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International sepsis definitions conference. 2001SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference
Abstract
In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.
Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS).
The conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference.
This document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.
... Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, i.e., the host response to the infection causes organ damage/ failure [1,2]. The organ functions are evaluated by the Sequential/sepsis-related Organ Failure Assessment (SOFA) score that is based on scoring respiration, coagulation, liver function, circulation, consciousness, and renal function. ...
... The organ functions are evaluated by the Sequential/sepsis-related Organ Failure Assessment (SOFA) score that is based on scoring respiration, coagulation, liver function, circulation, consciousness, and renal function. Finally, septic shock is observed when the circulatory dysfunctions are severe enough to substantially increase mortality; these patients can be clinically identified by the fact that they require vasopressor therapy and by their increased serum lactate levels despite adequate volume resuscitation [1,2]. Septic shock patients have a hospital mortality exceeding 40%. ...
... The systemic metabolic profiles at the time of hospital admission for patients with bacterial infections and either SIRS or sepsis according to the 2016 criteria [1,2] have recently been characterized [425,426]. These two patient groups differed with regard to the amino acid, lysophosphatidylcholine, and sphingolipid metabolism, but a minor subset of exceptional sepsis patients had a metabolomic profile similar to SIRS patients. ...
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.
... Recently however, due to evidence that qSOFA lacks sensitivity the Surviving Sepsis Campaign guidelines have cautioned against its use as a standalone sepsis screening tool [11]. Other severity scores commonly in use in the United Kingdom, and internationally, include the National Early Warning Score (NEWS & NEWS2) [12,13] and Systemic Inflammatory Response Syndrome (SIRS) criteria [14]. However, the scores differ in their ability to identify patients with infection at high risk of death [15,16]. ...
... Each patient with at least one episode of infection (as defined above) had the following scores calculated: SOFA, qSOFA, NEWS and SIRS (Table 1). NEWS and SIRS scores were calculated as per published tables [12,14]. As SOFA was designed for critical care it was anticipated that there would be a significant number of missing values for the respiratory component which requires an arterial blood gas to calculate the PaO 2 /FiO 2 ratio. ...
... Baseline SOFA score for patients in general wards was assumed to be zero, as per Sepsis-3 1 guidance so a SOFA score of �2 related to infection was considered to be indicative of sepsis, whilst critical care patients required a change in SOFA score of �2, consequent to infection. A cut off score of �2 was applied to qSOFA [1] and SIRS [14]. Performance of NEWS was assessed using both the medium (NEWS �5) and high (NEWS �7) clinical risk thresholds [12]. ...
Background:
Measuring sepsis incidence and associated mortality at scale using administrative data is hampered by variation in diagnostic coding. This study aimed first to compare how well bedside severity scores predict 30-day mortality in hospitalised patients with infection, then to assess the ability of combinations of administrative data items to identify patients with sepsis.
Methods:
This retrospective case note review examined 958 adult hospital admissions between October 2015 and March 2016. Admissions with blood culture sampling were matched 1:1 to admissions without a blood culture. Case note review data were linked to discharge coding and mortality. For patients with infection the performance characteristics of Sequential Organ Failure Assessment (SOFA), National Early Warning System (NEWS), quick SOFA (qSOFA), and Systemic Inflammatory Response Syndrome (SIRS) were calculated for predicting 30-day mortality. Next, the performance characteristics of administrative data (blood cultures and discharge codes) for identifying patients with sepsis, defined as SOFA ≥2 because of infection, were calculated.
Results:
Infection was documented in 630 (65.8%) admissions and 347 (55.1%) patients with infection had sepsis. NEWS (Area Under the Receiver Operating Characteristic, AUROC 0.78 95%CI 0.72-0.83) and SOFA (AUROC 0.77, 95%CI 0.72-0.83), performed similarly well for prediction of 30-day mortality. Having an infection and/or sepsis International Classification of Diseases, Tenth Revision (ICD-10) code (AUROC 0.68, 95%CI 0.64-0.71) performed as well in identifying patients with sepsis as having at least one of: an infection code; sepsis code, or; blood culture (AUROC 0.68, 95%CI 0.65-0.71), Sepsis codes (AUROC 0.53, 95%CI 0.49-0.57) and positive blood cultures (AUROC 0.52, 95%CI 0.49-0.56) performed least well.
Conclusions:
SOFA and NEWS best predicted 30-day mortality in patients with infection. Sepsis ICD-10 codes lack sensitivity. For health systems without suitable electronic health records, blood culture sampling has potential utility as a clinical component of a proxy marker for sepsis surveillance.
... Adult patients admitted with sepsis to the emergency department between December 2012 and 2014 were included. A total of 164 consecutive patients were admitted with clinical sepsis according to the Sepsis-2 criteria (definitions in [16]; more detailed review and discussion [17], but only 80 of them were immunocompetent patients with a later documented bacterial infection where 65% fulfilled the Sepsis-3 criteria and the others only fulfilled the Sepsis-2 criteria [1][2][3]. Patients with viral and parasitic infections, those without proven infections, immunocompromised patients (known congenital or acquired immunodeficiency) as well as patients receiving immunosuppressive/cytotoxic treatment were excluded. ...
... Finally, only four of the patients had a cause of sepsis that needed to be considered for surgical intervention, all other patients were treated in the Department of Medicine or Department of Pulmonary Diseases possibly in collaboration with the Intensive Care Unit. We classified our patients according to the Sepsis-3 [1] and Sepsis-2 definitions [16,17]. All the 60 patients included in the present study fulfilled the Sepsis-2 criteria (i.e., based on the Systemic Inflammatory Response Syndrome, SIRS) whereas only 35 patients fulfilled the Sepsis-3 criteria (i.e., based on Sequential Organ Failure Assessment, SOFA). ...
... Our original study included 80 consecutive patients with bacterial sepsis that fulfilled the criteria of sepsis according to the Sepsis-2 criteria [16,17], and for the present study we included 60 of these patients based on the selection criteria, described in detail in Section 2.1. (see Tables S3 and S4, Figure 1). ...
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In the present study, we investigated the systemic/serum lipidomic profile at the time of hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria (referred to as Sepsis-3) whereas the remaining 25 patients had sepsis only according to the previous Sepsis-2 definition and could be classified as having Systemic Inflammatory Response Syndrome (SIRS). A total of 966 lipid metabolites were identified. Patients fulfilling the Sepsis-3 criteria differed from the Sepsis-2 patients with regard to only 15 lipid metabolites, and especially sphingolipids metabolism differed between these patient subsets. A total of only 43 metabolites differed between patients with and without bacteremia, including 12 lysophosphatidylcholines and 18 triacylglycerols (15 C18/C20 fatty acid metabolites decreased and three C14 myristate acid metabolites that were increased in bacteremia). Unsupervised hierarchical clustering analyses based on the identified sphingolipids, phosphatidylcholine and triacylglycerols showed that (i) the majority of Sepsis-3 patients differed from SIRS patients especially with regard to lysophosphatidylcholine levels; (ii) the minority of Sepsis-3 patients that clustered together with the majority of SIRS patients showed lower Sequential Organ Failure Assessment (SOFA) scores than the other Sepsis-3 patients; and (iii) the variation between the patients in the identified/altered sphingolipid and triacylglycerol metabolites further increased the heterogeneity of Sepsis-3 patients with regard to their systemic lipidomic profile at the time of diagnosis. To conclude, patients fulfilling the Sepsis-3 criteria differ with regard to their metabolic profile, and this variation depends on disease severity.
... Detailed AHRQ criteria according to ICD9 codes are available on the AHRQ website [23]. Full EHR data of patients identified through these criteria were subsequently re-evaluated in depth by a doctor according to Sepsis Criteria before inclusion in the study [24]. Criteria are reported in Supplemental Material File S1. ...
... C-reactive protein was higher in non-survivors than survivors (17 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] vs. 13 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], p = 0.008), while serum lactate levels were similar. The median APACHE II score was higher in non-survivors than in survivors (15 [11][12][13][14][15][16][17] vs. 12 [8][9][10][11][12][13][14][15][16], p < 0.001). ...
Background: Sepsis is one of the major causes of in-hospital death, and is frequent in patients presenting to the emergency department (ED). Early identification of high-risk septic patients is critical. Machine learning (ML) techniques have been proposed for identification and prognostication of ED septic patients, but these models often lack pre-hospital data and lack validation against early sepsis identification scores (such as qSOFA) and scores for critically ill patients (SOFA, APACHE II). Methods We conducted an electronic health record (EHR) study to test whether interpretable and scalable ML models predict mortality in septic ED patients and compared their performance with clinical scores. Consecutive adult septic patients admitted to ED over 18 months were included. We built ML models, ranging from a simple-classifier model, to unbalanced and balanced logistic regression, and random forest, and compared their performance to qSOFA, SOFA, and APACHE II scores. Results: We included 425 sepsis patients after screening 38,500 EHR for sepsis criteria. Overall mortality was 15.2% and peaked in patients coming from retirement homes (38%). Random forest, like balanced (0.811) and unbalanced logistic regression (0.863), identified patients at risk of mortality (0.813). All ML models outperformed qSOFA, APACHE II, and SOFA scores. Age, mean arterial pressure, and serum sodium were major mortality predictors. Conclusions: We confirmed that random forest models outperform previous models, including qSOFA, SOFA, and APACHE II, in identifying septic patients at higher mortality risk, while maintaining good interpretability. Machine learning models may gain further adoption in the future with increasing diffusion and granularity of EHR data, yielding the advantage of increased scalability compared to standard statistical techniques.
... These pathological changes may explain the correlation between the ROX index and mortality in sepsis patients. The difference between plateau points of ROX index might be due to different de nitions of sepsis and changes in the concept of treatment (1,(19)(20)(21). Nevertheless, both studies veri ed that the ROX index could be a reliable and useful tool in the clinical setting to spontaneously identify patients with increased risk. ...
Background: The ROX index (peripheral oxygen saturation / fraction of inspired oxygen to respiratory rate) can help clinicians assessing patients' conditions. The purpose of this study was to evaluate the effects of time-weighted average ROX (ROX-TWA) index on short-term mortality in sepsis patients.
Methods: In this retrospective study, clinical data of patients diagnosed as sepsis was extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database (version 1.4). The septic patients were further categorized by quartiles of their ROX-TWA levels. The associations between ROX-TWA levels and 28-day mortality were assessed using multivariable Cox proportional hazards model and verified by two-piecewise linear regression model.
Main results: By smooth curve fitting, we find that a non-linear relationship between ROX-TWA index and 28-day mortality in sepsis patients, and inflection point was 8. The risk of developing mortality decreased significantly with an increase in ROX-TWA value until plateaued at a level of 8 (HR 0.75 (0.71, 0.80), P<0.001). Moreover. Subgroup analysis showed, a similar relationship between ROX-TWA index and 28-day mortality in patients using or not using mechanical ventilator.
Conclusion: The relationship between ROX-TWA index and 28-day mortality in sepsis patients is non-linear. ROX-TWA index is an independent risk factor of 28-day mortality in sepsis patients when ROX-TWA is less than 8.
