ArticleLiterature Review

The value of sepsis definitions in daily ICU-practice

September 2006
Acta clinica Belgica 61(5):220-6

DOI:10.1179/acb.2006.037

Source
PubMed

Authors:

Hasselt University

Sepsis is a major disease entity with important clinical and economic implications. Sepsis is the hosts' reaction to infection and is characterized by a systemic inflammatory response. Because of difficulties in defining sepsis, the SIRS was introduced trying to summarize the inflammatory response in a limited set of elementary characteristics (fever or hypothermia, leucocytosis or leucopenia, tachycardia, hyperventilation). In daily practice it is essential to identify septic patients as soon as possible because early recognition results in better survival rates. However, in order to allow early detection, a more stringent description of "the septic profile" is needed. From the start, even after revision of the primary sepsis description, these definitions have caused much controversy and debate because they lack sensitivity and specificity. Conclusively, almost all patients admitted to the intensive care unit meet or develop the systemic inflammatory response syndrome. Therefore, it is difficult to distinguish patients with true sepsis from those with severe inflammation due to non-infectious causes. This review highlights the current sepsis definitions, and discusses their strengths as well as their shortcomings for daily intensive care unit practice.

CHANGES IN PHARMACOKINETIC PROPERTIES OF ANTIBACTERIAL DRUGS IN CRITICALLY ILL PATIENTS

Article

Full-text available

Feb 2020

PL Krytycznie chorzy pacjenci są narażeni na wysokie ryzyko rozwoju zagrażającej życiu infekcji prowadzącej do ciężkiego wstrząsu i w konsekwencji niewydolności wielonarządowej, a nawet śmierci. Optymalna terapia przeciwdrobnoustrojowa ma kluczowe znaczenie w zwiększaniu szansy tych pacjentów na przeżycie. Jednak skuteczne dawkowanie leków jest problematyczne, ponieważ zmiany patofizjologiczne, związane z krytycznym stanem choroby, wpływają na ich właściwości farmakokinetyczne, głównie tych leków, które wykazują charakter hydrofilowy. Stężenia tych leków mogą być podwyższone u pacjentów krytycznie chorych, głównie z powodu zmniejszonego klirensu nerkowego, spowodowanego niewydolnością/uszkodzeniem nerek. I przeciwnie, stężenia leków przeciwbakteryjnych mogą ulec obniżeniu z powodu zwiększonej objętości dystrybucji i zwiększonego klirensu nerkowego, wywołanego przez zespół ogólnoustrojowej odpowiedzi zapalnej, wyciek kapilarny, zmniejszone wiązanie leku z białkami, podawanie dożylnych płynów oraz leków inotropowych. Częstość jednoczesnego występowania licznych powikłań, które mogą wpływać na właściwości farmakokinetyczne leków, nadmiernie komplikuje prognozowanie ich terapeutycznych stężeń. Zasadniczo, w warunkach klinicznych dominują sytuacje, gdy uzyskiwane stężenia leków przeciwdrobnoustrojowych u pacjentów krytycznie chorych są zbyt niskie. A uzyskanie nieodpowiedniego stężenia leków w osoczu pacjentów jest istotne z klinicznego punktu widzenia, ponieważ prowadzi do nieskutecznej eradykacji drobnoustrojów chorobotwórczych i braku poprawy klinicznej. Ponadto zbyt niskie stężenia leków wywołują rozwój oporności wielolekowej drobnoustrojów, co stanowi problem nie tylko medyczny, ale i społeczno-ekonomiczny. Jednym z zasadniczych rozwiązań tego problemu wydaje się powszechne stosowanie monitorowania stężeniem leku w osoczu, w celu indywidualnego dostosowania dawkowania leków przeciwdrobnoustrojowych do stanu klinicznego pacjenta. EN Changes in pharmacokinetic properties of antibacterial drugs in critically ill patients • Critically ill patients are at high risk of developing a lifethreatening infection leading to severe shock and, as a consequence, multi-organ failure and even death. Optimal antimicrobial therapy, especially in the first 48 hours, is crucial to increasing patients’ chances of survival. However, effective drug dosing is problematic because pathophysiological changes associated with the critical state of a disease affect their pharmacokinetic properties, mainly those drugs that are hydrophilic in nature. Concentrations of these drugs may be elevated in critically ill patients, mainly because of decreased renal clearance due to renal failure/damage. Conversely, antimicrobial concentrations may decrease due to increased volume of distribution and increased renal clearance, caused by the systemic inflammatory response syndrome, capillary leakage, reduced drug binding, intravenous fluids and inotropic drugs used. The frequency of simultaneous occurrence of numerous complications that may affect pharmacokinetic properties of drugs is excessively complicated by predicting their therapeutic concentrations. In general, situations where antimicrobial concentrations in serum of critically ill patients are too low dominate in clinical settings. And obtaining inappropriate plasma concentrations of patients is clinically important because it leads to ineffective eradication of pathogenic microorganisms and a lack of clinical improvement. In addition, too low drug levels trigger the development of multi-drug resistance, which is not only a medical but also a socio-economic problem. One of the major solutions to this problem seems to be the widespread use of plasma drug monitoring for individual adjustment of the dosage of antimicrobial drugs in a particular patient’s clinical condition. However, despite the successful implementation of the beta-lactam antibiotic monitoring program in critically ill patients in Poland, several problems remain to be solved, such as insufficient documentation of the advantage of such a procedure and its clinical success, the lack of necessary technical preparation and specialist knowledge of medical staff in hospitals, which has an impact for the time of determining the concentration of antibacterial drugs in the patient plasma, even the possibility of monitoring drug concentration therapy does not solve the problem of obtaining the most optimal pharmacokinetic-pharmacodynamic indicators that determine the dosage selection. One solution, though not without its drawbacks, is to use population models to calculate the dosage of antimicrobial drugs. These models should take into account the state of mechanical ventilation, diagnostic category and glomerular filtration of the patient. However, also in such model preparation, there are problems such as the state of patients’ kidney function, which may show large fluctuations and require frequent monitoring of creatinine, which is associated with additional work and time input, capillary leak affecting the value of distribution volume. The above pathophysiological changes significantly impede the development of appropriate models that would be adequate for use in optimization of the antimicrobial dosage in critically ill patients. Keywords: Antimicrobial agents, Pharmacokinetics, Pharmacodynamics, Intensive care unit, Sepsis, Organ failure.

Monitoring of Blood Glucose Level in Surgical Intensive Care Unit Patients with Sepsis

Article

Sep 2019

Analysis of Prognostic Risk Factors of Sepsis Patients in Intensive Care Unit Based on Data Analysis

