. At the
end of surgery, patient was turned to left lateral position prior to extubation. Under all aseptic
precautions, a high frequency linear probe was kept in longitudinal orientation and transverse process
of T5 vertebra was identified. 23 G spinal needle was introduced in plane under ultrasound guidance
between the transverse process and the erector spinae muscle (Fig. 1). After confirming the needle
placement with hydrodissection, 10 ml of 0.2% ropivacaine with 50 mg tramadol was injected on both
sides after negative aspiration and the spread of the drug was observed (Fig. 2). Patient was
extubated subsequently and shifted to postoperative recovery room. Pain was assessed
postoperatively with the visual analogue score (VAS) at 0, 1, 2, 6, 12, 24 and 48 hours. Injection
paracetamol was prescribed for postoperative pain if VAS>4. VAS was 3 at 0, 1, 2 hour and 2 from 6-
24 hours and 1 after 24 hours. Patient was comfortable, pain free and didn’t demand any analgesic in
postoperative period for first 48 hours.
3. DISCUSSION
In this case report we have used tramadol as an adjuvant to ropivacaine in ESP block for
postoperative pain control in patient undergoing midline sternotomy. ESP block is an effective
modality widely used for postoperative analgesia in midline sternotomy. The needle is directed under
ultrasound guidance into a musculofascial plane just superficial to the transverse processes. The
needle tip remains a significant distance away from the pleura and the risk of pneumothorax is thus
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Determination of Tramadol as an Adjuvant to Ropivacaine in Utrasound Guided Erector Spinae Plane Block for Postoperative
Analgesia after Sternotomy
165
negligible. It is a simpler technique compared to ultrasound-guided paravertebral block as the
transverse process is highly visible and more superficial on ultrasound. In addition there is minimum
risk of clinically significant hemorrhage or hematoma because this site is more compressible [10].
Fig. 1. Ultrasound image showing erector spinae muscle, transverse process of vertebra and
para vertebral space
Fig. 2. Ulrasound image after injection of drug for erector spinae plane block in the plane
between vertebra and erector spinae muscle
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Tramadol as an Adjuvant to Ropivacaine in Utrasound Guided Erector Spinae Plane Block for Postoperative
Analgesia after Sternotomy
166
Tramadol is a weak opioid agonist. It inhibits pain by two modes of action, an opioid action mediated
by µ receptor and a non-opioid action mediated by α2 -adrenergic and serotoninergic activity [11]. It
has monoaminergic activity which inhibits the descending pain pathways, and suppress the
nociceptive transmission at the spinal level. Tramadol blocks K+ channels and also has local
anaesthetic properties [11]. It had been used synergistically to prolong the duration of effect of local
anaesthetics in different blocks. Kapral et al. demonstrated prolonged duration of sensory and motor
block when tramadol 100 mg was added to mepivacaine 1% for axillary plexus block in comparison to
mepivacaine alone [12]. A study by Robauxet al. described that tramadol extends the duration and
improves the quality of postoperative analgesia in a dose-dependent fashion when combined with
mepivacaine 1.5% for brachial plexus block [13].
In this case we used tramadol as an adjuvant to local anaesthetics in ESP block for midline
sternotomy. The analgesia was adequate and patient was comfortable in postoperative period for 48
hours. Further large randomized control studies are advocated to study its effect in ESP block and to
validate the findings of this case report.
4. CONCLUSION
Bilateral ESP block is an easy and safe alternative for postoperative pain management in thoracic
surgeries requiring sternotomy. Tramadol used as an adjuvant to ropivacaine in bilateral ESP block
provides effective, prolonged postoperative analgesia and patient comfort with minimal side effects.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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Biography of author(s)
Sofia Jaswal
Department of Anaesthesia, Critical care and Pain, Homi Bhabha Cancer Hospital and Research Cente, Punjab, India.
Research and Academic Experience:
7 Publications, 1 research project
9 year experience in Anaesthesia, Critical care and Pain
Research Area: Oncoanaesthesia, Critical care
Number of Published papers: 7
Any other remarkable point(s): Special interest in Oncoanaesthesia, Pediatric Anaesthesia and Difficult airway.
Dr. Rashi Sarna
Department of Anaesthesia, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
Research and Academic experience: 6 years
Research Area: Obstetric anesthesia
Number of Publications: 25
Richa Saroa
Department of Anaesthesia, Government Medical College & Hospital, Chandigarh, India.
Research and Academic Experience: 16 years
Research Area: Use of ultrasound in anaesthesia and critical care
Number of Published papers: 50
Recent Developments in Medicine and Medical Research Vol. 7
Determination of Tramadol as an Adjuvant to Ropivacaine in Utrasound Guided Erector Spinae Plane Block for Postoperative
Analgesia after Sternotomy
169
Sanjeev Palta
Department of Anaesthesia, Government Medical College & Hospital, Chandigarh, India.
Research and Academic Experience: 26 years
Research Area: Ultrasound in anesthesia and Clinical care
Number of Published papers: 46
Special awards: Union Territory Chandigarh state award for work in COVID.
_________________________________________________________________________________
© Copyright (2021): Author(s). The licensee is the publisher (B P International).
DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Indian Journal of Clinical Anaesthesia, 7(2): 360–362, 2020.
London Tarakeswar
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