... Data was collected for all episodes by a single Infectious Diseases specialist according to a specifically designed protocol and included the following information: admitting ward, demographics, neutropenia (defined as an absolute neutrophil count of < 1000 cells/μL) site of infection, type of acquisition [community-acquired (CA) or hospital-acquired (HA)], severity of underlying diseases [13], exposure to invasive procedures and devices (including vascular or urinary catheter), antimicrobial use in preceding 7 days before BSI; source of infection, aetiology, clinical situation of patient presentation with severe sepsis/septic shock according to classic [14] and Sepsis-3 [15] criteria, empirical antimicrobial treatment, and 30-day mortality. Episodes were classified as HA if they occurred > 48 h after admission, or < 48 h if the patient had been hospitalised in the previous two weeks, otherwise, they were classified as CA. ...
Background
Studies have reported increased incidence of BSI over the past decades and indicate that it is necessary to investigate the causes. The aim of this study was to determine the factors affecting trends in the incidence of bacteraemias and associated mortality.
Methods
We conducted a retrospective cohort study assessing prospectively collected data of all clinically significant bacteraemias between 1991 and 2020 in a 450-bed hospital. We determined the evolution of bacteraemia-associated incidence, adjusted 30-day mortality and performed multivariable logistic regression to compare the evolution of variables associated with mortality between 5-year periods.
Results
6777 episodes were included, 59.7% males, age 66.5 ± 18.2, 39.4% ≥ 75 years. The incidence total increased: 43.8/100,000/year in 1991–1995 to 205 in 2016–2020; community-acquired bacteraemia (24.9 to 139) and hospital-acquired (0.36/1000 inpatients-days to 1.09). Bacteraemia with source in vascular catheter, urinary and biliary tract increased. The 30-day mortality rate of patients was 1179/6777 (17.4%) in the whole series and population-adjusted mortality incidence increased from 11.4/100,000 in 1991–1996 to 28.4 in 2016–2020 (RR 2.49, 95% CI 2.01–3.08). Mortality was higher in men (18.2% vs 16.3%) and those over 74 years (22.2% vs 14.3%). Appropriate empirical antimicrobial treatment improved (66.5% to 73.1%), 30-day mortality of patients decreased from 26.1 to 13.9%. When comparing the evolution of the factors associated with mortality between 1991 and 1996 vs 2016–2020, the frequency of some variables associated with higher mortality increased: male sex (OR 1.38, 95% CI 1.10–1,74), age (OR 1.02, 1.01–10.3), immunosuppressive treatment (OR 3.1, 2.09–4.6), polymicrobial bacteraemia (OR 1.76, 1.12–2.79), and others decreased: severe sepsis/septic shock (OR 0.70, 0.52–0.93), spontaneous bacterial peritonitis in cirrhosis (OR 0.06, 0.02–0.23), endocarditis (OR 0.54, 0.35–0.83); on the other hand, the frequency of factors associated with lower mortality increased: urinary (OR 1.67, 95% CI 1.23–2.27) and bile tract source (OR 1.59, 1.04–2.43), and adequate empirical treatment (OR 1.42, 95% CI 1.10–1.83).
Conclusions
The incidence of bacteraemia increased due to more elderly, co-morbid patients undergoing procedures and more device related bacteraemia. The percentage of mortality decreased because adequate empirical treatment improved, decreased spontaneous bacterial peritonitis in cirrhosis and endocarditis, and increased bacteraemia of urinary and biliary tract source.
... All patients on DOAC required mechanical ventilation (not including anesthesia for aneurysm occlusion) during their hospital stay compared to only 19 (55.9%) patients of matched controls (p = 0.014). The rate of patients suffering from sepsis, according to standing criteria, diagnosed by the presence of infection together with systemic manifestations of infection [30], was higher in patients who had received DOAC-treatment (n = 2 (22.2%) vs. n = 1 (2.9%); p = 0.043). No differences in the need for mechanical ventilation or the development of sepsis were noted between patients previously on VKA and matched controls. ...
Abstract: Objective—Direct oral anticoagulants (DOAC) are replacing vitamin K antagonists (VKA)
for the prevention of ischemic stroke and venous thromboembolism. We set out to assess the effect
of prior treatment with DOAC and VKA in patients with aneurysmal subarachnoid hemorrhage
(SAH). Methods—Consecutive SAH patients treated at two (Aachen, Germany and Helsinki, Finland)
university hospitals were considered for inclusion. To assess the association between anticoagulant
treatments on SAH severity measure by modified Fisher grading (mFisher) and outcome as measured
by the Glasgow outcome scale (GOS, 6 months), DOAC- and VKA-treated patients were compared
against age- and sex-matched SAH controls without anticoagulants. Results—During the inclusion
timeframes, 964 SAH patients were treated in both centers. At the time point of aneurysm rupture,
nine patients (0.93%) were on DOAC treatment, and 15 (1.6%) patients were on VKA. These were
matched to 34 and 55 SAH age- and sex-matched controls, re-spectively. Overall, 55.6% of DOACtreated patients suffered poor-grade (WFNS4–5) SAH compared to 38.2% among their respective
controls (p = 0.35); 53.3% of patients on VKA suffered poor-grade SAH compared to 36.4% in their
respective controls (p = 0.23). Neither treatment with DOAC (aOR 2.70, 95%CI 0.30 to 24.23; p = 0.38),
nor VKA (aOR 2.78, 95%CI 0.63 to 12.23; p = 0.18) were inde-pendently associated with unfavorable
outcome (GOS1–3) after 12 months. Conclusions—Iatrogenic coagulopathy caused by DOAC or
VKA was not associated with more severe radiological or clinical subarachnoid hemorrhage or worse
clinical outcome in hospitalized SAH patients.
... (2) All patients fulfilling the criteria of severe sepsis and septic shock using Goldstein et al. [17] international guidelines. ...
... Hypothermia among septic patients is thought to be caused by the loss of body temperature maintenance functions, and this is more likely to occur in patients with higher disease severity than those with fever. Hypothermia is defined as a temperature below 36°C according to the definition of the Acute Physiology and Chronic Health Evaluation II score, sepsis, or infectionrelated ventilator-associated complications [20,757,758]. Analyses based on sepsis registries in Japan also showed that hypothermia with temperatures below 36°C occurred among more than 10% of patients within 24 h of admission to the ICU, and the mortality rate of patients with hypothermia was high among those with sepsis [750,759]. ...
The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.
As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.
... In the context of sepsis diagnosis, the Systemic Inflammatory Response Syndrome (SIRS) criteria were considered to be central [7]. Recently, the third international consensus definition for sepsis and septic shock (Sepsis-3) was published. ...
In this paper, we devise a novel method involving deep neural networks (DNNs) that improves the early prediction of sepsis for patients admitted to the intensive care units (ICUs). It is assumed that the patient data sets are dramatically corrupted by missing information, which negatively impacts the detection of the onset of sepsis. We propose a generative learning framework to estimate the missing information in data. Our model involves Conditional Generative Adversarial Networks (GANs) utilizing Long Short-Term Memory (LSTM) networks as the generator and discriminator when conditioned on class labels. A deep LSTM network is also employed for prediction purposes. The prediction network is trained with an output of the conditional GAN and evaluated on an unseen test set to investigate the performance of the proposed model. Here, we show that the proposed framework not only identifies long-term temporal dependencies but also exploits the missing patterns. We present the performance results and compare them to other well-known techniques. For the 4-hour, 8-hour, and 12-hour prediction of sepsis, the proposed method attains area under the receiver operating characteristic (AUROC) of 94.49%, 93.74%, and 94.01%, respectively. It is shown here that the improvement in imputation and prediction promises a highly effective method that can offer early detection of sepsis in high-risk patients.
... Studies included classified patients with sepsis according to Sepsis 2 or Sepsis 3 definitions [27,28]. ...
Sepsis is one of the most common and deadly syndromes faced in Intensive Care settings globally. Recent advances in bedside imaging have defined the changes in the microcirculation in sepsis. One of the most advocated interventions for sepsis is fluid therapy. Whether or not fluid bolus affects the microcirculation in sepsis has not been fully addressed in the literature. This systematic review of the evidence aims to collate studies examining the microcirculatory outcomes after a fluid bolus in patients with sepsis. We will assimilate the evidence for using handheld intra vital microscopes to guide fluid resuscitation and the effect of fluid bolus on the sublingual microcirculation in patients with sepsis and septic shock. We conducted a systematic search of Embase, CENTRAL and Medline (PubMed) using combinations of the terms “microcirculation” AND “fluid” OR “fluid resuscitation” OR “fluid bolus” AND “sepsis” OR “septic shock”. We found 3376 potentially relevant studies. Fifteen studies published between 2007 and 2021 fulfilled eligibility criteria to be included in analysis. The total number of participants was 813; we included six randomized controlled trials and nine non-randomized, prospective observational studies. Ninety percent used Sidestream Dark Field microscopy to examine the microcirculation and 50% used Hydroxyethyl Starch as their resuscitation fluid. There were no clear effects of fluid on the microcirculation parameters. There was too much heterogeneity between studies and methodology to perform meta-analysis. Studies identified heterogeneity of affect in the sepsis population, which could mean that current clinical classifications were not able to identify different microcirculation characteristics. Use of microcirculation as a clinical endpoint in sepsis could help to define sepsis phenotypes. More research into the effects of different resuscitation fluids on the microcirculation is needed.
... Sepsis is a systemic inflammatory response to infection (Levy et al., 2003). Septic shock results from a cytokine storm and an inflammatory cascade leading to cardiac dysfunction and microvascular damage, followed by hypotension, shock, and life-threatening circulatory failure (Schulte et al., 2013). ...
The massive release of pro-inflammatory cytokines is a crucial step in triggering the inflammatory cascade in sepsis. Exploring the key molecules regulating the expression and release of multiple cytokines has important value for revealing the mechanism of the cytokine storm in sepsis. This study aimed to investigate the role of multifunctional nuclear protein non-POU domain containing octamer-binding protein (NONO) in the sepsis cytokine storm and to elucidate the underlying mechanism. We found that NONO expression in tissues and cells of sepsis mice was significantly upregulated. Downregulation of NONO expression inhibited the mRNA expression of multiple cytokines, including IL-6, IL-1β, MCP-1, MIP-1α, and MIP-1β in inflammatory cells from mice and human leukemic monocyte-THP1 cells challenged with lipopolysaccharide (LPS), and significantly decreased the level of these cytokines and TNF-α in the supernatant of THP1 cells challenged by LPS. Nono knockout also reduced the levels of TNF-α, IL-6, MIP-1α, and MIP-1β in serum, alleviated hepatocyte edema, and improved the survival rate of sepsis mice. Reduced NONO expression decreased the phospho-ERK1/2 level in inflammatory cells from sepsis mice or THP1 cells challenged by LPS. Phospho-ERK1/2 inhibitor decreased the mRNA expression and concentration of cytokines in the culture supernatant of LPS-induced THP1 cells, similar to the effect of NONO knockdown. After LPS challenge, the levels of phospho-ERK1/2 and NONO were increased, with obvious colocalization in the nucleus and vesicular-like organelles in macrophages. NONO knockdown decreased nuclear translocation of phospho-ERK1/2 in LPS-challenged THP1 cells. These results suggest that NONO is a potentially critical molecule involved in multiple cytokine production in sepsis. Upregulated NONO in sepsis may promote the expression and release of multiple cytokines to participate in a sepsis cytokine storm by promoting ERK1/2 phosphorylation.