Article

Full-text available

Jan 2022

In this paper, a data-enabled analysis of the prognostic risk factors of sepsis patients in the intensive care unit is presented. For this purpose, we have selected 220 sepsis patients, preferably those admitted to the intensive care unit for treatment in a tertiary a hospital in Tianjin from June 2018 to June 2019 and received complete data as the research objects, to explore the prognostic risk factors of sepsis patients in the intensive care unit. All patients met the SSC sepsis diagnosis guidelines and recorded the patients’ age, gender, underlying disease, and infection site. Laboratory indicators, such as blood routine, electrolytes, arterial blood gas, liver function, and renal function, were collected within 24 hours of admission. Furthermore, the corresponding specimens were cultured for pathogenic microorganisms according to the site of infection. The LAC value was measured at admission and 24 h after admission, and the 24 h lactate clearance rate was calculated. The Acute Physiological and Chronic Health Status Score II (APACHE-II) and SOFA score were calculated, which were based on the worst value of the index within 24 hours after admission. According to the prognosis of patients during hospitalization, they are divided into two groups: (i) survival group and (ii) death group. We entered all the data into Excel and used SPSS21.0 statistical software for data analysis and processing. Quantitative data are tested for normality. Quantitative data for normal distribution are expressed as mean ± standard deviation, and normal distribution and uniform variance are measured. The factors affecting the prognosis of patients with sepsis were first subjected to a single-factor logistic regression analysis, and a multiple logistic regression analysis was performed on the basis of the significance of the single-factor analysis. The results found that the prognosis of patients with sepsis in the ICU is affected by multiple factors such as underlying diseases, infectious microorganisms, comorbidities, and interventional therapy. APACHE-II score, 24 h lactate clearance rate, ARDS, and DIC are independent risk factors that affect the prognosis of ICU patients. 1. Introduction Sepsis is a systemic inflammatory response syndrome (SIRS) caused by the presence of various pathogenic microorganisms and their toxins in the blood or tissues. It is generally caused by trauma, burns, shock, infection, and surgical operations and other clinically critical diseases. Those with more severe illness can progress to severe sepsis, septic shock, and multiple organ dysfunction syndrome, which is clinically one of the main causes of death in critically ill patients. It is common in complications caused by major surgery, severe infection, shock, and severe trauma. Clinical studies have shown that pathogenic bacteria invade the body to destroy the normal balance of anti-inflammatory and proinflammatory reactions in the body, which is the pathogenesis of sepsis. Related investigations and studies have shown that sepsis has a higher morbidity and fatality rate in ICU. In recent years, with the increase of invasive operations, the number of patients has increased, and the fatality rate has exceeded 50%. This has become a major problem that the current ICU treatment needs to face and poses a great threat to human health. Sepsis is divided into three types: sepsis, severe sepsis, and septic shock. At present, the fatality rates of domestic sepsis, severe sepsis, and septic shock have reached 13.82%, 35.43%, and 52.65% respectively. The severe situation cannot be ignored and can be described as another important research topic in clinical medicine [1–5]. In view of the high morbidity and fatality rate of sepsis disease itself, it is very important to make prognostic analysis and research on it. Throughout the various clinical studies and publications that have appeared and implemented in the medical field, there are relatively few studies on the prognostic factors of sepsis. The number of cases in the existing studies is small, and it is a univariate analysis. There is no clear explanation for the prognostic interference factors. The specific influencing factors are not clear, and the analyzed factors themselves have certain limitations. Therefore, the analysis and research on the factors affecting the prognosis of sepsis has certain practical significance and practical value and can effectively fill a gap in the prognosis research of the disease in medicine. In foreign clinical studies of sepsis, it is pointed out that the case-fatality rate of patients with this type of disease will increase with the duration of the disease and the length of admission to the hospital. Once the best treatment period is missed, and no timely intervention is performed, sepsis will further increase. It develops and worsens and eventually evolves into MODS and septic shock, which increases the mortality rate. Another study by foreign scholars has shown that, in the group of patients with sepsis, elderly people over 60 years old account for a large proportion, reaching 65.2%. At the same time, as the age increases, the fatality rate of sepsis also increases. It suggests that age may be one of the prognostic factors. As sepsis has gradually become an important difficulty and subject content in clinical medical research, clinical research on sepsis has also begun to increase, and many clinical treatment results have been obtained, and valuable diagnosis and treatment experience has been accumulated. Comprehensive progress and updates have also been made in terms of the definition of the nature of the disease, diagnosis and treatment, and treatment standards of sepsis [6–10]. Pathogenesis of sepsis is more complicated, prognostic factors have not made substantial progress, and there is a lack of valuable research and scientific and accurate conclusions. Therefore, it has become an important reason for the high fatality rate of sepsis caused by delayed intervention and treatment, so it is necessary to analyze and study the prognostic factors of sepsis. Not only can it enhance the cognition and mastery of sepsis between doctors and patients but can also help doctors to effectively intervene and observe the development and changes of sepsis patients and then make reasonable judgments and correct diagnosis and treatment, in order to achieve the purpose of improving the clinical treatment effect of sepsis and reducing the mortality rate. Based on a retrospective research method, in this article, we have selected 220 sepsis patients with complete data who were treated in the ICU ward of a third-class hospital in Tianjin, particularly from June 2018 to June 2019, as the research object. All patients met the diagnostic criteria for sepsis. By analyzing the results of related laboratory examinations and the prognosis of patients, the relevant factors affecting the prognosis of patients with sepsis are explored, so as to provide a basis for effective treatment of the disease in clinical and the reduction of the mortality rate in the hospital. The remaining portions of these articles are organized as follows: in the subsequent section, a brief, but thorough, review of the existing literature is presented, where the focus is on the sepsis related diseases. In Section 3, the proposed mechanism is presented, where sophisticated detail is provided about various parts of the proposed setup. Experimental results and observations were presented in Section 4. Finally, concluding remarks and future directives are provided in the last section. 2. Related Work The concept of sepsis was first proposed in 1991 by the American College of Chest Physicians and the Society of Critical Care Medicine, which strengthened the understanding of the disease. In 2001, the American Academy of Critical Care Medicine and other institutions revised the criteria for sepsis, and indicators related to inflammation entered the diagnostic criteria for the disease, deepening the understanding from the perspective of the etiology. A year later in Spain, ESICM/SCCM/ISF published the famous Barcelona Declaration on Sepsis at the European Critical Care Medicine Conference [11, 12]. Studies have shown that when a patient’s infection is severe, systemic inflammation is formed in the body, which usually activates the anticoagulant system and coagulation system in the body, and inhibits the fibrinolytic system, leading to coagulation dysfunction. Once the coagulation system is activated, the concentration of anticoagulation factor proteins S, C, and antithrombin in the plasma decreases, and the concentration levels of TATC, prothrombin fragment F1 + 2, and soluble tissue factor are increased. Toxic disease progresses, coagulation factors are consumed, and APTT and PT are prolonged. The activation of the fibrinolytic system increased the levels of PAI-1, PAPC, D-dimer, and tissue-type plasminogen activator. Stimulating the procoagulant system usually leads to an increase in mortality. A large number of studies have shown that coagulation function can be stimulated by inflammatory response, and the activity of inflammatory response is affected by coagulation function. The two are highly correlated. Due to the procoagulant state formed by inflammation, inflammatory factors such as TNF-α, IL-1, and IL-6 participate in the formation of blood vessel thrombus and DIC in the body, which directly lead to serious damage to the body of patients with sepsis [13–18]. Studies have found that, after the initial explosive inflammatory response, an anti-inflammatory response is gradually induced, causing the patient to cause a secondary infection or the treatment is ineffective and fails. The apoptosis of epithelial cells, lymphocytes, and dendritic cells causes compensatory anti-inflammatory reactions such as decreased Th1 cell proliferation, low T lymphocyte reactivity, and ineffective antigen presentation, which is also called immune paralysis. Immune cell apoptosis is related to the host response caused by a variety of bacteria and many apoptotic pathways and has a very complex production mechanism [19–22]. The literature mentioned [23] to detect the blood lactic acid level of 50 patients with sepsis. The change curve of blood lactate over time was recorded, and the correlation between the prognosis of sepsis and blood lactate level was discussed. Through discussion, the author believes that increased blood lactic acid levels reduce the survival rate of patients with sepsis. Reducing the blood lactic acid concentration of patients with sepsis can improve the survival rate of patients. Finally, it is concluded that the survival rate of patients with sepsis is closely related to the blood lactic acid level of the body. The literature analyzed the value of lactic acid clearance rate on the clinical prognosis of patients with severe sepsis. It is pointed out that the blood lactate clearance rate can reflect the severity and prognosis of patients with severe sepsis. The lower the blood lactate clearance rate, the more severe the disease and the worse the prognosis [24]. The literature has studied the prognostic factors of 55 patients with sepsis. Through observation results pointed out that patients with sepsis PLT decreased, APTT time prolonged and INR increased, serum ALB level decreased, and APACHE-II score of more than 25 points all indicate worsening of the disease and poor prognosis [25]. 3. Materials and Methods 3.1. Research Object and Group In this study, 220 patients with sepsis, who were admitted to the intensive care unit for treatment in a tertiary A hospital in Tianjin from June 2018 to June 2019 with complete data, were used as clinical research subjects, including 147 males and 73 females. According to the prognosis of patients during hospitalization, they were divided into survival group and death group. There were 101 patients in the death group and 119 patients in the survival group. Among them, there were 69 males in the death group and 32 females, aged 26–79 years. The average age was 63.1 ± 1.6 years. There were 78 males and 41 females in the survival group, aged from 27 to 79 years, with an average age of 61.2 ± 1.6 years. 3.2. Clinical Diagnostic Criteria The diagnostic criteria included a clear or suspected infection, accompanied by some of the following general indicators: fever (body temperature>38.3°C); hypothermia (central body temperature <36.0°C); heart rate>90 beats/min or greater than 2 standard deviations of the normal heart rate range of different ages; shortness of breath, breathing rate>30 beats/min; changes in consciousness; obvious edema or positive fluid balance (>20 mg/kg over 24 hours); hyperglycemia (blood sugar>140 mg/dL or 7.7 mmol/L) without history of diabetes. Inflammatory response parameters included leukocytosis (white blood cell count>12 × 109/L); leukopenia (white blood cell count<4 × 109/L). The white blood cell count is normal, but the immature white blood cell is > 0.10. Plasma C-reactive protein was > 2 standard deviations from the normal value. Precalcitonin was > 2 standard deviations from the normal value. Hemodynamic parameters included hypotension (systolic blood pressure <90 mmHg, mean arterial pressure <70 mmHg, or adult systolic blood pressure drop >40 mmHg, or drop by age >2 standard deviations); mixed venous blood oxygen saturation >0.70; cardiac bleeding index >58.3 ml/s·m. Organ dysfunction parameters included hypoxemia (oxygenation index PaO2/FiO2<300 mmHg); acute oliguria (urine volume <0.5 ml/kg·h or osmotic concentration of 45 mmol/L for at least 2 h); creatinine increased ≥4.4 mmol/L; abnormal coagulation (international normalized ratio >1.5 or partially activated thromboplastin time >60 s); abdominal distension (bowel sounds disappear); thrombocytopenia (PLT < 100 × 109/L); hyperbilirubinemia (TBIL > 7.0 mmol/L). Tissue perfusion parameters included hyperlactic acidemia (>1 mmol/L). The capillary refilling time is prolonged or the skin appears mottling. 3.3. Inclusion and Exclusion Criteria This study included the following eligible patients: patients who were diagnosed with sepsis based on clinical symptoms and signs, laboratory examination results, and so on and were hospitalized in the intensive care unit of our hospital; being over 18 years old and under 80 years old. The hospitalization time was more than 24 hours, and the data of the included subjects were complete. Those with the following conditions are excluded: age <18 years old or age >80 years old; definite diagnosis of primary or secondary adrenal insufficiency; patients with immune diseases who have been treated with glucocorticoids in the past year; patients who have used glucocorticoids in the past two weeks. Human immunodeficiency virus (HIV) positive is test during pregnancy and breastfeeding. 3.4. Research Method Using the method of retrospective investigation and analysis, 220 sepsis patients with complete data who were treated in the ICU ward of a tertiary hospital from June 2018 to June 2019 were selected as the clinical research objects. According to the patient’s prognosis, all sepsis patients are divided into two groups: survival group and death group, and the patient’s age, gender, vital signs at the time of admission, infection site, underlying disease were recorded. Laboratory indicators, such as blood routine, electrolytes, arterial blood gas, liver function, and renal function, were collected within 24 hours of admission, and corresponding specimens were cultured for pathogenic microorganisms according to the site of infection. The LAC value was measured at admission and 24 h after admission, and the 24 h lactate clearance rate was calculated. The Acute Physiological and Chronic Health Status Score II (APACHE-II) and SOFA score were calculated based on the worst value of the indicators within 24 hours after admission. And the patient’s organ function is good, whether there is failure and septic shock, and the relevant diagnosis and treatment measures are taken. A series of biochemical indicators are checked and measured for patients, including oxygenation index, blood lactate (Lac), 24 h lactate clearance, serum procalcitonin (PCT), C-reactive protein (CRP), total bilirubin (TBiL), platelet count (PLT), clotting time (PT), albumin (ALB), urea nitrogen (BUN), white blood cell count (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (Cr) and creatine kinase isoenzyme (CK-MB), and many other project parameter indicators. 3.5. Statistical Method We have used Excel to build a database for all basic patient data. In this study, SPSS21.0 statistical software was used to perform statistical analysis and processing on all research test data, and the results of all measurement data were expressed in the form of mean ± standard deviation. The two groups of patients were compared and analyzed by independent sample t-test, and all count data were measured and compared with each index using the test. According to the patient’s survival or death, a single-factor analysis was performed, and statistically significant indicators were obtained for the study of the method of multiple logistic regression analysis. 4. Experimental Results 4.1. General Data Research and Analysis Among the 220 patients in this clinical investigation, there are 147 males and 73 females. There are 101 patients in the death group and 119 patients in the survival group. Among them, there are 69 males in the death group and 32 females, aged 26∼79 years, with an average age of 63.1 ± 1.6 years. In the surviving group, there were 78 males and 41 females, aged 27–79 years, with an average age of 61.2 ± 1.6 years. There was no statistical difference between the death group and the survival group in terms of gender, average age, and age <60 years. The proportion of the death group ≥60 years old was more than that of the survival group. The proportion of people in the death group in terms of Gram-negative bacterial infection, fungal infection, combined ARDS/AKI/DIC, and the number of failed organs was higher than that in the survival group. The proportion of Gram-positive bacterial infection was lower than that of the survival group, and the difference was statistically significant. There was no difference in the proportion of infection sites, myocardial injury, septic encephalopathy, acute liver injury, and stress ulcer. The proportion of patients with cardiac insufficiency in the death group was higher than that in the survival group. There was no difference between the two groups in the proportion of people suffering from diabetes, COPD, and hypertension, and the difference was not statistically significant. The proportion of the survival group receiving anticoagulation therapy and continuous blood purification was higher than that of the death group. There was no difference in the time of receiving TPN treatment and mechanical ventilation between the two groups. There was no difference in the length of hospitalization between the survival group and the death group, and the difference was not statistically significant (Table 1 for details). GNI is Gram-negative infection. GPI is Gram-positive infection. FI is fungal infection. MI is myocardial injury. SE is septic encephalopathy. ALI is acute liver injury. SU is stress ulcer. AT is anticoagulant therapy. MVT is mechanical ventilation time. CBP is continuous blood purification. Item Group Survival group Death group Gender Male 78 69 0.138 Female 41 32 0.130 Age <60 50 26 0.158 ≥60 69 75 0.008 Site of infection Lung 61 56 0.078 Urinary 30 22 0.823 Abdomen 13 14 0.245 Others 15 9 0.151 Pathogen classification GNI 43 89 0.005 GPI 76 12 0.002 FI 12 19 0.023 Organ disorders ARDS 41 62 0.003 AKI 34 67 0.000 DIC 21 34 0.004 MI 54 46 0.731 SE 61 52 0.765 ALI 27 23 0.265 SU 66 57 0.481 Number of failed organs 1 91 34 0.005 2 25 13 3 3 25 4 0 19 5 0 10 Basic illness Diabetes 23 24 0.356 COPD 9 13 0.231 Hypertension 53 45 0.981 Heart failure 107 98 0.038 Treatment TPN 81 57 0.168 AT 77 48 0.027 MVT 152.4 223.5 0.162 CBP 38 13 0.008 Hospital stay ICU time 12.6 9.6 0.276