... According to previous research, H-ferritin operates as an immune modulator with both pro-inflammatory and immunosuppressive activities. Increased ferritin levels may signal a severe inflammatory reaction in response to viral entrance into the human body and its influence on iron metabolism [10]. Eloseily et al. [11] have reported that an increased ferritin measurement (e.g., >700 ng/mL) should alert clinicians to conduct further diagnostic work-up so that treatment methods can be addressed without delay. ...
Background:
Acute respiratory failure develops quickly in patients with a severe form of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome Coronavirus 2 (SARS‑CoV‑2). Despite being commonly acknowledged as a measure of the body's overall iron storage, ferritin's predictive value is associated with COVID-19.
Objective:
This study aimed to evaluate the relationship between COVID-19 and serum ferritin levels as the biochemical markers of SARS-CoV-2 infection in Sulaymaniyah, Iraq.
Method:
A biochemical test was performed at Baxshin Hospital in the period from February 2022 to April 2022. It was performed on a total of 85 patients (63.53% males and 36.47% females), ranging in age from 25 to 79 years old, with an average age of 48.4 years old. The patient's blood samples were taken to screen for ferritin levels.
Result:
The resulting outcome of this work is high serum ferritin levels for the majority of infected patients. Overall, there is a significant difference between male and female serum ferritin observed with a p-value < 0.05. The median interquartile range (IQR) of serum ferritin was 896 ng/mL for males, while it was only 611 ng/mL for females. The current study showed that age level has a great effect on elevated ferritin levels. It has been discovered that gender impacts increasing ferritin levels; 62% were found to be men and 38% were found to be women, with average ferritin levels of 1111 ng/mL and 712.8 ng/mL, respectively.
Conclusion:
SARS-CoV-2 infection causes significant laboratory abnormalities, including a high level of serum ferritin.
Background:
Few sepsis biomarkers accurately predict severity and mortality. Previously, we had reported that first-day histidine-rich glycoprotein (HRG) levels were significantly lower in patients with sepsis and were associated with mortality. Since the time trends of HRG are unknown, this study focused on the time course of HRG in patients with sepsis and evaluated the differences between survivors and non-survivors.
Methods:
A multicenter prospective observational study was conducted involving 200 patients with sepsis in 16 Japanese hospitals. Blood samples were collected on days 1, 3, 5, and 7, and 28-day mortality was used for survival analysis. Plasma HRG levels were determined using a modified quantitative sandwich enzyme-linked immunosorbent assay.
Results:
First-day HRG levels in non-survivors were significantly lower than those in survivors (mean, 15.7 [95% confidence interval (CI), 13.4-18.1] vs 20.7 [19.5-21.9] μg/mL; P = 0.006). Although there was no time × survivors/non-survivors interaction in the time courses of HRG (P = 0.34), the main effect of generalized linear mixed models was significant (P < 0.001). In a univariate Cox proportional hazards model with each variable as a time-dependent covariate, higher HRG levels were significantly associated with a lower risk of mortality (hazard ratio, 0.85 [95% CI, 0.78-0.92]; P < 0.001). Furthermore, presepsin levels (P = 0.02) and Sequential Organ Function Assessment scores (P < 0.001) were significantly associated with mortality. Harrell's C-index values for the 28-day mortality effect of HRG, presepsin, procalcitonin, and C-reactive protein were 0.72, 0.70, 0.63, and 0.59, respectively.
Conclusions:
HRG levels in non-survivors were consistently lower than those in survivors during the first seven days of sepsis. Repeatedly measured HRG levels were significantly associated with mortality. Furthermore, the predictive power of HRG for mortality may be superior to that of other singular biomarkers, including presepsin, procalcitonin, and C-reactive protein.
Background:
Postpancreatectomy acute pancreatitis is challenging to diagnose and poorly characterized in its early phases. However, it represents the ideal target for novel therapeutic opportunities possibly gleaned from medical acute pancreatitis. This study aims to systematically investigate early radiologic, biochemical, and clinical features of postpancreatectomy acute pancreatitis.
Methods:
This was a prospective observational study of patients undergoing pancreatoduodenectomy from September 2019 to January 2021. Diffusion-weighted magnetic resonance imaging was performed on postoperative day 3. Serum pancreatic amylase and lipase were assessed daily until postoperative day 5. Postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis were defined based on the International Study Group for Pancreatic Surgery definition.
Results:
A total of 65 patients were enrolled according to the sample size calculation. Patients with postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis had significantly lower apparent diffusion coefficient values at diffusion-weighted magnetic resonance imaging but no macroscopic features consistent with acute pancreatitis. Subsequently, 21 patients (32.3%) underwent computed tomography imaging for clinical worsening, and 6 had radiologic features of acute pancreatitis. All these latter patients had postoperative serum hyperamylasemia and worse outcomes, characterized by local (postoperative pancreatic fistula: 83%) and systemic morbidity (sepsis: 66.7%). The postoperative serum hyperamylasemia incidence was 21.5% (n = 14), and postpancreatectomy acute pancreatitis occurred in 6 patients (9.2%), with 4 grade B (6.1%) and 2 grade C (3%).
Conclusion:
Postpancreatectomy acute pancreatitis is characterized by early serum hyperamylasemia and hyperlipasemia. Although pancreatic changes may appear at postoperative day 3 diffusion-weighted magnetic resonance imaging, its standard use has no impact on postoperative management. Macroscopic radiologic features appear later and correlate with worse clinical scenarios. This paper paves the ground for including postpancreatectomy acute pancreatitis in the spectrum of acute pancreatitis, promoting the transfer of treatment strategies for acute pancreatitis into managing postpancreatectomy acute pancreatitis.
The acute innate immune response to infection and tissue trauma is affected and regulated through the release of a large number of inducible proteins known as cytokines. Normally present in the circulation at very low levels, cytokine expression and release are induced in response to danger signals detected by pattern recognition receptors on innate immune cells. The dynamic nature of the cytokine response and the ease with which it can be shown to impact survival in animal models of acute inflammation have made these mediators attractive candidates for the targeted therapy of sepsis. The results of their manipulation in critical illness have been disappointing, though many have emerged as promising treatments for chronic inflammatory disorders such as rheumatoid arthritis. This chapter reviews the biology of the cytokine response and its potential as a therapeutic target. Building on insights derived from studies of cytokine manipulation in COVID-19, it discusses the reasons for an apparent lack of efficacy in sepsis and identifies priorities to overcome these.
The objective of this study was to develop and compare the performance of nomogram model and machine learning models for predicting the possibility of systemic inflammatory response syndrome (SIRS) following percutaneous nephrolithotomy (PCNL). We retrospectively reviewed the clinical data of 337 patients who received PCNL between May 2020 and June 2022. Eighty percent of the data were used as the training set, and the remaining data were used as the testing set. The nomogram and machine learning (ML) models were created using the training set and were validated using the testing set. Based on the areas under the receiver operating characteristic curve (AUC) and the calibration curve, we evaluated the predictive ability of the nomogram. The predictive performance of six machine learning models was determined by the AUC and accuracy. Multivariate logistic regression analysis revealed four independent risk factors associated with SIRS, including preoperative monocyte, serum fibrinogen, serum prealbumin, and preoperative SII. The above independent related factors were used as variables to construct the nomogram model. Among the six machine learning algorithms, the support vector machine (SVM) delivered the best performance with accuracy of 0.926, AUC of 0.952 [95% Confidence Interval (CI): 0.906–0.999], while the nomogram showed an AUC of 0.818. Compared with the nomogram model, the SVM model can provide more reliable prognostic information about the possibility of SIRS after PCNL, which can assist surgeons in clinical decision-making.
Objectives:
Standard once-daily dosing of ceftriaxone may not lead to adequate antibiotic exposure in all cases of Staphylococcus aureus bacteraemia (SAB). Therefore, we compared clinical effectiveness of empirical antibiotic treatment with flucloxacillin, cefuroxime and ceftriaxone in adult patients with MSSA bacteraemia.
Methods:
We analysed data from the Improved Diagnostic Strategies in Staphylococcus aureus bacteraemia (IDISA) study, a multicentre prospective cohort study of adult patients with MSSA bacteraemia. Duration of bacteraemia and 30 day SAB-related mortality were compared between the three groups using multivariable mixed-effects Cox regression analyses.
Results:
In total, 268 patients with MSSA bacteraemia were included in the analyses. Median duration of empirical antibiotic therapy was 3 (IQR 2-3) days in the total study population. Median duration of bacteraemia was 1.0 (IQR 1.0-3.0) day in the flucloxacillin, cefuroxime and ceftriaxone groups. In multivariable analyses, neither ceftriaxone nor cefuroxime was associated with increased duration of bacteraemia compared with flucloxacillin (HR 1.08, 95% CI 0.73-1.60 and HR 1.22, 95% CI 0.88-1.71). In multivariable analysis, neither cefuroxime nor ceftriaxone was associated with higher 30 day SAB-related mortality compared with flucloxacillin [subdistribution HR (sHR) 1.37, 95% CI 0.42-4.52 and sHR 1.93, 95% CI 0.67-5.60].
Conclusions:
In this study, we could not demonstrate a difference in duration of bacteraemia and 30 day SAB-related mortality between patients with SAB empirically treated with flucloxacillin, cefuroxime or ceftriaxone. Since sample size was limited, it is possible the study was underpowered to find a clinically relevant effect.
As the prevalence of heart failure (HF) continues to rise, prompt diagnosis and management of various medical conditions, which may lead to HF exacerbation and result in poor patient outcomes, are of paramount importance. Infection has been identified as a common, though under-recognized, precipitating factor of acute heart failure (AHF), which can cause rapid development or deterioration of HF signs and symptoms. Available evidence indicates that infection-related hospitalizations of patients with AHF are associated with higher mortality, protracted length of stay, and increased readmission rates. Understanding the intricate interaction of both clinical entities may provide further therapeutic strategies to prevent the occurrence of cardiac complications and improve prognosis of patients with AHF triggered by infection. The purpose of this review is to investigate the incidence of infection as a causative factor in AHF, explore its prognostic implications, elucidate the underlying pathophysiological mechanisms, and highlight the basic principles of the initial diagnostic and therapeutic interventions in the emergency department.
Purpose of review:
Prostate biopsy is commonly performed in men suspected to have prostate cancer. It has traditionally been performed using a transrectal approach, but transperineal prostate biopsy has been increasingly adopted in part because of its lower associated infectious risk. We review recent studies evaluating the rate of potentially life-threatening post-biopsy sepsis and potential preventive strategies.
Recent findings:
After performing a comprehensive literature search, 926 records were screened and 17 studies published in 2021 or 2022 were found to be relevant. Studies varied in periprocedural perineal and transrectal preparation, antibiotic prophylaxis, and definition of sepsis. The sepsis rates after transperineal ultrasound-guided versus transrectal ultrasound-guided biopsy ranged between 0 and 1 versus 0.4 and 9.8%. Mixed efficacy was found for the topical application of antiseptics before transrectal biopsy to decrease postprocedural sepsis. Promising strategies include the use of topical rectal antiseptics before transrectal prostate biopsy and using a rectal swab to guide the antibiotic selection and the route of the biopsy.