Extravascular lung water index as a sign of developing sepsis

Article

Oct 2021

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Platelet count patterns and patient outcomes in sepsis at a tertiary care center: Beyond the APACHE score

Article

Full-text available

May 2021
MEDICINE

Acute physiology and chronic health evaluation II (APACHE-II) scoring system is used to classify disease severity of patients in the intensive care unit. However, several limitations render the scoring system inadequate in identifying risk factors associated with outcomes. Little is known about the association of platelet count patterns, and the timing of platelet count and other hematologic parameters in predicting mortality in patients with sepsis. This retrospective observational study included 205 septic shock patients, with an overall mortality of 47.8%, enrolled at a tertiary care hospital in Riyadh, Kingdom of Saudi Arabia between 2018 and 2020. Bivariate and multivariate regression analyses were used to identify hematologic risk factors associated with mortality. We used the bivariate Pearson Correlation test to determine correlations between the tested variables and APACHE-II score. Two platelet count patterns emerged: patients with a decline in platelet count after admission (group A pattern, 93.7%) and those with their lowest platelet count at admission (group B pattern, 6.3%). The lowest mean platelet count was significantly lower in nonsurvivors (105.62 ± 10.67 × 103/μL) than in survivors (185.52 ± 10.81 × 103/μL), P < .001. Bivariate Pearson correlation revealed that the lowest platelet count and platelet count decline were significantly correlated with APACHE-II score (r = −0.250, P < .01), (r = 0.326, P < .001), respectively. In multiple logistic regression analysis, the independent mortality risk factors were degree of platelet count decline in group A (odds ratio, 1.028 [95% confidence interval: 1.012–1.045], P = .001) and platelet pattern in group B (odds ratio, 6.901 [95% confidence interval: 1.446–32.932], P = .015). The patterns, values, subsets, and ratios of white blood cell count were not significantly associated with mortality. Nadir platelet count and timing, and degree of platelet count decline are useful markers to predict mortality in early septic shock. Therefore, platelet count patterns might enhance the performance of severity scoring systems in the intensive care unit.

Increased cytokine expression in the choroid plexus stroma and epithelium in response to endotoxin-induced systemic inflammation in mice

Article

Full-text available

Mar 2021

Sepsis-associated encephalopathy (SAE) is characterized as diffuse brain dysfunction in patients with excessive systemic inflammatory reaction to an infection. In our previous studies using a mouse model of SAE with intraperitoneal injection of lipopolysaccharide (LPS), tissue concentrations of various cytokines were elevated in the entire brain parenchyma 4 and 24 h following LPS administration. Cytokines elevated at 4 h were produced by the choroid plexus, leptomeninges and vascular endothelium, while those at 24 h were produced by astrocytes. Interleukin (IL)-1β did not increase in the concentration in the brain parenchyma during the period from 1 to 24 h following LPS. In the present study, we hypothesized that the intracranial cells that initially respond to systemic inflammation are situated in the choroid plexus and produce IL-1β to initiate cytokine-mediated reactions. We quantified the transcript levels of related cytokines within the choroid plexus and specified the choroid plexus cells that are involved in the immediate cytokine-mediated responses. Mice received LPS or saline by intraperitoneal injection. Four hours after treatments, the choroid plexuses were isolated and subjected to cytokine gene expression analyses using real-time reverse transcription-polymerase chain reaction. Another group of mice was fixed at 1, 4 and 24 h after treatments and the expression of cytokines and receptors was studied with double immunohistofluorescence staining. The transcript levels of IL-1β, CC-motif ligand (CCL)2, CXC-motif ligand (CXCL)1, CXCL2 and IL-6 in the choroid plexus were significantly increased in mice treated with LPS compared to saline control. The IL-1β expression was remarkable in choroid plexus macrophages at 1 and 4 h but not in the brain parenchyma. Choroid plexus stromal cells expressed IL-1 receptor type 1 (IL-1R1). The IL-1R1-bearing stromal cells produced CCL2, CXCL1, CXCL2 and IL-6 at 4 h. Choroid plexus epithelial cells expressed CXCR2, a common receptor for CXCL1 and CXCL2. Choroid plexus epithelial cells also expressed CCL2, CXCL1 and CXCL2 at 4 h, and IL-1R1-bearing stromal cells expressed CXCR2. Therefore, in response to systemic LPS injection, one of the intracranial reactions was initiated within the choroid plexus using IL-1β derived from macrophages. The choroid plexus stromal cells subsequently had elevated expression of CCL2, CXCL1, CXCL2 and IL-6. The choroid plexus epithelial cells also had elevated expression of CCL2, CXCL1 and CXCL2. The presence of receptors for these cytokines on both epithelial and stromal cells raised the possibility of reciprocal interactions between these cells. The results suggested that the immediate early responses exerted by the choroid plexus are relevant to understanding how SAE is initiated in clinical settings.

Widespread time-dependent changes in tissue cytokine concentrations in brain regions during the acute phase of endotoxemia in mice

Article

Oct 2019
NEUROTOXICOLOGY

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction induced by the systemic response to infection in septic patients. In the present study, we modeled SAE by administering lipopolysaccharide (LPS) intraperitoneally to mice at a concentration of 3.0 mg/kg. We investigated regional preferences for cytokine-mediated brain reactions to endotoxemia and at what time point brain inflammation begins, as well as what cytokines are involved in acute brain reactions. Brains were divided into seven parts: cortex (CTX), olfactory system (Olf), hippocampus (Hip), striatum (Str), diencephalon (Die), brain stem (BS), and cerebellum (CBL). In each brain region, we determined the tissue concentrations of 11 cytokines: CCL2, CCL3, CCL11, CXCL1, CXCL2, CXCL9, CXCL10, G-CSF, IL-1β, IL-6, and TNF-α, in mice injected with LPS or saline, at 1, 4, and 24 h after injection using multiplex cytokine assays. Every brain region responded with the production of multiple cytokines to LPS-induced systemic inflammation during the acute phase (4-24 h) after LPS injection. IL-6, CCL2, CCL3, CXCL1, CXCL2, CXCL9, and TNF-α were "early cytokines" that increased only at 4 h but not at 24 h after LPS injection in most brain regions. CCL11, CXCL10, and G-CSF were "late cytokines" that were elevated up to 24 h after LPS injection in selected brain regions. The regions Olf, Hip, and Die were the most responsive to endotoxemia; these regions produced ten cytokines and continued to produce three "late cytokines" up to 24 h after LPS injection. Str was the least responsive to endotoxemia. The widespread nature of brain cytokine production explains the characteristics of SAE. Further studies on the roles of CCL11, CXCL10, and G-CSF may be especially important in terms of potential prevention of SAE between 4 and 24 h after the onset of sepsis.

Histological Architecture Underlying Brain–Immune Cell–Cell Interactions and the Cerebral Response to Systemic Inflammation

Article

Full-text available

Jun 2017

Sanae Hasegawa-Ishii

Although the brain is now known to actively interact with the immune system under non-inflammatory conditions, the site of cell–cell interactions between brain parenchymal cells and immune cells has been an open question until recently. Studies by our and other groups have indicated that brain structures such as the leptomeninges, choroid plexus stroma and epithelium, attachments of choroid plexus, vascular endothelial cells, cells of the perivascular space, circumventricular organs, and astrocytic endfeet construct the histological architecture that provides a location for intercellular interactions between bone marrow-derived myeloid lineage cells and brain parenchymal cells under non-inflammatory conditions. This architecture also functions as the interface between the brain and the immune system, through which systemic inflammation-induced molecular events can be relayed to the brain parenchyma at early stages of systemic inflammation during which the blood–brain barrier is relatively preserved. Although brain microglia are well known to be activated by systemic inflammation, the mechanism by which systemic inflammatory challenge and microglial activation are connected has not been well documented. Perturbed brain–immune interaction underlies a wide variety of neurological and psychiatric disorders including ischemic brain injury, status epilepticus, repeated social defeat, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Proinflammatory status associated with cytokine imbalance is involved in autism spectrum disorders, schizophrenia, and depression. In this article, we propose a mechanism connecting systemic inflammation, brain–immune interface cells, and brain parenchymal cells and discuss the relevance of basic studies of the mechanism to neurological disorders with a special emphasis on sepsis-associated encephalopathy and preterm brain injury.

The Role of Acetylcholine in the Inflammatory Response in Animals Surviving Sepsis Induced by Cecal Ligation and Puncture

Article

Full-text available

Dec 2016
MOL NEUROBIOL

The cholinergic anti-inflammatory pathway controls the inflammatory response and nonreflexive consciousness through bidirectional communication between the brain and immune system. Moreover, brain acetylcholinesterase activity may have a role in regulating the vagus nerve in this pathway. Thus, we analyzed the role of acetylcholine (ACh) in the inflammatory response 15 days after induction of sepsis by cecal ligation and puncture (CLP). Balb/c mice were pretreated with or without donepezil (5 mg/kg/day, orally) 7 days before CLP, and mice homozygous for vesicular ACh transporter (VAChT) knockdown (KD) were subjected to CLP. All animals were sacrificed 15 days after CLP, and the plasma, spleen, and hippocampus were collected. Characterization of splenic lymphocytes and cytokine levels in the plasma, spleen, and hippocampus was determined. Our results showed a splenomegaly in group CLP. The numbers of cytotoxic T cells, helper T cells, regulatory T cells, B cells, and Th17 cells differed between mice subjected to CLP and to sham operation in both untreated and donepezil-treated groups. In VAChT-KD mice, CLP resulted in decreased cytotoxic and helper T cells and increased in Th17 cells compared with the sham. Additionally, in VAChT-KD mice, the levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, were increased following CLP. Thus, we concluded that ACh affected the inflammatory response at 15 days after CLP since stimulation of cholinergic transmission increased the proliferation of lymphocytes, including regulatory T cells, in association with a lower inflammatory profile and VAChT-KD decreased the number of lymphocytes and increased inflammation.