Summary:
The transperineal approach to biopsy is increasingly used because of lower associated sepsis rates. Our review of the recent literature supports this practice pattern change. Hence, transperineal biopsy should be offered as an option to all men.
The management of sepsis in patients with pulmonary hypertension (PH) is challenging due to significant conflicting goals of management and complex hemodynamics. As PH progresses, the ability of right heart to perfuse lungs at a normal central venous pressure (CVP) is impaired. Elevated pulmonary vascular pressure, due to pulmonary vasoconstriction and vascular remodeling, opposes blood flow through lungs thus limiting the ability of right ventricle (RV) to increase cardiac output (CO) and maintain adequate oxygen delivery to tissue. In sepsis without PH, avoidance of volume depletion with intravascular volume replacement, followed by vasopressor therapy if hypoperfusion persists, remains the cornerstone of therapy. Intravenous fluid (IVF) resuscitation based on individualized hemodynamic assessment can help improve the prognosis of critically ill patients. This is accomplished by optimizing CO by maintaining adequate preload, afterload and contractility. Particular challenges in patients with PH include RV failure as a result of pressure and volume overload, gas exchange abnormalities, and managing IVF and diuretic use. Suggested approaches to remedy these difficulties include early recognition of symptoms associated with pressure and volume overload, intravascular volume management strategies and serial lab monitoring to assess electrolytes and renal function.
Objective:
To evaluate the use of a modified Sepsis-3 (mSepsis-3) definition compared to the currently used modified Sepsis-2 (mSepsis-2) definition to determine whether the mSepsis-2 or mSepsis-3 stratifications were able to identify populations of dogs ultimately more likely to die from canine parvovirus (CPV) infection.
Design:
Retrospective, January 2009 to March 2020.
Setting:
A private, small animal, urban, referral emergency and specialty hospital.
Animals:
Fifty-nine client-owned dogs hospitalized for treatment of CPV.
Interventions:
None.
Measurements and main results:
Dogs were divided into mSepsis-2 and mSepsis-3 categories based on the highest level of illness severity reached during hospitalization. Greater illness severity based on mSepsis-2 criteria (ie, sepsis, severe sepsis, septic shock) was associated with an increase in average length of stay (P < 0.001), increase in average cost of stay (P < 0.01), and presence of leukopenia (P < 0.05). An increase in illness severity within the mSepsis-2 criteria was not associated with hyperlactatemia (P = 0.29), presence of neutropenia (P = 0.12), or mortality (P = 0.35). Greater illness severity based on mSepsis-3 criteria (ie, infection only, sepsis, septic shock) was associated with an increase in mortality (P < 0.05), increase in average length of stay (P < 0.001), increase in average cost of stay (P < 0.01), presence of leukopenia (P < 0.01), and presence of neutropenia (P < 0.05). The mSepsis-3 criteria were not associated with the presence of hyperlactatemia (P = 0.68). There was no significant difference between survivors and nonsurvivors in the presence of leukopenia (P = 0.19), neutropenia (P = 0.67), or hyperlactatemia (P = 0.58).
Conclusions:
The mSepsis-3 diagnostic criteria appear to better identify dogs with CPV at higher risk for mortality compared to the mSepsis-2 criteria.
Background
Guidelines emphasize rapid antibiotic treatment for sepsis, but infection presence is often uncertain at initial presentation. We investigated the incidence and drivers of false-positive presumptive infection diagnosis among emergency department (ED) patients meeting Sepsis-3 criteria.
Methods
For a retrospective cohort of patients hospitalized after meeting Sepsis-3 criteria (acute organ failure and suspected infection including blood cultures drawn and intravenous antimicrobials administered) in one of 4 EDs from 2013 to 2017, trained reviewers first identified the ED-diagnosed source of infection and adjudicated the presence and source of infection on final assessment. Reviewers subsequently adjudicated final infection probability for a randomly selected 10% subset of subjects. Risk factors for false-positive infection diagnosis and its association with 30-day mortality were evaluated using multivariable regression.
Results
Of 8,267 patients meeting Sepsis-3 criteria in the ED, 699 (8.5%) did not have an infection on final adjudication, and 1,488 (18.0%) patients with confirmed infections had a different source of infection diagnosed in the ED versus final adjudication (i.e., initial/final source diagnosis discordance). Among the subset of patients whose final infection probability was adjudicated (n=812), 79 (9.7%) had only “possible” infection and 77 (9.5%) were not infected. Factors associated with false-positive infection diagnosis included hypothermia, altered mental status, comorbidity burden, and an “unknown infection source” diagnosis in the ED (OR 6.39, 95% CI 5.14-7.94). False-positive infection diagnosis was not associated with 30-day mortality.
Conclusions
In this large multihospital study, <20% of ED patients meeting Sepsis-3 criteria had no infection or only possible infection on retrospective adjudication.
Background
Sepsis is characterized by a dysregulated immune response to infection. The complement system plays an important role in the host defence to pathogens. However, exaggerated complement activation might contribute to a hyperinflammatory state. The interplay between complement activation and inflammation in relationship with adverse outcomes in sepsis patients is unclear.
Methods
Secondary analysis of complement factors in a prospective study in 209 hospitalized sepsis patients, of whom the majority presented with shock. Concentrations of complement factors C3, C3a, C3c, C5, C5a, and soluble terminal complement complex were assessed in ethylenediaminetetraacetic acid plasma samples collected within 24 h after sepsis diagnosis using enzyme-linked immunosorbent assays.
Results
The concentration of complement factors in plasma of severely ill sepsis patients indicated profound activation of the complement system (all P < 0.01 compared to healthy controls). Spearman rank correlation tests indicated consistent relationships between the different complement factors measured, but no significant correlations were observed between the complement factors and other inflammatory biomarkers such as leukocyte numbers, C-reactive protein and ferritin concentrations, or HLA-DR expression on monocytes. The concentration of complement factors was not associated with Sequential Organ Failure Assessment score, the incidence of septic shock, and mortality rates (all P > 0.05) in this cohort of patients with high disease severity.
Conclusions
Once an infection progresses to severe sepsis or septic shock, the complement pathway is already profoundly activated and is no longer related to a dysregulated inflammatory response, nor to clinical outcome. This implies that in this patient category with severe disease, the complement system is activated to such an extent that it no longer has predictive value for clinical outcome.
Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.
The International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for disseminated intravascular coagulation (DIC) are widely used for DIC diagnosis. However, the prognostic value of the score may vary between different patient populations and settings. This systematic review investigated the association between the ISTH DIC score and mortality in sepsis patients. A literature search was conducted in PubMed and Embase. Inclusion criteria were studies including adult and pediatric patients hospitalized with sepsis, using any sepsis definition, and investigating the association between mortality and the ISTH DIC score. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 42 studies were included. A positive association between the ISTH DIC score and mortality was consistently reported, with odds ratios of death in DIC versus non-DIC patients ranging from 1.125 (95% confidence interval [CI]: 0.838–1.511) to 21.008 (95% CI: 1.408–313.405) in adults and from 1.378 (95% CI: 1.004–1.893) to 2.99 (95% CI: 0.54–16.6) in pediatric populations. However, the DIC score only had a low-moderate positive predictive value for mortality, as area under receiver-operator characteristics ranged from 0.602 (95% CI: 0.575–0.630) to 0.815 (95% CI: 0.676–0.954) in adults. Of note, only few studies adjusted for potential confounders such as age, gender, and comorbidity. The ISTH DIC score is consistently associated with sepsis-related mortality but is not a strong positive predictor for mortality. Nevertheless, the score may still have a prognostic value and its use in sepsis is encouraged.
How to cite this article: Kannan A, Jindal A. Predisposition, Insult, Response, and Organ Dysfunction: A Well-constructed Score! Indian J Crit Care Med 2023;27(2):150.
Sepsis is a dysregulated host response to infection that causes potentially life-threatening organ dysfunction. We investigated the serum metabolomic profile at hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria whereas the remaining 25 patients only fulfilled the previous Sepsis-2 criteria and could therefore be classified as having systemic inflammatory response syndrome (SIRS). A total of 1011 identified metabolites were detected in our serum samples. Ninety-seven metabolites differed significantly when comparing Sepsis-3 and Sepsis-2/SIRS patients; 40 of these metabolites constituted a heterogeneous group of amino acid metabolites/peptides. When comparing patients with and without bacteremia, we identified 51 metabolites that differed significantly, including 16 lipid metabolites and 11 amino acid metabolites. Furthermore, 42 metabolites showed a highly significant association with the maximal total Sequential Organ Failure Assessment (SOFA )score during the course of the disease (i.e., Pearson’s correlation test, p-value < 0.005, and correlation factor > 0.6); these top-ranked metabolites included 23 amino acid metabolites and a subset of pregnenolone/progestin metabolites. Unsupervised hierarchical clustering analyses based on all 42 top-ranked SOFA correlated metabolites or the subset of 23 top-ranked amino acid metabolites showed that most Sepsis-3 patients differed from Sepsis-2/SIRS patients in their systemic metabolic profile at the time of hospital admission. However, a minority of Sepsis-3 patients showed similarities with the Sepsis-2/SIRS metabolic profile even though several of them showed a high total SOFA score. To conclude, Sepsis-3 patients are heterogeneous with regard to their metabolic profile at the time of hospitalization.
PurposeTo evaluate the impact of an optimal and reproducible cutoff value set according to a predefined lymphopenia scale as an early predictor of in-hospital mortality and other outcomes in patients hospitalized with pneumococcal pneumonia and positive urinary antigen at admission to the emergency department.Methods
An observational cohort study was conducted based on analysis of a prospective registry of consecutive immunocompetent adults hospitalized for pneumococcal pneumonia in two tertiary hospitals. Generalized additive models were constructed to assess the smooth relationship between in-hospital mortality and lymphopenia.ResultsWe included 1173 patients. Lymphopenia on admission was documented in 686 (58.4%). No significant differences were observed between groups regarding the presence of comorbidities. Overall, 299 (25.5%) patients were admitted to intensive care and 90 (7.6%) required invasive mechanical ventilation. Fifty-nine (5%) patients died, among them 23 (38.9%) in the first 72 h after admission. A lymphocyte count < 500/μL, documented in 282 (24%) patients, was the predefined cutoff point that best predicted in-hospital mortality. After adjustment, these patients had higher rates of intensive care admission (OR 2.9; 95% CI 1.9–4.3), invasive mechanical ventilation (OR 2.2; 95% CI 1.2–3.9), septic shock (OR 1.8; 95% CI 1.1–2.9), treatment failure (OR 2.1; 95% CI 1.2–3.5), and in-hospital mortality (OR 2.2; 95% 1.1–4.9). Severe lymphopenia outperformed PSI score in predicting early and 30-day mortality in patients classified in the higher-risk classes.Conclusion
Lymphocyte count < 500/μL could be used as a reproducible predictor of complicated clinical course in patients with an early diagnosis of pneumococcal pneumonia.
Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation. Metabolites are generally viewed as intermediates or products of metabolism. However, many metabolites are also signalling molecules that regulate metabolic reactions and other processes in development, homeostasis and disease. As such, metabolites can confer adaptive responses to environmental changes.
Background:
The endothelial glycocalyx layer (EGL) is a complex meshwork of glycosaminoglycans and proteoglycans that protect the vascular endothelium. Cleavage or shedding of EGL-specific biomarkers, such as hyaluronic acid (HA) and syndecan-1 (SDC-1, CD138) in plasma, have been shown to be associated with poor clinical outcomes. However, it is unclear whether levels of circulating EGL biomarkers are representative of the EGL injury within the tissues. The objective of the present feasibility study was to describe a pathway for plasma and tissue procurement to quantify EGL components in a cohort of surgical patients with intra-abdominal sepsis. We sought to compare differences between tissue and plasma EGL biomarkers and to determine whether EGL shedding within the circulation and/or tissues correlated with clinical outcomes.
Methods:
This was a prospective, observational, single-center feasibility study of adult patients (N = 15) with intra-abdominal sepsis, conducted under an approved IRB. Blood and resected tissue (pathologic specimen & unaffected peritoneum) samples were collected from consented subjects at the time of operation and 24-48 hours post-surgery. EGL biomarkers (i.e., HA and SDC-1) were quantified in both tissue and plasma samples using a CD138 stain and ELISA kit, respectively. Pairwise comparisons were made between plasma and tissue levels. In addition, we tested the relationships between measured EGL biomarkers and clinical status and patient outcomes.
Results:
Fifteen patients with intra-abdominal sepsis were enrolled in the study. Elevations in EGL-specific circulating biomarkers (HA, SDC-1) were positively correlated with post-operative SOFA scores and weakly associated with resuscitative volumes at 24 hours. Syndecan-1 levels from resected pathologic tissue significantly correlated with SOFA scores at all time points (R = 0.69 and p-value<0.0001) and positively correlated with resuscitation volumes at 24 hours (R = 0.41 and p-value = 0.15 for t = 24 h). Tissue and circulating HA and SDC-1 positively correlated with SOFA >6.
Conclusions:
Elevations in both circulating and tissue EGL biomarkers were positively correlated with post-operative SOFA scores at 24 hours, with resected pathologic tissue EGL levels displaying significant correlations with SOFA scores at all time points. Tissue and circulating EGL biomarkers were positively correlated at higher SOFA scores (SOFA>6) and could be used as indicators of resuscitative needs within 24 hrs of surgery. The present study demonstrates the feasibility of tissue and plasma procurement in the operating room, though larger studies are needed to evaluate the predictive value of these EGL biomarkers for patients with intra-abdominal sepsis.
ObjectivesC-reactive protein (CRP) is an established marker for systemic inflammation in dogs that is especially elevated in dogs with sepsis. Some dogs with acute hemorrhagic diarrhea syndrome (AHDS) develop bacterial translocation and consequent sepsis during hospitalization. This study aimed to evaluate the course of CRP plasma concentrations during hospitalization and its correlation with clinical and other laboratory variables in dogs with AHDS.Methods
In this prospective, observational study, CRP was evaluated on days 0, 1, 2, and 3 in 27 client-owned dogs who presented with AHDS. Clinical examination data, blood pressure, acute patient physiologic and laboratory evaluation (APPLE) full and APPLE fast scores, and canine hemorrhagic diarrhea severity (CHDS) index were measured on the same days to evaluate the severity of the disease.ResultsTwenty-five of the 27 dogs were discharged from hospital. Nineteen dogs received antimicrobial treatment due to sepsis or neutropenia. CRP values were mildly elevated on day 0 (median 27.3 mg/L; 1.0–125.8 mg/L) and markedly elevated on day 1 (median 88.9 mg/L; 1.4–192.7 mg/L). CRP concentrations decreased gradually over the following days. Moreover, CRP concentrations correlated moderately with albumin, leucocyte count, neutrophil count, and APPLE full and fast scores, but not with antimicrobial treatment.Conclusion and relevanceCRP concentrations were significantly elevated in patients with AHDS. In this study population, CRP did not help in detecting the requirement of antimicrobial treatment in dogs with AHDS. Nevertheless, as CRP can monitor the response to treatment, regular analysis can guide treatment.
Up to now, sepsis is one of the most threatening diseases and its therapy remains challenging. Sepsis is currently defined as a severely dysregulated immune response to an infection resulting in organ dysfunction. The pathophysiology is mainly driven by exogenous PAMPs ("pathogen-associated molecular patterns") and endogenous DAMPs ("damage-associated molecular patterns"), which can activate PRRs ("pattern recognition receptors") on different cell types (mainly immune cells), leading to the initiation of manifold downstream pathways and a perpetuation of patients' immune response. Sepsis is neither an exclusive pro- nor an anti-inflammatory disease: both processes take place in parallel, resulting in an individual immunologic disease state depending on the severity of each component at different time points. Septic shock is a complex disorder of the macro- and microcirculation, provoking a severe lack of oxygenation further aggravating sepsis defining organ dysfunctions. An in-depth knowledge of the heterogeneity and the time-dependency of the septic immunopathology will be essential for the design of future sepsis trials and therapy planning in patients with sepsis. The big aim is to achieve a more individualized treatment strategy in patients suffering from sepsis or septic shock.
Cardiopulmonary bypass has been established as the gold standard technique for performing certain heart, aorta or lung surgeries. First, the purpose of using extracorporeal circulation is to maintain blood circulation and to provide tissue perfusion throughout the body intraoperatively. Cardiac and/or pulmonary functions should be shut down during life-saving surgical interventions to obtain a bloodless surgical area and movement less target organs. Second, body temperature must be sustained normally, hypo- or deep hypothermic during surgical procedures, mainly to protect the cerebrum and collectively the whole body from any temporary, permanent, or fatal ischemic and reperfusion damage. Finally, adequate and aggressive immunoregulation must be maintained to prevent severe cytokine storm due to the foreign structure of the cardiopulmonary bypass circuit and infectious invasion through all invasive cannulations and intravenous treatments, as well as surgical wounds. Understanding the immunological changes associated with cardiopulmonary bypass and recognizing the factors that increase the risk of postoperative infection can help physicians develop strategies to prevent infections and sepsis. Although the benefits versus risks have not been established, it is also common practice to extend “prophylaxis” for 48 hours after open-heart surgery. Antimicrobial prophylaxis is particularly beneficial in cardiac surgery to prevent serious superficial or potentially life-threatening deep wound infections, such as mediastinitis, and it must also account for altered pharmacokinetics with cardiopulmonary bypass. This chapter focuses on infection propensity, strategies to reduce perioperative risks and preventive approaches, while elimination of microbial colonization should be the main strategy to avoid postoperative nosocomial infections.
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are both associated with significant morbidity and mortality in daily clinical practice, as well as in a critical care setting. It is unclear whether colistin susceptible-only Acinetobacter baumannii (CSO AB) is a unique phenotype separate from or a subset of CRAB-associated pneumonia. The aim of this study is to investigate the prevalence of CSO AB pneumonia and compare the presentation and outcome between CSO AB and CRAB-associated pneumonia in critically ill patients. This multicenter retrospective cohort study initially recruited 955 patients with CR-GNB pneumonia. After exclusion, 575 patients left who were ICU-admitted and had CRAB nosocomial pneumonia remained. Among them, 79 patients had CSO AB pneumonia, classified as the CSO AB group. The other 496 patients were classified as the CRAB group. We compared demographic characteristics, disease severity, and treatment outcomes between the two groups. The prevalence of CSO AB among all cases of CRAB pneumonia was 13.74% (79/575). The CSO AB and CRAB groups had similar demographic characteristics and disease severities at initial presentation. The in-hospital mortality rate was 45.6% and 46.4% for CSO AB and CRAB groups, respectively (p = 0.991). The CSO AB group had significantly better clinical outcomes at day 7 (65.8% vs 52.4%, p = 0.036) but longer length of ICU stay (27 days vs 19 days, p = 0.043) compared to the CRAB group. However, other treatment outcomes, including clinical outcomes at day 14 and 28, mortality, microbiological eradication, ventilator weaning, and newly onset dialysis, were similar. In conclusion, CSO AB accounted for 13.74% of all cases of CRAB pneumonia, and the clinical presentation and treatment outcomes of CSO AB and CRAB pneumonia were similar.
A clinical–epidemiological score to predict CR-GNB sepsis to guide empirical antimicrobial therapy (EAT), using local data, persists as an unmet need. On the basis of a case–case–control design in a prospective cohort study, the predictive factors for CR-GNB sepsis were previously determined as prior infection, use of mechanical ventilation and carbapenem, and length of hospital stay. In this study, each factor was scored according to the logistic regression coefficients, and the ROC curve analysis determined its accuracy in predicting CR-GNB sepsis in the entire cohort. Among the total of 629 admissions followed by 7797 patient-days, 329 single or recurrent episodes of SIRS/sepsis were enrolled, from August 2015 to March 2017. At least one species of CR-GNB was identified as the etiology in 108 (33%) episodes, and 221 were classified as the control group. The cutoff point of ≥3 (maximum of 4) had the best sensitivity/specificity, while ≤1 showed excellent sensitivity to exclude CR-GNB sepsis. The area under the curve was 0.80 (95% CI: 0.76–0.85) and the number needed to treat was 2.0. The score may improve CR-GNB coverage and spare polymyxins with 22% (95% CI: 17–28%) adequacy rate change. The score has a good ability to predict CR-GNB sepsis and to guide EAT in the future.
Introducción La sepsis es la principal causa de mortalidad en unidades de cuidado crítico, factores de riesgo de mortalidad como la edad, el género y las escalas de severidad han sido estudiados. En nuestra población de estudio las otras complicaciones durante la hospitalización fueron las más relacionadas con el descenlace. Materiales y métodos Estudio de cohorte de 150 pacientes admitidos a unidad de cuidado critico de cuatro unidades del área metropolitana de Bucaramanga, con diagnostico de sepsis severa o choque séptico fueron estudiados mediante un cuestionario sobre variables socio-económicas, clínicas y microbiológicas. Se realizó análisis bivariado con pruebas t de student y chi cuadrado. El análisis multivariado mediante regresión de cox con el tiempo al evento como variable de descenlace. Resultados Los pacientes sobrevivientes tuvieron un promedio de edad de 64 años y los no sobrevivientes de 67 años, sin que se demostraran diferencias estadísticas entre los dos grupos de pacientes. No se encontraron diferencias en cuanto al género. El factor de riesgo más importante asociado a mortalidad por sepsis fueron las complicaciones durante la hospitalización, incluso luego de ajustar por el puntaje sofá inicial, el sitio de infección y los indicadores de respuesta inflamatoria como la hiperlactatemia e hiperbilirrubinemia. Conclusiones Se encontraron tres modelos de riesgo para mortalidad por sepsis con otras complicaciones durante la hospitalización como el factor de riesgo más relevante y el control glicemico como el factor de protección más importante.