Protective effects of rosmarinic acid on sepsis-induced DNA damage in the liver of Wistar albino rats

Article

Full-text available

Jun 2015

Sepsis is an imbalance between pro and anti-inflammatory responses. Sepsis induced multiple organ failure that is associated with mortality is characterized by liver, renal, cardiovascular and pulmonary dysfunction and reactive oxygen species (ROS) are believed to be involved in the development of sepsis. Plant polyphenols may act as antioxidants by different mechanisms such as free radical scavenging, metal chelation and protein binding. Data indicates possible beneficial effects of plant derived phenolic compounds against sepsis. Rosmarinic acid (RA) (α-O-caffeoyl-3,4-dihydroxyphenyllactic acid) is a phenolic compound commonly found in various plants such as Rosmarinus officinalis (rosemary), Origanum vulgare (oregano), Thymus vulgaris (thyme), Mentha spicata (spearmint), Perilla frutescens (perilla), Ocimum basilicum (sweet basil) and several other medicinal plants. It has been shown that RA has many biological activities including antioxidant, anti-inflammatory, antiallergic, anticancer and actimicrobial and is widely used in cosmetic and food industry. In the present study, we aimed to determine the protective effects of RA against the oxidative DNA damage induced by sepsis in Wistar albino rats. The rats were divided into four groups; sham, sepsis induced, RA-treated, RA treated and sepsis induced groups. Wistar rats were subjected to sepsis by cecal ligation puncture. The liver tissues were carefully dissected from their attachments and totally excised. The concentrations of the hepatic tissue cells were adjusted to approximately 2 x 106 cells/ml. Standard and formamidopyrimidine-DNA glycosylase (Fpg) modified comet assay described by Singh et al were used. There were no statistically significant differences in terms of tail length, tail intensity and tail moment between the sham group and the RA-treated groups (p>0.05). The DNA damage was found significantly higher in the sepsis-induced group compared to the sham group (p

Does rosmarinic acid treatment have protective role against sepsis-induced oxidative damage in Wistar Albino rats?

Article

Full-text available

Oct 2015

Reactive oxygen species are believed to be involved in the development of sepsis. Plant-derived phenolic compounds are thought to be possible therapeutic agents against sepsis because of their antioxidant properties. Rosmarinic acid (RA) is a phenolic compound commonly found in various plants, which has many biological activities including antioxidant activity. The aim of this study was to investigate the effects of RA on sepsis-induced DNA damage in the lymphocytes and liver and kidney cells of Wistar albino rats by alkaline comet assay with and without formamidopyrimidine DNA glycosylase protein. The oxidative stress parameters such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and total glutathione (GSH) and malondialdehyde (MDA) levels in the liver and kidney tissues and an inflammatory cytokine, tumor necrosis factor a (TNF-a) level in plasma were also evaluated. It is found that DNA damage in the lymphocytes, livers, and kidneys of the RA-treated rats was significantly lower than that in the sepsisinduced rats. RA treatment also decreased the MDA levels and increased the GSH levels and SOD and GSH-Px activities in the livers and kidneys of the sepsis-induced rats. Plasma TNF-a level was found to be decreased in the RA-treated rats. It seems that RA might have a role in the attenuation of sepsis-induced oxidative damage not only by decreasing the DNA damage but also by increasing the antioxidant status and DNA repair capacity of the animals.

Effects of rosmarinic acid on oxidative stress parameters in livers and kidneys of sepsis induced wistar albino rats

Article

Full-text available

Oct 2015

The Severity of Cecal Ligature and Puncture-Induced Sepsis Correlates with the Degree of Encephalopathy, but the Sepsis Does Not Lead to Acute Activation of Spleen Lymphocytes in Mice

Article

Full-text available

Jun 2015
MOL NEUROBIOL

Septic encephalopathy represents the most frequently observed form of encephalopathy in intensive care units. Interactions between the immune and nervous systems have been observed in experimental sepsis. Therefore, the aim of the current study was to characterize the effect of different severities of sepsis on encephalopathy and the inflammatory profile of the spleen. We hypothesized that different grades of sepsis severity would lead to variations in encephalopathy and activation of spleen cells. We induced sepsis of different severities in Balb/c mice by cecal ligature and puncture (CLP). Six and 12 h after CLP induction, behavioral impairment was assessed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) test. The animals were then killed, and the plasma, spleen, and hippocampus were removed. Levels of the encephalopathy marker S100β were measured in plasma. Spleens were weighed and then a characterization of splenic lymphocytes was performed by flow cytometry (cytotoxic T lymphocyte, T helper lymphocytes, B lymphocytes, T regulatory cells, and Th17 cells). Cytokine levels in the spleen and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA), and cytokine levels in plasma were performed with MilliPlex® technology. Our results showed that behavioral impairment as measured by the SHIRPA test and elevation in plasma S100β levels were significant in moderate and severe CLP groups compared to those in the sham control group. Regarding immunological alterations, we were unable to observe changes in the weights of the spleen and the profile of lymphocytes 6 h after CLP. However, several cytokines, including IL-6, IL-10, and IL-1β, were increased in spleen and plasma. In conclusion, we observed variations in encephalopathy as measured by plasma S100β, which were mediated by the severity of sepsis; however, we did not observe a different activation of spleen cells 6 h post-CLP, despite evidence of inflammation. Taken together, our data indicate that the severity of sepsis impacts the brain in absence of a change in the spleen lymphocyte profile.

To the editor:

Article

Full-text available

Aug 2007

Curcumin protects against lipopolysaccharide-induced vasoconstriction dysfunction via inhibition of thrombospondin-1 and transforming growth factor-β1

Article

Full-text available

Feb 2015
Exp Ther Med

Sepsis is a complex syndrome characterized by the development of progressive dysfunction in multiple organs. The aim of the present study was to investigate the protective effect of curcumin against lipopolysaccharide (LPS)-induced vasoconstrictive dysfunction, and to investigate the possible underlying mechanism. Male Sprague-Dawley rats were randomly divided into the following groups: Control, sepsis and curcumin. A sepsis model was established by an intraperitoneal (i.p.) injection of 5 mg/kg LPS. Thoracic aortic rings obtained from the rats were mounted in an organ bath and the vasoconstriction of the rings was recorded. In addition, the serum E-selectin levels were determined by an enzyme-linked immunosorbent assay. The expression levels of thrombospondin (TSP)-1 and transforming growth factor (TGF)-β1 in the aortic tissue were detected by immunohistochemistry. Vasoconstriction of the aortic rings was found to significantly decrease in the sepsis rats when compared with the control group. However, curcumin (10 or 20 mg/kg, i.p.) prevented the vasoconstrictive dysfunction induced by LPS. The serum level of E-selectin and the expression levels of TSP-1 and TGF-β1 significantly increased in the sepsis rats when compared with the control group rats; however, the levels decreased significantly following treatment with curcumin (10 or 20 mg/kg). Furthermore, hematoxylin and eosin staining revealed that curcumin alleviated the LPS-induced damage in the aortic tunica intima and tunica media. Therefore, the results indicated that curcumin alleviates LPS-induced vasoconstrictive dysfunction in the thoracic aorta of rats. In addition, the inhibition of TSP-1 and TGF-β1 expression may be involved in the mechanism underlying this protective effect.

N-acetylcysteine and fructose-1,6-bisphosphate: Immunomodulatory effects on mononuclear cell culture

Article

Full-text available

Apr 2012

INTRODUCTION: Sepsis is a complex syndrome caused by an uncontrolled systemic inflammatory response. Inflammatory cytokines play a pivotal role in septic shock pathogenesis. Therapeutic strategies have been tested in order to modulate the excessive generation or function of sepsis mediators. OBJECTIVE: The objective of the present study was to investigate the therapeutic effect of N-acetylcysteine (NAC) and its association with fructose-1,6-bisphosphate (FBP) on T-lymphocytes proliferation, interleukin-1β (IL-1β) and monocyte chemotactic protein-1 (MCP-1) levels. MATERIAL AND METHODS: Peripheral blood mononuclear cell samples were isolated from healthy individuals. T-lymphocytes were stimulated with phytohemagglutinin for 96 hours and submitted to different concentrations of NAC or NAC associated with FBP. RESULTS: NAC (10 and 15 mM) and NAC (15 mM) associated with FBP reduced T-lymphocytes proliferation. IL-1β levels rose in the presence of both NAC (15 mM) and NAC with FBP (1.25 mM). MCP-1 levels were reduced only by NAC (15 mM) associated with FBP (1.25 mM). CONCLUSION: The results suggest that both NAC itself and NAC associated with FBP inhibit cellular proliferation, acting as potent immunomodulatory agents, which corroborates its use in the treatment of inflammatory diseases.

Potential amelioration of upregulated renal HIF-1alpha-Endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

Article

Full-text available

May 2014
LIFE SCI

Aims Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α -ET-1 system and inflammatory cytokines in a rat model of endotoxemia. Main methods Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle. Key findings At 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased; c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury, up-regulated levels of renal HIF-1α -ET-1 system with normalization of TNF-α. Significance Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α-ET-1 system in minimally morphologically-injured kidney andnormalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.

Dual endothelin blockade exacerbates upregulated VEGF angiogenic signaling in the heart of a /INS;lipopolysaccharide-induced endotoxemic rat model

Article

Full-text available

Feb 2014

Aims Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxaemic developments, ultimately leading to damage of multiple organs, including heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in sepsis heart and the effects of endothelin dual blocker (ETDB) on it. Main methods Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS : 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. Key findings Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET) -1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. Significance We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in myocardiam following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxaemic heart.

Septic Encephalopathy

Article

Full-text available

Oct 2013
CURR NEUROL NEUROSCI

Marek Ziaja

Every year, more cases of sepsis appear in intensive care units. The most frequent complication of sepsis is septic encephalopathy (SE), which is also the essential determinant of mortality. Despite many years of research, it still is not known at which stage of sepsis the first signs of SE appear; however, it is considered the most frequent form of encephalopathy. Patients have dysfunction of cognitive abilities and consciousness, and sometimes even epileptic seizures. Despite intensive treatment, the effects of SE remain for many years and constitute an important social problem. Numerous studies indicate that changes in the brain involve free radicals, nitric oxide, increased synthesis of inflammatory factors, disturbances in cerebral circulation, microthromboses, and ischemia, which cause considerable neuronal destruction in different areas of the brain. To determine at what point during sepsis the first signs of SE appear, different experimental models are needed to detect the aforementioned changes and to select the proper therapy for this syndrome.