Abstract Background The current German S3 guideline for polytrauma lists five criteria for prehospital intubation: apnea, severe traumatic brain injury (GCS ≤8), severe chest trauma with respiratory failure, hypoxia, and persistent hemodynamic instability. These guideline criteria, used in adults in daily practice, have not been previously studied in a collection of severely injured children. The aim of this study was to assess the extent to which the criteria are implemented in clinical practice using a multivariate risk analysis of severely injured children. Methods Data of 289,698 patients from the TraumaRegister DGU® were analyzed. Children meeting the following criteria were included: Maximum Abbreviated Injury Scale 3+, primary admission, German-speaking countries, years 2008–2017, and declaration of intubation. Since children show age-dependent deviating physiology, four age groups were defined (years old: 0–2; 3–6; 7–11; 12–15). An adult collective served as a control group (age: 20–50). After a descriptive analysis in the first step, factors leading to prehospital intubation in severely injured children were analyzed with a multivariate regression analysis. Results A total of 4489 children met the inclusion criteria. In this cohort, young children up to 2 years old had the significantly highest injury severity (Injury Severity Score: 21; p ≤ 0.001). Falls from both high (> 3 m) and low heights (
Purpose of review:
Organ dysfunction severity scores (sequential organ failure assessment or SOFA) are commonly used in the adult and pediatric populations when assessing risk of mortality and adverse outcomes from sepsis. In contrast to sepsis definition in adults and children, clinical and laboratory criteria for defining neonatal sepsis have been inconclusive. More recently, studies have attempted to better understand the clinical progression of neonatal sepsis and associated mortality. This data has guided the development of a neonatal SOFA (nSOFA) score, based on common patterns of organ dysfunction observed in this population.
Recent findings:
Although SOFA scores in the adult and pediatric populations have their limitations with moderate sensitivities and specificities depending on the clinical setting, the nSOFA score has been validated in predicting sepsis attributable mortality in very low birth weight (VLBW) infants across several patient cohorts. Furthermore, the nSOFA score has been adapted for use in neonatal disease states, other than sepsis, with similar prognostic utility.
Summary:
Utilizing an nSOFA scoring system for prediction of sepsis attributable mortality in preterm infants allows for targeted interventions based on risk stratification, as well as better delineation of neonatal sepsis with subsequent improvements in research and patient safety outcomes.
Unlabelled:
Administrative databases are increasingly used in research studies to capture clinical outcomes such as sepsis. This systematic review and meta-analysis examines the accuracy of International Classification of Diseases, 10th revision (ICD-10), codes for identifying sepsis in adult and pediatric patients.
Data sources:
We searched MEDLINE, EMBASE, Web of Science, CENTRAL, Epistemonikos, and McMaster Superfilters from inception to September 7, 2021.
Study selection:
We included studies that validated the accuracy of sepsis ICD-10 codes against any reference standard.
Data extraction:
Three authors, working in duplicate, independently extracted data. We conducted meta-analysis using a random effects model to pool sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We evaluated individual study risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool and assessed certainty in pooled diagnostic effect measures using the Grading of Recommendations Assessment, Development, and Evaluation framework.
Data synthesis:
Thirteen eligible studies were included in the qualitative synthesis and the meta-analysis. Eleven studies used manual chart review as the reference standard, and four studies used registry databases. Only one study evaluated pediatric patients exclusively. Compared with the reference standard of detailed chart review and/or registry databases, the pooled sensitivity for sepsis ICD-10 codes was 35% (95% CI, 22-48, low certainty), whereas the pooled specificity was 98% (95% CI: 98-99, low certainty). The PPV for ICD-10 codes ranged from 9.8% to 100% (median, 72.0%; interquartile range [IQR], 50.0-84.7%). NPV ranged from 54.7% to 99.1% (median, 95.9%; interquartile range, 85.5-98.3%).
Conclusions:
Sepsis is undercoded in administrative databases. Future research is needed to explore if greater consistency in ICD-10 code definitions and enhanced quality measures for ICD-10 coders can improve the coding accuracy of sepsis in large databases.
Background:
ECMO support is associated with the development of a systemic hyper-inflammatory response, which may become quite significant and extreme in some cases. We hypothesise that Cytosorb or Jafron therapy may benefit patients on V-A ECMO in terms of levels of inflammatory markers such as IL-6, complications and overall outcomes.
Methods:
We conducted a retrospective study of prospectively collected data in a single tertiary care center between January 2021 and April 2022. At the time of the analysis of this article, 20 patients on V-A ECMO had cytokine adsorption while on ECMO support: Cytosorb group (n=10), Jafron group (n=10). In 10 ECMO supported patients cytokine adsorption was not used, this group served as a control group, which may be quite significant in some cases. Evaluation of the level of inflammatory markers (IL-1, 6, 8; CRP, Leukocyte, Lactate, PCT, NT-proBNP, TNF-α) were performed.
Results:
There were statistically significant longer CPB time, aortic cross clamp time and ICU stay in cytokine adsorption groups than in control group, but there were no differences between subgroups with different types of haemoadsorption used. Moreover, in control group mortality rate was higher than the cytokine adsorption groups (60 % vs 20%, p 0.02). All patients had elevation of inflammatory markers in perioperative and immediate postoperative period. After 72 hours of intensive care, blood inflammation markers had tendency to decline.
Conclusion:
At the time of writing, hemadsorption in patients requiring V-A ECMO support represents good therapeutic effect. This effect is permanent for the whole period of extracorporeal cytokine hemadsorption application for both CytoSorb and Jafron HA330 devices.
Background
The Japan Society for Blood Purification in Critical Care (JSBPCC) has reported survey results on blood purification therapy (BPT) for critically ill patients in 2005, 2009, and 2013. To clarify the current clinical status, including details of the modes used, treated diseases, and survival rate, we conducted this cohort study using data from the nationwide JSBPCC registry in 2018.
Methods
We analyzed data of 2371 patients who underwent BPT in the intensive care units of 43 facilities to investigate patient characteristics, disease severity, modes of BPTs, including the dose of continuous renal replacement therapy (CRRT) and hemofilters, treated diseases, and the survival rate for each disease. Disease severity was assessed using Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores.
Results
BPT was performed 2867 times in the 2371 patients. Mean APACHE II and SOFA scores were 23.5 ± 9.4 and 10.0 ± 4.4, respectively. The most frequently used mode of BPT was CRRT (67.4%), followed by intermittent renal replacement therapy (19.1%) and direct hemoperfusion with the polymyxin B-immobilized fiber column (7.3%). The most commonly used anticoagulant was nafamostat mesilate (78.6%). Among all patients, the 28-day survival rate was 61.7%. CRRT was the most commonly used mode for many diseases, including acute kidney injury (AKI), multiple organ failure (MOF), and sepsis. The survival rate decreased according to the severity of AKI ( P = 0.001). The survival rate was significantly lower in patients with multiple organ failure (MOF) (34.6%) compared with acute lung injury (ALI) (48.0%) and sepsis (58.0%). Multivariate logistic regression analysis revealed that sepsis, ALI, acute liver failure, cardiovascular hypotension, central nervous system disorders, and higher APACHE II scores were significant predictors of higher 28-day mortality.
Conclusion
This large-scale cohort study revealed the current status of BPT in Japan. It was found that CRRT was the most frequently used mode for critically ill patients in Japan and that 28-day survival was lower in those with MOF or sepsis. Further investigations are required to clarify the efficacy of BPT for critically ill patients.
Trial Registration : UMIN000027678.
Introduction
Sepsis is a life-threatening dysfunction resulting from the dysregulated host response to infection. The mortality of sepsis in Jamaica remains high amid the proven efficacy of the Surviving Sepsis Guidelines implementation in some countries.
Aim of study
To evaluate the inter-relationship of healthcare workers’ attitude towards, knowledge of and practice of sepsis management in Jamaica.
Material and methods
A survey was done using an anonymous self-administered validated questionnaire to healthcare workers across Jamaica. Questions on knowledge, attitude, and practice of sepsis within private and public hospitals were answered.
Results
A total of 616 healthcare workers were eligible for analysis. Most respondents agree that healthcare workers need more training on sepsis (93.7%) and that formal sepsis training modules should be implemented at their hospitals or practice (93.2%). Several signs of sepsis as outlined by qSOFA were correctly identified as such by most respondents (60.6% to 76.4%), with the exception of a low PaCO2 (34.9%), which was correctly identified by a minority of respondents. While a majority (69.3%) were able to correctly define sepsis, only 8.8% of respondents knew the annual sepsis mortality rate. Postgraduate training (p<0.01) and formal sepsis training (p<0.05) were both predictive of high correct knowledge and practice scores. Specialization in Anaesthesia/ Critical Care Medicine (p<0.05) or Emergency Medicine (p<0.05) was predictive of high knowledge scores and Internal Medicine predictive of high practice scores (p<0.01).
Conclusions
This study revealed that education for healthcare workers on sepsis and the implementation of SSC is needed in Jamaica.
To determine the cumulated incidence and the density of incidence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) in critically ill children; to distinguish patients with primary from those with secondary MODS.
Prospective cohort study.
Pediatric ICU of a university hospital.
One thousand fifty-eight consecutive hospital admissions.
None.
SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died. The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9 +/- 3.6 (no SIRS), 7.0 +/- 7.0 (SIRS), 9.5 +/- 8.3 (sepsis), 8.8 +/- 7.8 (severe sepsis), 21.8 +/- 15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis. The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups). Among, patients with MODS, the difference in mortality between groups did not reach significance (p=0.057). Children with secondary MODS had a longer duration of organ dysfunction (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 [2.7 to 15.9], p<0.0001) than patients with primary MODS.
SIRS and sepsis occur frequently in critically ill children. The presence of SIRS, sepsis, or septic shock is associated with a distinct risk of mortality among critically ill children admitted to the pediatric ICU; more data are needed concerning children with MODS. Secondary MODS is much less common than primary MODS, but it is associated with an increased morbidity and mortality; we speculate that distinct pathophysiologic mechanisms are involved in these two conditions.
Criteria of the systemic inflammatory response syndrome (SIRS) are known to include patients without systemic inflammation. Our aim was to explore additional markers of inflammation that would distinguish SIRS patients with systemic inflammation from patients without inflammation. The study included 100 acutely ill patients with SIRS. Peripheral blood neutrophil and monocyte CD11b expression, serum interleukin-6, interleukin-1beta, tumour necrosis factor-alpha and C-reactive protein were determined, and severity of inflammation was evaluated by systemic inflammation composite score based on CD11b expression, C-reactive protein and cytokine levels. Levels of CD11b expression, C-reactive protein and interleukin-6 were higher in sepsis patients than in SIRS patients who met two criteria (SIRS2 group) or three criteria of SIRS (SIRS3 group). The systemic inflammation composite score of SIRS2 patients (median 1.5; range 0-8, n=56) was lower than that of SIRS3 patients (3.5; range 0-9, n=14, P=0.013) and that of sepsis patients (5.0; range 3-10, n=19, P<0.001). The systemic inflammation composite score was 0 in 13/94 patients. In 81 patients in whom systemic inflammation composite scores exceeded 1, interleukin-6 was increased in 64 (79.0%), C-reactive protein in 59 (72.8%) and CD11b in 50 (61.7%). None of these markers, when used alone, identified all patients but at least one marker was positive in each patient. Quantifying phagocyte CD11b expression and serum interleukin-6 and C-reactive protein concurrently provides a means to discriminate SIRS patients with systemic inflammation from patients without systemic inflammation.
We measured the plasma levels of adrenomedullin (AM), a novel vasodilating peptide, in 89 patients with various forms of systemic inflammatory response syndrome (SIRS) and 13 healthy volunteers serving as controls. Plasma levels of AM in SIRS (burns: 20.5 +/- 3. 2 fmol/ml [mean +/- SEM]; pancreatitis: 13.8 +/- 3.8 fmol/ml; trauma: 14.9 +/- 2.5 fmol/ml; traumatic shock: 41.1 +/- 7.8 fmol/ml; severe sepsis: 59.9 +/- 11.2 fmol/ml; septic shock: 193.5 +/- 30.1 fmol/ml) were significantly increased over those of controls (5.1 +/- 0.2 fmol/ml). The patients with traumatic shock or septic shock especially had higher levels of plasma AM than those with trauma or severe sepsis, respectively. These data showed that in patients with SIRS, plasma AM levels increased in proportion to the severity of illness. Subsequently, we measured the plasma levels of mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, plasminogen activator inhibitor (PAI)-1, and thrombomodulin (TM) in patients with traumatic shock and septic shock. A significant correlation was observed between plasma AM and TNF-alpha levels in patients with septic shock, suggesting an important role for AM as well as of TNF-alpha in the pathophysiology of inflammation. Plasma AM and IL-8 levels correlated positively with Acute Physiology and Chronic Health Evaluation (APACHE) II score, peak multiple organ failure (MOF) score during the first month and prognosis in patients with septic shock, as did plasma IL-6 levels in patients with traumatic shock. The plasma AM level might serve as a useful marker for evaluating the severity of disease and as an early predictor of subsequent organ failure and outcome in septic shock.
Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.
We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C.
A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).
Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
To assess the diagnostic value of procalcitonin (PCT), interleukin (IL)-6, IL-8, and standard measurements in identifying critically ill patients with sepsis, we performed prospective measurements in 78 consecutive patients admitted with acute systemic inflammatory response syndrome (SIRS) and suspected infection. We estimated the relevance of the different parameters by using multivariable regression modeling, likelihood-ratio tests, and area under the receiver operating characteristic curves (AUC). The final diagnosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and septic shock in 25. PCT yielded the highest discriminative value, with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75; CI, 0.63 to 0.87), and IL-8 (0.71; CI, 0.59 to 0.83; p < 0.001). At a cutoff of 1.1 ng/ml, PCT yielded a sensitivity of 97% and a specificity of 78% to differentiate patients with SIRS from those with sepsis-related conditions. Median PCT concentrations on admission (ng/ ml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 (0.4 to 6.7) for sepsis; 6.2 (2.2 to 85) for severe sepsis; and 21.3 (1.2 to 654) for septic shock (p < 0.001). The addition of PCT to a model based solely on standard indicators improved the predictive power of detecting sepsis (likelihood ratio test; p = 0.001) and increased the AUC value for the routine value-based model from 0.77 (CI, 0.64 to 0.89) to 0.94 (CI, 0.89 to 0.99; p = 0.002). In contrast, no additive effect was seen for IL-6 (p = 0.56) or IL-8 (p = 0.14). Elevated PCT concentrations appear to be a promising indicator of sepsis in newly admitted, critically ill patients capable of complementing clinical signs and routine laboratory parameters suggestive of severe infection.
Evaluation of trends in organ dysfunction in critically ill patients may help predict outcome.
To determine the usefulness of repeated measurement the Sequential Organ Failure Assessment (SOFA) score for prediction of mortality in intensive care unit (ICU) patients.
Prospective, observational cohort study conducted from April 1 to July 31, 1999.
A 31-bed medicosurgical ICU at a university hospital in Belgium.
Three hundred fifty-two consecutive patients (mean age, 59 years) admitted to the ICU for more than 24 hours for whom the SOFA score was calculated on admission and every 48 hours until discharge.
Initial SOFA score (0-24), Delta-SOFA scores (differences between subsequent scores), and the highest and mean SOFA scores obtained during the ICU stay and their correlations with mortality.
The initial, highest, and mean SOFA scores correlated well with mortality. Initial and highest scores of more than 11 or mean scores of more than 5 corresponded to mortality of more than 80%. The predictive value of the mean score was independent of the length of ICU stay. In univariate analysis, mean and highest SOFA scores had the strongest correlation with mortality, followed by Delta-SOFA and initial SOFA scores. The area under the receiver operating characteristic curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score during the first 96 hours, regardless of the initial score, the mortality rate was at least 50% when the score increased, 27% to 35% when it remained unchanged, and less than 27% when it decreased. Differences in mortality were better predicted in the first 48 hours than in the subsequent 48 hours. There was no significant difference in the length of stay among these groups. Except for initial scores of more than 11 (mortality rate >90%), a decreasing score during the first 48 hours was associated with a mortality rate of less than 6%, while an unchanged or increasing score was associated with a mortality rate of 37% when the initial score was 2 to 7 and 60% when the initial score was 8 to 11.
Sequential assessment of organ dysfunction during the first few days of ICU admission is a good indicator of prognosis. Both the mean and highest SOFA scores are particularly useful predictors of outcome. Independent of the initial score, an increase in SOFA score during the first 48 hours in the ICU predicts a mortality rate of at least 50%.
We prospectively evaluated serum procalcitonin concentrations in patients who presented to an emergency department (ED) with
suspected infectious or inflammatory disease. Of 195 study patients, 68 had final diagnosis of systemic infection, and 24
of those 68 had elevated serum procalcitonin levels (>0.5 ng/mL). The procalcitonin level had a sensitivity of 0.35 and specificity
of 0.99 for the diagnosis of systemic infection. In multivariate analysis, the procalcitonin level was the only independent
variable associated with this diagnosis; in contrast, the C-reactive protein level was not. All patients with systemic infections
who ultimately died had procalcitonin levels of µ0.5 ng/mL at admission. Procalcitonin levels were significantly higher in
patients who ultimately died of systemic infection than in patients who survived. The optimal procalcitonin threshold for
the ED population may be lower than that proposed for critically ill patients. Determination of the procalcitonin level may
be useful for screening and prognosis of more-severely ill ED patients.
Criteria of the systemic inflammatory response syndrome (SIRS) are known to include patients without systemic inflammation. Our aim was to explore additional markers of inflammation that would distinguish SIRS patients with systemic inflammation from patients without inflammation. The study included 100 acutely ill patients with SIRS. Peripheral blood neutrophil and monocyte CD11b expression, serum interleukin-6, interleukin-1b, tumour necrosis factor-a and C-reactive protein were determined, and severity of inflammation was evaluated by systemic inflammation composite score based on CD11b expression, C-reactive protein and cytokine levels. Levels of CD11b expression, C-reactive protein and interleukin-6 were higher in sepsis patients than in SIRS patients who met two criteria (SIRS2 group) or three criteria of SIRS (SIRS3 group). The systemic inflammation composite score of SIRS2 patients (median 1.5; range 0‐8, n fl 56) was lower than that of SIRS3 patients (3.5; range 0‐9, n fl 14, P fl 0.013) and that of sepsis patients (5.0; range 3‐10, n fl 19, P ! 0.001). The systemic inflammation composite score was 0 in 13/94 patients. In 81 patients in whom systemic inflammation composite scores exceeded 1, interleukin6 was increased in 64 (79.0%), C-reactive protein in 59 (72.8%) and CD11b in 50 (61.7%). None of these markers, when used alone, identified all patients but at least one marker was positive in each patient. Quantifying phagocyte CD11b expression and serum interleukin-6 and C-reactive protein concurrently provides a means to discriminate SIRS patients with systemic inflammation from patients without systemic inflammation.
Background:
The Institute of Medicine has called for the development of clinical guidelines and practice parameters to develop "best practice" and potentially improve patient outcome.
Objective:
To provide American College of Critical Care Medicine clinical guidelines for hemodynamic support of neonates and children with septic shock.
Setting:
Individual members of the Society of Critical Care Medicine with special interest in neonatal and pediatric septic shock were identified from literature review and general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (1998-2001).
Methods:
The MEDLINE literature database was searched with the following age-specific keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, and extracorporeal membrane oxygenation. More than 30 experts graded literature and drafted specific recommendations by using a modified Delphi method. More than 30 more experts then reviewed the compiled recommendations. The task-force chairman modified the document until <10% of experts disagreed with the recommendations.
Results:
Only four randomized controlled trials in children with septic shock could be identified. None of these randomized trials led to a change in practice. Clinical practice has been based, for the most part, on physiologic experiments, case series, and cohort studies. Despite relatively low American College of Critical Care Medicine-graded evidence in the pediatric literature, outcomes in children have improved from 97% mortality in the 1960s to 60% in the 1980s and 9% mortality in 1999. U.S. hospital survival was three-fold better in children compared with adults (9% vs. 27% mortality) in 1999. Shock pathophysiology and response to therapies is age specific. For example, cardiac failure is a predominant cause of death in neonates and children, but vascular failure is a predominant cause of death in adults. Inotropes, vasodilators (children), inhaled nitric oxide (neonates), and extracorporeal membrane oxygenation can be more important contributors to survival in the pediatric populations, whereas vasopressors can be more important contributors to adult survival.
Conclusion:
American College of Critical Care Medicine adult guidelines for hemodynamic support of septic shock have little application to the management of pediatric or neonatal septic shock. Studies are required to determine whether American College of Critical Care Medicine guidelines for hemodynamic support of pediatric and neonatal septic shock will be implemented and associated with improved outcome.
Objective: To define the terms "sepsis" and "organ failure" in a precise manner. Data Sources: Review of the medical literature and the use of expert testimony at a consensus conference. Setting: American College of Chest Physicians (ACCP) headquarters in Northbrook, IL. Participants: Leadership members of ACCP/Society of Critical Care Medicine (SCCM). Results: An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. Conclusion: The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Study objectives: To determine the cumulated incidence and the density of incidence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) in critically ill children; to distinguish patients with primary from those with secondary MODS.
Design: Prospective cohort study.
Setting: Pediatric ICU of a university hospital.
Patients: One thousand fifty-eight consecutive hospital admissions.
Interventions: None.
Measurements and results: SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died. The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9±3.6 (no SIRS), 7.0±7.0 (SIRS), 9.5±8.3 (sepsis), 8.8±7.8 (severe sepsis), 21.8±15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis. The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups). Among patients with MODS, the difference in mortality between groups did not reach significance (p=0.057). Children with secondary MODS had a longer duration of organ dysfunctions (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 [2.7 to 15.9], p<0.0001) than patients with primary MODS.
Conclusions: SIRS and sepsis occur frequently in critically ill children. The presence of SIRS, sepsis, or septic shock is associated with a distinct risk of mortality among critically ill children admitted to the pediatric ICU; more data are needed concerning children with MODS. Secondary MODS is much less common than primary MODS, but it is associated with an increased morbidity and mortality; we speculate that distinct pathophysiologic mechanisms are involved in these two conditions.
Measurements and results: SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died. The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9±3.6 (no SIRS), 7.0±7.0 (SIRS), 9.5±8.3 (sepsis), 8.8±7.8 (severe sepsis), 21.8±15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis. The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups). Among patients with MODS, the difference in mortality between groups did not reach significance (p=0.057). Children with secondary MODS had a longer duration of organ dysfunctions (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 [2.7 to 15.9], p<0.0001) than patients with primary MODS.