Epidemiology and outcome of nosocomial bloodstream infection in elderly critically ill patients: A comparison between middle-aged, old, and very old patients *

Article

May 2009
CRIT CARE MED

Background: We investigated the epidemiology of nosocomial bloodstream infection in elderly intensive care unit (ICU) patients. Methods: In a single-center, historical cohort study (1992–2006), we compared middle-aged (45–64 years; n = 524), old (65–74 years; n = 326), and very old ICU patients (≥75 years; n = 134) who developed a nosocomial bloodstream infection during their ICU stay. Results: Although the total number of ICU admissions (patients aged ≥45 years) decreased by ∼10%, the number of very old patients increased by 33% between the periods 1992–1996 and 2002–2006. The prevalence of bloodstream infection (per 1,000 ICU admissions) increased significantly over time among old (p = 0.001) and very old patients (p = 0.002), but not among middle-aged patients (p = 0.232). Yet, this trend could not be confirmed with the incidence data expressed per 1,000 patient days (p > 0.05). Among patients with bloodstream infection, the proportion of very old patients increased significantly with time from 7.2% (1992–1996) to 13.5% (1997–2001) and 17.4% (2002–2006) (p < 0.001). The incidence of bloodstream infection (per 1000 patient days) decreased with age: 8.4‰ in middle-aged, 5.5‰ in old, and 4.6‰ in very old patients (p < 0.001). Mortality rates increased with age: 42.9%, 49.1%, and 56.0% for middle-aged, old, and very old patients, respectively (p = 0.015). Regression analysis revealed that the adjusted relationship with mortality was borderline significant for old age (hazard ratio, 1.2; 95% confidence interval, 1.0–1.5) and significant for very old age (hazard ratio, 1.8; 95% confidence interval, 1.4–2.4). Conclusion: Over the past 15 years, an increasing number of elderly patients were admitted to our ICU. The incidence of nosocomial bloodstream infection is lower among very old ICU patients when compared to middle-aged and old patients. Yet, the adverse impact of this infection is higher in very old patients.

The Decrease on Na+, K+-ATPase Activity in the Cortex, but not in Hippocampus, is Reverted by Antioxidants in an Animal Model of Sepsis

Article

Jul 2012
MOL NEUROBIOL

In the present study, we investigated whether sepsis induced by cecal ligation and puncture (CLP) modifies Na(+), K(+)-ATPase activity, mRNA expression, and cerebral edema in hippocampus and cerebral cortex of rats and if antioxidant (ATX) treatment prevented the alterations induced by sepsis. Rats were subjected to CLP and were divided into three groups: sham; CLP-rats were subjected to CLP without any further treatment; and ATX-CLP plus administration of N-acetylcysteine plus deferoxamine. Several times (6, 12, and 24) after CLP or sham operation, the rats were killed and hippocampus and cerebral cortex were isolated. Na(+), K(+)-ATPase activity was inhibited in the hippocampus 24 h after sepsis, and ATX treatment was not able to prevent this inhibition. The Na(+), K(+)-ATPase activity also was inhibited in cerebral cortex 6, 12, and 24 h after sepsis. No differences on Na(+), K(+)-ATPase catalytic subunit mRNA levels were found in the hippocampus and cerebral cortex after sepsis. ATX treatment prevents Na(+), K(+)-ATPase inhibition only in the cerebral cortex. Na(+), K(+)-ATPase inhibition was not associated to increase brain water content. In conclusion, the present study demonstrated that sepsis induced by CLP inhibits Na(+), K(+)-ATPase activity in a mechanism dependent on oxidative stress, but this is not associated to increase brain water content.

Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies

Article

Full-text available

May 2008

Objective To compare the characteristics and outcome of patients with hematological malignancies referred to the ICU with severe sepsis and septic shock who had or had not received recent intravenous chemotherapy, defined as within 3 weeks prior to ICU admission. Design and setting Retrospective observational cohort study on prospectively collected data in a medical ICU of a university hospital. Patients 186 ICU patients with hematological malignancies with severe sepsis or septic shock (2000–2006). Measurements and results There were 77 patients admitted with severe sepsis and 109 with septic shock; 91 (49%) had received recent intravenous chemotherapy. Patients with recent chemotherapy more often had a high-grade malignancy and were more often neutropenic, less often had pulmonary infiltrates, and less often required mechanical ventilation. ICU, 28-day, in-hospital, and 6-month mortality rates were 33% vs. 48.4%, 40.7% vs. 57.4%, 45.1% vs. 58.9%, and 50.5% vs. 63.2% in patients with and without recent chemotherapy, respectively. Logistic regression identified four variables independently associated with 28-day mortality: SOFA score at ICU admission, pulmonary site of infection, and fungal infection were associated with worse outcome whereas previous intravenous chemotherapy was protective at borderline significance. After adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. Conclusions Patients referred to the ICU with severe sepsis and septic shock complicating active chemotherapeutic treatment have better prognosis than commonly perceived.

Increased NTPDase Activity in Lymphocytes during Experimental Sepsis

Article

Full-text available

May 2012
TSWJ

We investigated in rats induced to sepsis the activity of ectonucleoside triphosphate diphosphohydrolase (NTPDase; CD39; E.C. 3.6.1.5), an enzyme involved in the modulation of immune responses. After 12 hours of surgery, lymphocytes were isolated from blood and NTPDase activity was determined. It was also performed the histology of kidney, liver, and lung. The results demonstrated an increase in the hydrolysis of adenosine-5'-triphosphate (ATP) (P < 0.01), but no changes regarding adenosine-5'-monophosphate (ADP) hydrolysis (P > 0.05). Histological analysis showed several morphological changes in the septic group, such as vascular congestion, necrosis, and infiltration of mononuclear cells. It is known that the intracellular milieu contains much more ATP nucleotides than the extracellular. In this context, the increased ATPasic activity was probably induced as a dynamic response to clean up the elevated ATP levels resulting from cellular death.

Erythropoietin reverts cognitive impairment and alters the oxidative parameters and energetic metabolism in sepsis animal model

Article

Feb 2012
J NEURAL TRANSM

Sepsis is characterized by systemic biochemical alterations including the central nervous system in the early times and cognitive impairment at later times after sepsis induction in the animal model. Recent studies have shown that, besides its hematological activity, erythropoietin (EPO) has cytoprotective effects on various cells and tissues. In order to corroborate elucidating the effects of alternative drugs for sepsis treatment, we evaluated the effects of both acute and chronic EPO treatment on oxidative stress and energetic metabolism in the hippocampus, and cognitive impairment, respectively, after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or sham operation. In the acute treatment, EPO was administered once immediately after CLP induction. The rats were then killed after 6 and 24 h, and the hippocampus was removed for analysis of oxidative stress and energetic metabolism, respectively. Regarding the chronic treatment, EPO was administered once daily until the 4th day after induction. Aversive memory was tested on the 10th day after surgery. It was observed that the acute use of EPO (a single dose) alters the oxidative parameters and energetic metabolism. Chronic use (4 days) reversed cognitive impairment in the sepsis animal model. Mortality rates were attenuated only during chronic treatment.

Hypothermia Associated With Antipsychotic Drug Use: A Clinical Case Series and Review of Current Literature

Article

Sep 2011
J CLIN PHARMACOL

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5-HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.

[Hypothermia under olanzapine treatment: clinical case series and review of current literature].

Article

Jun 2011
NERVENARZT

Antipsychotic drugs may lead to hypothermia as well as hyperthermia. Although known for decades and clinically highly relevant, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are still far from being fully understood. In clinical practice, much attention is paid to antipsychotic drug-induced elevation of body core temperature as observed in the neuroleptic malignant syndrome (NMS). But also hypothermia is a clinically highly relevant adverse reaction to antipsychotic drugs. Here we report a case series of three patients who developed severe hypothermia after administration of olanzapine. A review of the current literature is given with a focus on risk factors for the development of antipsychotic drug-induced hypothermia and its pathophysiologic mechanisms. A 51-year-old female patient suffering from catatonic schizophrenia, cachectic nutritional condition and hypothyroidism developed severe hypothermia of 30.0°C body core temperature after administration of 30 mg olanzapine per day under comedication with lorazepam and L-thyroxine. A 48-year-old female patient with catatonic schizophrenia showed hypothermia of 31.0°C (rectal measurement) after single-dose administration of olanzapine 10 mg orally and a total of 3 mg lorazepam (1-1-1 mg). The third case report describes a 69-year-old male patient with acute delusional disorder exhibiting hypothermia of 33.0°C (rectal measurement) in combination with a reversible atrioventricular block grade III without any further comedication. A review of the current literature reveals that thermoregulatory disturbances as sequelae of antipsychotic drug administration depend on individual disposition as well as various independent risk factors such as environmental temperature, somatic comorbidities, endocrinological abnormalities (e.g. hypothyroidism) and structural damage of the brain. A complex interaction of dopaminergic regulatory mechanisms in the ventral hypothalamus and peripheral vaso- and sudomotor adjustments seems to be causative. Hypothermia following antipsychotic drug administration represents a serious adverse drug reaction and a potentially life-threatening event.

Effect of N-Acetylcysteine and Fructose-1,6-Bisphosphate in the Treatment of Experimental Sepsis

Article

Sep 2010
INFLAMMATION

Sepsis is a syndrome caused by uncontrolled systemic inflammatory response of the individual, which represents a serious epidemiological problem worldwide. The aim of this study was to investigate the effect of N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP) in the treatment of experimental sepsis. We used rats that were divided into five experimental groups: normal control (not induced), septic control (induced using a capsule with non sterile fecal content and Escherichia coli), treated with FBP (500 mg/kg i.p.), treated with NAC (150 mg/kg i.p.), and treated with the combination of FBP with NAC. In the group treated with NAC, 16.68% of the mice survived, the FBP reduced the mortality of mice during the acute stage of the disease and increased the animals' survival time in 33.34%, and the combination of drugs had no effect. Our results show that NAC prevented the mortality of animals after septic induction. These data confirm the validity of the use of NAC in the treatment of sepsis. Our data also show that the synergistic action with FBP does not improve the picture.

Implementation of an evidence-based sepsis program in the intensive care unit: Evident or not?

Article

Full-text available

Oct 2009

Severe sepsis and septic shock are among the most serious health conditions and are associated with unwelcome clinical, social, and economic outcomes. With the introduction of the Surviving Sepsis Campaign guidelines, the campaign leaders aimed to reduce mortality from severe sepsis by at least one quarter by 2009 by means of a six-point action plan, namely, building awareness among health care professionals, improving early and accurate disease recognition and diagnosis, increasing the use of appropriate treatments and interventions, education, getting better post-intensive care unit access, and developing standard processes of care. However, adherence to these recommendations is a first but crucial step in obtaining these goals. A comprehensive evaluation of both, adherence to a sepsis program and whether this results in better outcomes for patients, is therefore essential to guide informed decision-making regarding the implementation of such an evidence-based protocol.

Dynamics of C-reactive protein and white blood cell count in critically ill patients with nosocomial Gram positive vs. Gram negative bacteremia: a historical cohort study

Article

Full-text available

Jan 2007
BMC INFECT DIS

Abstract Background Nosocomial bacteremia is associated with a poor prognosis. Early adequate therapy has been shown to improve outcome. Consequently, rapid detection of a beginning sepsis is therefore of the utmost importance. This historical cohort study was designed to evaluate if different patterns can be observed in either C-reactive protein (CRP) and white blood cell count (WCC) between Gram positive bacteremia (GPB) vs. Gram negative bacteremia (GNB), and to assess the potential benefit of serial measurements of both biomarkers in terms of early antimicrobial therapy initiation. Methods A historical study (2003–2004) was conducted, including all adult intensive care unit patients with a nosocomial bacteremia. CRP and WCC count measurements were recorded daily from two days prior (d-2) until one day after onset of bacteremia (d+1). Delta (Δ) CRP and Δ WCC levels from the level at d-2 onward were calculated. Results CRP levels and WCC counts were substantially higher in patients with GNB. Logistic regression analysis demonstrated that GNB and Acute Physiology and Chronic Health Evaluation (APACHE) II score were independently associated with a CRP increase of 5 mg/dL from d-2 to d+1, and both were also independently associated with an increase of WCC levels from d-2 to d+1 of 5,000 × 103 cells/mm3. Conclusion Increased levels of CRP and WCC are suggestive for GNB, while almost unchanged CRP and WCC levels are observed in patients with GPB. However, despite the different patterns observed, antimicrobial treatment as such cannot be guided based on both biomarkers.

Cognitive Impairment in the Septic Brain

Article

Full-text available

Sep 2009

Sepsis is a major disease entity with important clinical implications. It is associated with a high mortality rate in humans. Recently, several studies have demonstrated that Intensive Care Unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. The pathogenesis of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. Here we discuss the clinical presentation and underlying pathophysiology of the encephalopathy and neurobiology of the cognitive impairment associated with sepsis.

Hypothermia Associated With Antipsychotic Medication: A Clinical Surveillance Study

Article

Oct 2017
J CLIN PSYCHOPHARM

Fatores de risco associados ao agravamento de sepse em pacientes em Unidade de Terapia Intensiva

Article

Full-text available

Nov 2016

Marta Chagas Monteiro

Introduction: sepsis is a serious public health problem, leading cause of death in Intensive Care Unit (ICU) worldwide. Objective: this study evaluated the aggravation and mortality of sepsis patients in ICU, relating to risk factors, different etiologies and therapies. Methodology: the study was observational descriptive, and evaluated the cases of sepsis (sepsis, severe sepsis and septic shock) from January 2009 to December 2010. Results: of the 212 patients hospitalized in ICU, 181 presented sepsis at different severities, whose sepsis mortality in the ICU was 63%, especially in patients with septic shock (53%), followed by severe sepsis (8.3%). Moreover, the risk factors associated with the aggravation of sepsis were older than 65 years, longer ICU hospitalization time, high frequency of comorbidities and the use of invasive procedures. The highest consumption of antibiotics was carbapenems, and the main isolated multiresistant strains were MRSA, VRE, P. aeruginosa and A. baumannii resistant to carbapenems. Conclusion: this study showed a high mortality from sepsis patients in the ICU, especially in patients with septic shock with comorbidities, who underwent invasive procedures and longer hospitalization time. Keywords: sepsis; septic shock; risk factors; Intensive Care Unit

Prevention as a key measure to improve healthcare quality and patient safety

Chapter

Mar 2013

Oral Care in Intubated Patients: Necessities and Controversies

Chapter

Jan 2014

Healthcare professionals in both the community and hospital settings are responsible for maintaining good oral health of patients who are not able to perform this simple activity themselves. Cancer patients receiving chemotherapy or radiotherapy, institutionalized elderly, and patients in a critical care environment (intensive care unit [ICU]) are undeniably among the most vulnerable patients, in whom oral status deserves adequate attention because they may suffer from poor oral health [1, 2]. Oral health deteriorates following admission to hospital, and in the critical care setting in particular [3]. Patients who are tracheally intubated and mechanically ventilated are most prone to bad oral health, as a result of various physiological, pathological, mechanical and immunological factors [2, 4, 5]. In addition to issues relating to patient comfort, a lack of oral hygiene is associated with increased morbidity [6, 7]. Poor oral health may lead to the development of caries, thus causing permanent damage to teeth. Potentially lethal complications, such as ventilator-associated pneumonia (VAP), may also be the result of inadequate oral care. The added costs of complications are exponentially higher than the expenses associated with thorough prevention so that complications due to inadequate oral hygiene may carry a substantial health-economic burden [8].

The advantages of the introduction of a medical electronic file system in vascular surgery

Article

Jan 2011

Background. A rising number of claims against hospitals and the lack of a standardized consent form based on individual calculations of death and complications is a growing problem in Poland. Aim: Evaluation of the usefulness of the Medical Electronic File System (ESDM) in clinical practice on the Vascular Surgery Ward. Accuracy evaluation of the P-POSSUM scale as a tool supplying detailed risk calculation for the patient consent form. Material and methods. A comparison of the time consumption of the two parallel patient's medical file systems (electronic and classic/paper) done on 50 elective cases. Evaluation of the predictive accuracy of the P-POSSUM scale in a group of 1270 patients treated in the Vascular Surgery Department of Pomerania University during one year. A prospective comparison of the time taken in dealing with the two systems of medical data files (electronic versus paper). Statistical (Statistica PL) assessment of the accuracy of the P-POSSUM risk calculator and searching for new predictors of early death in Vascular Surgery. Results. The Medical Electronic File System (ESDM) was certified with ISO (hospital quality standard). It allowed a saving of almost half the time for dealing with medical files (14 hours and 6 minutes versus 7 hours and 53 minutes). The time consumed in doctors' paperwork has been decreased by about 30 per cent (3 hours and 43 minutes versus 2 hours and 42 minutes) and the quality of the paperwork has been improved. We confirmed the clinical effectiveness of P-POSSUM as well as ASA scale in vascular surgery. Additional multifactor analysis of early death predictors shows the independent influence of the new factors never used in calculators, e.g. glomellular filtration rate (GFR) beloved 30 ml/min/1.73 msq (p = 0.0014), systemic inflamatory response syndrome (SIRS) (p = 0.00078), critical limb ischaemia (p = 0.000039), acute limb ischaemia (p = 0.000001). Conclusions. 1. Introduction of the Medical Electronic File System (ESDM) in the Vascular Surgery Department of Pomerania Medical University in Szczecin has improved the quality of medical files and greatly reduces the paperwork time. 2. The P-POSSUM calculator is suitable for risk assessment in Vascular Surgery but, due to the progress in medicine, might need to be refreshed. 3. The creation of the National Vascular Surgery Register (KRON) might support work on the suitable risk calculator for "vascular patent" and allow comparison of the results between the sites and the surgeons in Poland.

The Effect of IgM-Enriched Immunoglobulin as Adjunctive Therapy in A Patient Following Sepsis after Thoracoabdominal Aortic Aneurysm Open Repair

Article

Aug 2015

A case of severe hypothermia following anti - Psychotic medication: A case report

Article

Jan 2015
NERVENHEILKUNDE

Thermoregulatory dysfunction is a well-known side effect of central acting drugs. Particularly there is a high awareness that fever can develop in patients receiving antipsychotic medication. It may occur either unescorted or in the context of the malignant neuroleptic syndrome (NMS). However, in comparison to neuroleptics induced hyperthermia, a neuroleptics induced reduction of body temperature draws only minor attention. This is especially surprising as even before the discovery of the antipsychotic effect of the first neuroleptic drug (chlorpromazine) in the year 1952, anaesthesiologists have already tried to use its hypothermia-inducing effects for therapeutic reasons. Here we present the case of a 93-year-old lady with dementia developing a hypothermic episode of 29.5°C receiving a poly-psychopharmacological therapy consisting of risperidone, doxepin, and buspirone. A literature search illustrated that antipsychotic drugs may lead to both hypo- and hyperthermia, which is additionally based on individual predisposition and independent risk factors such as environmental temperature, somatic comorbidity, endocrinological dysfunction and structural brain damage. A complex interaction between dopaminergic regulatory mechanisms concerning the ventral hypothalamus, and peripheral vasomotoric dysregulation may play a vital pathophysiological role.

Gefährliche Kälte durch Neuroleptika

Article

Apr 2012

Apigenin attenuates heart injury in lipopolysaccharide-induced endotoxemic model by suppressing sphingosine kinase 1/sphingosine 1-phosphate signaling pathway

Article

Dec 2014
CHEM-BIOL INTERACT

Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. This study is to investigate the effects of apigenin on heart injury in lipopolysaccharide-induced endotoxemic rat model. Normal Wistar rats were randomly divided into four groups: control group, LPS group (15 mg/kg), LPS plus apigenin groups with different apigenin doses (50 mg/kg, 100 mg/kg). Serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) were measured after the rats were sacrificed. SphK1/S1P signaling pathway proteins, cleaved caspase-3, cleaved caspase-9, Bax and Bcl-2 in heart were measured by Western blot. In vitro, we evaluated the protective effect of apigenin on rat embryonic heart-derived myogenic cell line H9c2 induced by LPS. Apigenin decreased serum levels of CK-MB, LDH, TNF-α, IL-6, IL-1β. SphK1/S1P signaling pathway proteins, cleaved caspase-3, cleaved caspase-9, Bax in heart were found inhibited and Bcl-2 increased in the apigenin groups in vivo. In addition, apigenin inhibited intracellular calcium, the MAPK pathway and SphK1/S1P signaling pathway in vitro. Apigenin exerts pronounced cardioprotection in rats subjected to LPS likely through suppressing myocardial apoptosis and inflammation by inhibiting the SphK1/S1P signaling pathway.

The Effect of Pathophysiology on Pharmacokinetics in the Critically Ill Patient – Concepts appraised by the example of antimicrobial agents

Article

Full-text available

Nov 2014
ADV DRUG DELIVER REV

Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.

Inhibition of brain citrate synthase activity in an animal model of sepsis

Article

Full-text available

Jun 2011

Objective: An extensive body of evidence from experimental studies indicates that sepsis is associated with increased reactive oxygen species production, depletion of antioxidants, and accumulation of markers of oxidative stress. Moreover, mitochondrial dysfunction has been implicated in the pathogenesis of multiple organ dysfunction syndrome (MODS). Citrate synthase is an enzyme localized in the mitochondrial matrix and an important component of the Krebs cycle; consequently, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase activity in the brains of rats submitted to a cecal ligation puncture model of sepsis. Methods: At several times points (3, 6, 12, 24 and 48 hours) after the cecal ligation puncture operation, six rats were killed by decapitation. Their brains were removed, and the hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex were dissected and used to determine citrate synthase activity. Results: We found that citrate synthase activity in the prefrontal cortex was inhibited 12, 24 and 48 hours after cecal ligation puncture. In the cerebral cortex, citrate synthase activity was inhibited 3, 12, 24 and 48 hours after cecal ligation puncture. Citrate synthase was not affected in the hippocampus, striatum or cerebellum up to 48 hours after cecal ligation puncture. Conclusion: Considering that energy impairment due to mitochondrial dysfunction in sepsis has been well described and that oxidative stress plays a crucial role in sepsis development, we believe that energy impairment may also be involved in these processes. If citrate synthase inhibition also occurs in a sepsis model, it is tempting to speculate that a reduction in brain metabolism may be related to the pathophysiology of this disease.