Objective: To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gramnegative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia. Design: Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial. Setting: 603 investigators at 513 community and university-affiliated hospitals in the United States
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Context Evaluation of trends in organ dysfunction in critically ill patients
may help predict outcome.Objective To determine the usefulness of repeated measurement the Sequential Organ
Failure Assessment (SOFA) score for prediction of mortality in intensive care
unit (ICU) patients.Design Prospective, observational cohort study conducted from April 1 to July
31, 1999.Setting A 31-bed medicosurgical ICU at a university hospital in Belgium.Patients Three hundred fifty-two consecutive patients (mean age, 59 years) admitted
to the ICU for more than 24 hours for whom the SOFA score was calculated on
admission and every 48 hours until discharge.Main Outcome Measures Initial SOFA score (0-24), Δ-SOFA scores (differences between
subsequent scores), and the highest and mean SOFA scores obtained during the
ICU stay and their correlations with mortality.Results The initial, highest, and mean SOFA scores correlated well with mortality.
Initial and highest scores of more than 11 or mean scores of more than 5 corresponded
to mortality of more than 80%. The predictive value of the mean score was
independent of the length of ICU stay. In univariate analysis, mean and highest
SOFA scores had the strongest correlation with mortality, followed by Δ-SOFA
and initial SOFA scores. The area under the receiver operating characteristic
curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score
during the first 96 hours, regardless of the initial score, the mortality
rate was at least 50% when the score increased, 27% to 35% when it remained
unchanged, and less than 27% when it decreased. Differences in mortality were
better predicted in the first 48 hours than in the subsequent 48 hours. There
was no significant difference in the length of stay among these groups. Except
for initial scores of more than 11 (mortality rate >90%), a decreasing score
during the first 48 hours was associated with a mortality rate of less than
6%, while an unchanged or increasing score was associated with a mortality
rate of 37% when the initial score was 2 to 7 and 60% when the initial score
was 8 to 11.Conclusions Sequential assessment of organ dysfunction during the first few days
of ICU admission is a good indicator of prognosis. Both the mean and highest
SOFA scores are particularly useful predictors of outcome. Independent of
the initial score, an increase in SOFA score during the first 48 hours in
the ICU predicts a mortality rate of at least 50%.
Definition of MI. Criteria for acute, evolving or recent MI. Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: a) ischemic symptoms; b) development of pathologic Qwaves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); or d) coronary artery intervention (e.g., coronary angioplasty). 2) Pathologic findings of an acute MI. Criteria for established MI. Any one of the following criteria satisfies the diagnosis for established MI: 1) Development of new pathologic Q waves on serial ECGs. The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed. 2) Pathologic findings of a healed or healing MI.
Objective: To determine the incidence, cost, and outcome of severe sepsis in the United States.
Design: Observational cohort study.
Setting: All nonfederal hospitals (n = 847) in seven U.S. states.
Patients: All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification.
Interventions: None.
Measurements and Main Results : We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association. We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals. We generated national age- and gender-adjusted estimates of incidence, cost, and outcome. We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit. Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum.
Conclusions: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages.
The pathophysiology of severe acute pancreatitis (AP) resembles other conditions with systemic inflammatory response syndrome (SIRS) such as sepsis predisposing to remote organ failure. Because extracellular phospholipases A2 (PLA2) have been implicated in AP, their serum concentrations were analyzed with respect to SIRS and systemic complications in patients with severe AP. The serum samples were collected daily for 12 days in 57 patients with severe AP. SIRS, early organ complications, local complications, and outcome of AP were recorded. Time-resolved fluoroimmunoassays were used for group I and group II PLA2 measurements. Thirty-nine (68.4%) patients fulfilled the criteria of SIRS within 12 days from admission. Pancreatic necrosis was detected in 43 (75.4%) patients. Infected necrosis was found preoperatively or at operation in five (8.8%) patients. Twenty-six (45.6%) and eight (14.0%) patients had respiratory or renal failure, respectively. Seven (12.3%) patients died of their disease. All patients with systemic complications fulfilled the criteria of SIRS. The increasing number of positive SIRS criteria was associated with increased frequency of systemic complications. Pancreatic necrosis was not significantly associated with SIRS. The serum concentration of group II PLA2 was significantly higher in patients with SIRS (p <0.05) compared with patients without from day 7 onward. The concentration of group II PLA2 increased (p <0.01) in patients with SIRS but decreased in patients without. The serum concentration of group II PLA2 did not differ significantly with respect to systemic complications. The concentration of group I PLA2 decreased (p <0.05) similarly in patients with and without SIRS or systemic complications during follow-up, respectively. Early systemic complications of severe AP are associated with SIRS with increasing frequency as the number of positive SIRS criteria increases. Group II PLA2 but not group I PLA2 may have pathophysiologic importance in severe AP-associated SIRS. Increasing serum concentration of group II PLA2 seems to reflect the ongoing systemic inflammation in severe AP-associated SIRS.
(C) 1999 Lippincott Williams & Wilkins, Inc.
The proinflammatory response triggered by infection and injury is initially protective and mediated by a number of host factors including tumor necrosis factor (TNF)-, interleukin (IL)-1, IL-6, and IL-8. In excess, these factors may cause severe tissue damage and life-threatening physiologic perturbations. If patients with a hyperinflammatory response can be identified early, they may benefit from treatment aimed at attenuating this response. In experimental models of sepsis, proinflammatory cytokines appear in the circulation in a relatively ordered manner but clinical sepsis is not as predictable. Compromised response mechanisms, interfering physiologic disturbances and therapeutic agents, and a variable temporal relationship to the onset of infection probably all contribute to the wide variability in both frequency and magnitude of their appearance seen in different studies. Although TNF- is a proximal mediator of sepsis, circulating TNF- concentrations at the time of diagnosis do not consistently correlate with disease severity. IL-6 is induced by TNF, appears in the circulation after the initial TNF response, often remains elevated, and is more consistently measurable. These properties may make it a good surrogate measure of localized TNF- activity. In numerous studies, IL-6 was consistently shown to be elevated in septic patients, and serum concentrations correlated well with measures of disease severity and mortality. Assessing circulating IL-6 at the time of sepsis diagnosis may enable treatment decisions that are more directed to the individual patient's inflammatory response.
Gram-negative sepsis is caused by endotoxin-induced release of tumor necrosis factor (TNF) and other cytokines. HA-1A is a
human monoclonal antibody that binds specifically to endotoxin. HA-1A should prevent death in endotoxemic patients and reduce
serum levelsofTNF and interleukin-6 (lL-6). This hypothesis was tested in 82 septic patients who were randomly allocated to
receive a single intravenous 100-mg dose ofHA-1A or placebo. Pretreatment endotoxemia was detected in 27 patients (33%). Death
occurred within 28 days of treatment in 8 (73%) of 11 placebo recipients and in 5 (31%) of 16 HA-1A recipients (P = .02). The median decrease in serum TNF level 24 h after treatment was 12 nglL in patients given HA-1A and 0 ng/L in placebo
recipients (n = 65; P = .04). For IL-6, this was 204 ng/L in patients given HA-1A and 44 ng/L in placebo recipients (n = 67; P = .4). Thus, HA-1A reduces mortality in septic patients with endotoxemia and lowers serum TNF levels.
Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.
HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia.
To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol.
Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected.
HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.
The association of multiple organ system failure (MOSF) with mortality was investigated in 831 consecutive admissions to a pediatric ICU. The incidence of MOSF (at least two organ system failures, OSF) was 27%. Of the 62 nonsurvivors, 60 (97%) had MOSF. The mortality for patients with MOSF was 54%, compared to a mortality of 0.3% for patients without MOSF. Mortality increased directly with increasing number of OSF (p less than .0001). The mortality was 1% for one OSF, 11% for two OSF, 50% for three OSF, and 75% for four OSF. Comparison of these results with data from adult ICU patients indicates that the mortality and clinical course of MOSF in children is distinct from adults. MOSF is significantly associated with mortality in pediatric patients; however, it is not sufficiently discriminating to determine continuation or withdrawal of ICU support.
To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness.
Systematic literature review; prospective cohort study.
Surgical intensive care unit (ICU) of a tertiary-level teaching hospital.
All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990.
None.
Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of < 5%, whereas a value of 4 represented marked functional derangement and an ICU mortality rate of > or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices.
This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)
Ruling out myocardial infarction in patients coming to the emergency room with chest pain is hindered by the lack of a specific early diagnostic marker. Less than 30 percent of patients admitted to coronary care units have infarction, resulting in substantial unnecessary expenditures. We developed a rapid assay of the subforms of creatine kinase MB (CK-MB) and prospectively analyzed its sensitivity and specificity in diagnosing myocardial infarction in the first six hours after the onset of chest pain.
In 1110 consecutive patients who came to the emergency room with chest pain, blood samples were collected every 30 to 60 minutes until at least 6 hours after the onset of symptoms; in patients who were then admitted to the hospital, samples were collected every 4 hours for up to 48 hours. The samples were analyzed for CK-MB subforms, and the diagnosis of myocardial infarction was confirmed by conventional CK-MB analysis.
Of the 1110 patients evaluated, 121 had myocardial infarction. The sensitivity of the assay of CK-MB subforms to detect myocardial infarction in the first six hours after the onset of symptoms was 95.7 per cent, as compared with only 48 percent for the conventional CK-MB assay; the specificity was 93.9 percent among patients hospitalized without myocardial infarction and 96.2 percent among those sent home. Among the patients with myocardial infarction, definitive results of the subform assay were available a mean (+/- SD) of 1.22 +/- 1.17 hours after their arrival in the emergency room.
The assay of CK-MB subforms reliably detected myocardial infarction within the first six hours after the onset of symptoms, and its use could reduce admission to the coronary care unit by 50 to 70 percent, thereby reducing costs.
To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia.
Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial.
603 investigators at 513 community and university-affiliated hospitals in the United States.
Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required.
Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated.
2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, -6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, -0.8% to 8.8%).
In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.
To determine whether plasma nitrite and nitrate concentrations are associated with the development of sepsis-induced multiple organ failure.
Prospective study.
University children's hospital.
Fifty-three consecutive children meeting criteria for sepsis and not receiving exogenous sources of nitric oxide.
Plasma nitrite and nitrate concentrations were measured, and the number of organs failing was scored using an organ failure index on the first 3 days of sepsis.
Children with three or more organs failing on day 3 of sepsis had higher plasma nitrite and nitrate concentrations than children who had resolution of failure of three or more organs by day 3 of sepsis (days 2 and 3) and children who never had three organs failing in the first 3 days of sepsis (days 1, 2, and 3). Children who developed sequential pulmonary/hepatic/renal organ failure had significantly higher plasma nitrite and nitrate concentrations (days 1, 2, and 3). Nonsurvivors had significantly higher plasma nitrite and nitrate concentrations (days 2 and 3) than survivors. Plasma nitrite and nitrate concentrations on day 1 predicted the development of persistent failure of three of more organs and sequential multiple organ failure but not mortality.
Increased plasma nitrite and nitrate concentrations are associated with the development of multiple organ failure in pediatric sepsis.