Infection prevention and control strategies in the era of limited resources and quality improvement: A perspective paper

Article

Aug 2013
Aust Crit Care

This paper aims to describe, using an evidence-based approach, the importance of and the resources necessary for implementing effective infection prevention and control (IPC) programmes. The intrinsic and explicit values of such strategies are presented from a clinical, health-economic and patient safety perspective. Policy makers and hospital managers are committed to providing comprehensive, accessible, and affordable healthcare of high quality. Changes in the healthcare system over time accompanied with variations in demographics and case-mix have considerably affected the availability, quality and ultimately the safety of healthcare. The main goal of an IPC programme is to prevent and control healthcare-associated infections (HAI). Many patient-, healthcare provider-, and organizational factors are associated with an increased risk for acquiring HAIs and may impact both the quality and outcome of patient care. Evidence has been published in support of having an effective IPC programme. It has been estimated that about one-third of HAIs could be prevented if key elements of the evidence-based recommendations for IPC are adequately introduced and followed. However, several healthcare agencies from over the world have reported deficits in the essential resources and components of current IPC programmes. To meet its main goal, staffing, training, and infrastructure requirements are needed. Nevertheless, and given the economic crisis, policy makers and hospital managers may be tempted to not increase or even to reduce the budget as it consumes resources and does not generate sufficient visible revenue. IPC is a critical issue in patient safety, as HAIs are by far the most common complication affecting admitted patients. The significant clinical and health-economic burden HAIs place on the healthcare system speak to the importance of getting introduced effective IPC programmes.

Oral Care of Intubated Patients

Article

May 2008
Clin Pulm Med

Receiving care in an intensive care unit (ICU) can greatly influence patients' survival and quality of life. The benefit achieved in terms of improved survival rates is particularly attributed to the favorable changes in supportive care made over the past decades. The improved acute phase survival, however, was associated with a growing number of long-term ICU residents at high risk for infection, especially when orally intubated. Today, one of the most dreaded complications associated with endotracheal intubation is ventilator-associated pneumonia. Bad oral health and microaspiration of subglottic secretions and debris are pivotal in the pathogenesis of this harmful complication. Good oral hygiene is a key issue in preventing dental plaque formation and microbial growth in the mouth. However, evidence-based recommendations for oral care are not available. Therefore, substantial efforts aiming to provide this information are urgently needed, as well as training and motivation of all health care workers involved in the care of intubated patients. In the meantime, providing adequate chemical (ie, use of chlorhexidine or povidone-iodine solutions) as well as mechanical (ie, manual or electric toothbrush, and subglottic aspiration) oral care is considered suitable because both approaches may be the main contributing factors to decrease the risk of respiratory infections.

Hypothermie unter Olanzapin

Article

May 2012

Hintergrund Hypothermien unter Antipsychotikabehandlung sind seit Jahrzehnten bekannt, finden jedoch im klinischen Alltag nur geringe Beachtung. Material und Methoden Die vorliegende Arbeit beschreibt eine Serie von 3 Fällen ausgeprägter Hypothermie nach Applikation von Olanzapin. Risikofaktoren und Pathomechanismen der neuroleptikainduzierten Hypothermie werden anhand der vorgestellten Fälle und einer Literaturübersicht zum Thema diskutiert. Ergebnisse Eine 51-jährige Frau mit katatoner Schizophrenie und Hypothyreose entwickelte bei kachektischem Ernährungszustand unter antipsychotischer Medikation mit 30 mg Olanzapin pro Tag eine Hypothermie von 30,0°C Körperkerntemperatur unter Komedikation mit Lorazepam und L-Thyroxin. Bei einer 48-jährigen Patientin mit ebenfalls katatoner Schizophrenie kam es nach Einmalgabe von 10 mg Olanzapin per os und 3 mg Lorazepam auf 3 Einzeldosen verteilt zu einer Hypothermie auf 31,0°C. Die dritte kasuistische Darstellung berichtet von einem 69-jährigen Patienten mit akuter schizophreniformer Störung, welcher nach Einmalgabe von 5 mg Olanzapin ohne weitere Komedikation eine Hypothermie von 33,0°C in Verbindung mit einem reversiblen AV-Block 3. Grades entwickelte. Schlussfolgerung Antipsychotika können bei individueller Disposition und in Kombination mit unabhängigen Risikofaktoren wie Umgebungstemperatur, somatischer Begleiterkrankung, endokrinologischen Störungen (z. B. Hypothyreose) oder organischer ZNS-Vorschädigung sowohl zu Hypo- als auch zu Hyperthermie führen. Ursächlich hierfür erscheint ein komplexes Zusammenspiel dopaminerger Regulationsmechanismen im ventralen Hypothalamus mit Veränderungen der Thermoregulation im Bereich der Vasomotorik von Hautgefäßen. Im klinischen Alltag sollte an die antipsychotikaassoziierte Hypothermie gedacht werden, da sie eine hochrelevante unerwünschte Arzneimittelwirkung mit potenziell lebensbedrohlichem Charakter darstellt.

Sepsis and septic shock: Pathophysiological and cardiovascular background as basis for therapy

Article

Sep 2010
ACTA CLIN BELG

Sepsis and septic shock are common causes for admission to intensive care units. The morbidity and mortality remain unacceptably high despite the advanced treatments. To review the most commonly reported underlying mechanisms of sepsis and septic shock, besides discussion of sepsis-induced cardiovascular dysfunction. Therapeutic strategies for sepsis-induced myocardial depression are briefly discussed. The development of sepsis and septic shock is multifactorial. Two major mechanisms contribute to the haemodynamic collapse. The extrinsic and intrinsic mechanisms induce a complex cascade which results in the release of pro- and anti-inflammatory mediators. Sepsis develops when the initial, appropriate host response to an infection becomes amplified and then dysregulated leading to haemodynamic and circulatory changes. The pro-inflammatory mediators tumour necrosis factor alpha, interleukin-beta and nitric oxide play a significant role in sepsis-related hypotension, shock and depression of cardiomyocyte contractility. Septic cardiac dysfunction can be explained by various mechanisms: changes in circulating volume, down-regulation of beta-adrenergic receptors, depressed post-receptor signalling pathways, reduced calcium release from the sarcoplasmic reticulum and impaired electromechanical coupling and reduced calcium sensibility at the myofibrillar level. Mitochondrial derangement seems to be of great importance in tissue injury and sepsis-associated multi organ failure. There is no consistent protocol for treating sepsis and septic shock. Guidelines include early goal-directed therapy, source control and haemodynamic supportive measures. Further studies are needed to distinguish the importance of these various mechanisms. We recommend that further investigational work should focus on the recovery of the mitochondria-related bio-energetic shut down as the mitochondria could play a key role in the understanding of apoptosis and protective measures. Understanding the pathophysiology of sepsis and septic shock will inevitably lead to a more accurate treatment of these still too often fatal syndromes.

Prevention of nosocomial infections in intensive care patients*

Article

Sep 2010
Nurs Crit Care

Background: Changes in patient profile, and in the health care environment, altering socioeconomic conditions and advances in science and information technology challenge the nursing profession, in particular intensive care nursing. All these changes will undoubtedly affect the way we will practice in the (near) future. A comprehensive understanding of these factors is therefore essential if nursing is to meet the challenges presented by tomorrow's critical care environment. Precisely because of the often expensive high-tech evolutions that have occurred at a rapid pace and are to be further expected, a continued focus on the basics of nursing, the core role of care, as well as maintaining confidence in the capacity to deliver safe, high-quality, and evidence-based patient care will increasingly be a challenge to critical care nurses. In particular, basic nursing skills and knowledge remain a key prerequisite in the prevention of nosocomial infections, which is a continuing major complication and threat to intensive care unit patients. However, critical care nurses' knowledge about the evidence-based consensus recommendations for infection prevention and control has been found to be rather poor. It has nevertheless been demonstrated that a meticulous implementation of such preventive bundles may result in significantly better patient and process outcomes. Moreover, many preventive strategies are considered to be easy to implement and inexpensive. As such, a first and critical step should be to increase critical care nurses' adherence to the recommendations of the Centers for Disease Control and Prevention. Aim: In this article, an up-to-date assessment of evidence-based recommendations for the prevention of nosocomial infections, with special focus on catheter-related bloodstream infections and strategies relevant for nurses working in critical care environments, will be provided. Additionally, we will detail on a number of approaches advocated to translate the internationally accepted consensus recommendations to the needs and expectations of critical care nurses, and to consequently enhance the likelihood of successful implementation and adherence. These steps will help critical care nurses in their striving towards excellence in their profession. Summary: Intensive care nurses can make a significant contribution in preventing nosocomial infections by assuming full responsibility for quality improvement measures such as evidence-based infection prevention and control protocols. However, as general knowledge of the preventive measures has been shown to be rather poor, nurses' education should include supplementary support from evidence-based recommendations.

Extravascular lung water index as a sign of developing sepsis in burns

Article

Dec 2010

Sepsis and multiple organ failure remain the leading cause of mortality and morbidity in burns. The aim of our study was to analyse the predictive value of extravascular lung water index (EVLWI) in the development of severe septic complications and mortality. The records of 28 patients with total burned surface area >20% were analysed (EVLWI, procalcitonin (PCT), intrathoracic blood volume index (ITBVI), positive end-expiratory pressure (PEEP), Baltimore Sepsis Scale (BaSS)). Diagnosis of infection (day 0) was based on consensus conference of the American Burn Association. EVLWI correlated with PCT (r=0.597), and PEEP (r=0.501) on day 0 and with BaSS (r=0.524) and MODS (r=0.513) from day 1. EVLWI was elevated (p<0.05) from one day before diagnosis of infection, PCT was higher (p<0.05) from day 0 only. ROC analysis for EVLWI on day -1 and for PCT on day 0 showed similar areas under curve (0.760; 0.766). EVLWI >9 ml kg(-1) on day -1 predicted sepsis (89% sensitivity, 72% specificity). After antibiotic treatment EVLWI remained high in non-survivors, decreased in survivors, whereas PCT decreased in both groups. Our data suggest that EVLWI is an early warning sign of developing infection and its continuous elevation can predict poor prognosis in burns.

Effects of hydroxyethyl starch (130 kD) on brain inflammatory response and outcome during normotensive sepsis

Article

May 2010

During sepsis, the dysfunction of blood-brain barrier (BBB) was mediated by inflammation and subsequently caused sepsis-associated encephalopathy. Hydroxyethyl starch (HES, 130/0.4) is most widely used for volume replacement to maintain or improve tissue perfusion in patients with sepsis, trauma, and shock. This study was undertaken to investigate the effects of HES on BBB permeability, brain edema, inflammatory response and clinical outcome in septic rats. Using the cecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with 15 ml/kg HES or normal saline 4h after the operation. Two hours later, expressions of brain toll-like receptor (TLR)-2, TLR4 and intercellular adhesion molecule (ICAM)-1 mRNA was determined by real-time reverse transcription-polymerase chain reaction; inflammatory cytokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by enzyme-linked immunosorbent assay; activity of nuclear factor-kappa B (NF-kappaB) by electrophoretic mobility shift assay; BBB permeability by Evans blue extravasation method; brain edema by wet/dry weight ratio. Weight loss, and clinical symptoms were also observed. Without obvious influence on systemic macrohemodynamics, HES could markedly attenuate BBB dysfunction and brain edema. Meanwhile, HES could significantly reduce TNF-alpha, IL-6, and ICAM-1 mRNA, inhibit NF-kappaB activation, and down-regulate TLR2 and TLR4 expression in the brain. In addition, CLP-induced increase in weight loss, and clinical symptoms was not reduced after treatment with HES. HES could ameliorate BBB dysfunction and inflammation mediators by modulating brain TLR2 and TLR4 expression during sepsis. However, HES could not improve clinical outcome.

Thrombocytopenia and outcome in critically ill patients with bloodstream infection

Article

Feb 2010

Thrombocytopenia is common in intensive care units (ICUs), and is associated with a poor prognosis. An acute decrease in total platelet count is frequently observed in severe sepsis, followed by a relative increase indicating organ-failure recovery. However, few data are available describing this effect and its relationship with outcomes in specific subgroups of ICU patients. A retrospective, observational cohort study was conducted to investigate the incidence and prognosis of thrombocytopenia in a cohort of critically ill patients (n=155) with a microbiologically documented nosocomial bloodstream infection. Thrombocytopenia occurred more frequently in nonsurvivors. The ICU mortality rates increased according to severity of thrombocytopenia. Thrombocytopenia was independently associated with worse outcomes in ICU patients with nosocomial bloodstream infection. Determining trends in platelet counts is of additional prognostic value, compared with single measurements.

Severe sepsis in critically ill patients: Early recognition and outcome

Article

Dec 2009
ACTA ANAESTH SCAND

Dominique M Vandijck

Predicting Bacteremia in Patients with Sepsis Syndrome

Article

Full-text available

Dec 1997

The goal of this study was to develop and validate clinical prediction rules for bacteremia and subtypes of bacteremia in patients with sepsis syndrome. Thus, a prospective cohort study, including a stratified random sample of 1342 episodes of sepsis syndrome, was done in eight academic tertiary care hospitals. The derivation set included 881 episodes, and the validation set included 461. Main outcome measures were bacteremia caused by any organism, gram-negative rods, gram-positive cocci, and fungal bloodstream infection. The spread in probability between low- and high-risk groups in the derivation sets was from 14.5% to 60.6% for bacteremia of any type, from 9.8% to 32.8% for gram-positive bacteremia, from 5.3% to 41.9% for gram-negative bacteremia, and from 0.6% to 26.1% for fungemia. Because the model for gram-positive bacteremia performed poorly, a model predicting Staphylococcus aureus bacteremia was developed; it performed better, with a low- to high-risk spread of from 2.6% to 21.0%. The prediction models allow stratification of patients according to risk of bloodstream infections; their clinical utility remains to be demonstrated.

Cost-effectiveness of early goal-directed therapy in the treatment of severe sepsis and septic shock

Article

Full-text available

Mar 2003
CRIT CARE

Early goal-directed therapy (EGDT) for severe sepsis and septic shock has been shown to significantly decrease 60 day mortality and survivor hospital length of stay [1]. However, concern exists over the additional resources and personnel required for this labor-intensive therapy.

CDC Definitions for Nosocomial Infections

Article

Full-text available

Jul 1988
AM J INFECT CONTROL

The Centers for Disease Control (CDC) has developed a new set of definitions for surveillance of nosocomial infections. The new definitions combine specific clinical findings with results of laboratory and other tests that include recent advances in diagnostic technology; they are formulated as algorithms. For certain infections in which the clinical or laboratory manifestations are different in neonates and infants than in older persons, specific criteria are included. The definitions include criteria for common nosocomial infections as well as infections that occur infrequently but have serious consequences. The definitions were introduced into hospitals participating in the CDC National Nosocomial Infections Surveillance System (NNIS) in 1987 and were modified based on comments from infection control personnel in NNIS hospitals and others involved in surveillance, prevention, and control of nosocomial infections. The definitions were implemented for surveillance of nosocomial infections in NNIS hospitals in January 1988 and are the current CDC definitions for nosocomial infections. Other hospitals may wish to adopt or modify them for use in their nosocomial infections surveillance programs.

Molecular interactions on microarrays

Article

Full-text available

Feb 1999

The structural features of nucleic acid probes tethered to a solid support and the molecular basis of their interaction with targets in solution have direct implication for the hybridization process. We discuss how arrays of oligonucleotides provide powerful tools to study the molecular basis of these interactions on a scale which is impossible using conventional analysis.

Early Goal-Directed Therapy In The Treatment Of Severe Sepsis And Septic Shock

Article

Full-text available

Nov 2001

Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001). Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

Systemic Inflammatory Response and Progression to Severe Sepsis in Critically Ill Infected Patients

Article

Full-text available

Mar 2005

The systemic inflammatory response syndrome has low specificity to identify infected patients at risk of worsening to severe sepsis or shock. To examine the incidence of and risk factors for worsening sepsis in infected patients. A 1-year inception cohort study in 28 intensive care units of patients (n = 1,531) having a first episode of infection on admission or during the stay. The cumulative incidence of progression to severe sepsis or shock was 20% and 24% at Days 10 and 30, respectively. Variables independently associated (hazard ratio [HR]) with worsening sepsis included: temperature higher than 38.2 degrees C (1.6), heart rate greater than 120/minute (1.3), systolic blood pressure higher than 110 mm Hg (1.5), platelets higher than 150 x 109/L (1.5), serum sodium higher than 145 mmol/L (1.5), bilirubin higher than 30 mumol/L (1.3), mechanical ventilation (1.5), and five variables characterizing infection (pneumonia [HR 1.5], peritonitis [1.5], primary bacteremia [1.8], and infection with gram-positive cocci [1.3] or aerobic gram-negative bacilli [1.4]). The 12 weighted variables were included in a score (Risk of Infection to Severe Sepsis and Shock Score, range 0-49), summarized in four classes of "low" (score 0-8) and "moderate" (8.5-16) risk (9% and 17% probability of worsening, respectively), and of "high" (16.5-24) and "very high" (score > 24) risk (31% and 55% probability, respectively). One of four patients presenting with infection/sepsis worsen to severe sepsis or shock. A score estimating this risk, using objectively defined criteria for systemic inflammatory response syndrome, could be used by physicians to stratify patients for clinical management and to test new interventions.

Plasma level of a triggering receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with suspected sepsis (vol 141, pg 9, 2004)

Article

Apr 2005

Increase in National Hospital Discharge Survey rates for septicemia—United States, 1979–1987

Article

Jan 1990

Centers for Disease Control

The International Sepsis Forum Consensus definitions of infections in the intensive care unit

Article

Jan 2005
CRIT CARE MED

The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study

Article

Jan 1995

Manuel Sigfrido Rangel-Frausto

Occult bacterial infection in adults with unexplained fever. Validation of a diagnostic index

Article

Jun 1990
ARCH INTERN MED

L. Leibovici

Occult Bacterial Infection in Adults With Unexplained Fever

Article

Jun 1990
ARCH INTERN MED

Leonard Leibovici

• We tested the performance of a previously developed index to diagnose occult bacterial infection and bacteremia in febrile patients. A total of 113 patients consecutively hospitalized because of an acute febrile disease, without a recognizable source of fever, were divided into four groups, with increasing probability of bacterial infection and bacteremia. None of the patients in the first group had bacterial infection or bacteremia. The incidence of bacterial infection and bacteremia was 27% and 11% in the second group, 32% and 17% in the third group, and 53% and 35% in the fourth group. No patient in the first group died, as opposed to 29% of patients in the fourth group. The use of the index at admission would have probably changed the treatment of 11% of patients. Thus, the index could be used to identify patients to be discharged from the emergency department (first group) or hospitalized and treated empirically (fourth group). (Arch Intern Med. 1990;150:1270-1272)

Electronic Alerts to Prevent Venous Thromboembolism Among Hospitalized Patients

Article

Jul 2005

The authors hypothesized that use of a computer alert program to alert physicians regarding hospitalized patients at high risk for VTE might reduce the frequency of DVT by increasing the frequency of prophylaxis. A computer program was developed linked to a patient database to identify hospitalized patients at risk for VTE. The patients were randomly assigned to an intervention group in which the treating physician was made aware of the patient’s risk of VTE (n = 1255) or to a control group in which no such alert was issued (n = 1251). Physicians receiving the alert for VTE prophylaxis were required to acknowledge the alert and could then order or withhold prophylaxis according to clinical judgment. Prophylaxis included graduated compression stockings, pneumatic compression boots, unfractionated heparin, warfarin, or low-molecular-weight heparin. Clinically diagnosed, objectively confirmed VTE (DVT or pulmonary embolism) at 90 days was the primary end point.

Sepsis/septic shock

Article

Jun 1996
CRIT CARE MED

L B Hinshaw

Objective: An overview of the importance of understanding mechanisms occurring in the microcirculation during septic and endotoxic shock. The thesis of the paper is to place emphasis on this important vascular network to ultimately benefit the patient. Data sources: Early descriptions of vascular reactions to endotoxin which suggest that the microcirculation is a major site of attack during shock. More recent studies were sought out and examined as to their possible impacts on the microcirculation. Study selection: Early comprehensive studies concerning vascular reactions in the microcirculation during shock were selected. Subsequent studies identified from the mainstream scientific medical literature describe the actions of blood, cells, and the emerging significant role of the vascular endothelium among other factors. A consensus view is identified, pointing to the causes of a malfunctioning microcirculation during shock. Data extraction: Data gathered from reports in the mainstream, well-established basic and clinical literature, from reviews and forum reports, from studies by well-established investigators, and from more recent reports of excellent quality. Data synthesis: The microcirculation undergoes massive alterations during sepsis/septic shock. There are numerous changes, including slowing of capillary blood flow due to depressed perfusion pressure as a result of systemic pressure reduction and local arteriolar constriction. Observations suggest that the microcirculation is shut off early in severe sepsis, allowing the effects of hypoperfusion and attacks by microorganisms to prevail in their destructive capabilities. Widespread capillary dilation may ultimately occur. However, with blood flow diverted through some arteriovenous channels, important areas of capillary exchange are bypassed. Decreased capillary blood flow during shock results from failure to allow normal passage of cellular elements, including erythrocytes and neutrophils. This defect occurs, in part, because of decreased perfusion pressure, decreased deformability of red and white cells, constricted arterioles, circulating obstructive fragments (including hemoglobin), and plugging of microvessels with "sludge." Other factors are adherence of cells to capillary and venular epithelial membranes creating increased resistance to flow, loss of fluid through abnormal transcapillary exchange, differential vascular resistance changes between various beds (e.g., intestinal vs. muscle), and the relative absence of regulatory neurohumoral control of small vessel segments of the circulation. During sepsis/septic shock, endothelial cells are reported to modulate vascular tone, control local blood flow, influence the rate of leakage of fluids and plasma proteins into tissues, modulate the accumulation and extravasation of white cells into tissues, and influence white cell activation. As a result of the predominance of many destructive factors, a subsequent round of tissue damage may occur. Because of prolonged capillary vascular stasis, deficient flow, and factors released from injured cells, the microcirculation becomes a trap for uncontrolled bacterial growth enhanced by sustained hypoxemia, acidosis and toxemia. These events may combine to contribute to the loss of normal cell integrity and death of the host. Conclusions: The purpose of this review is to draw the readers' attention to the growing list of adverse factors occurring in the microcirculation during sepsis/septic shock. A further aim is to point to the realization of the complexity of factors which may contribute to the importance of a well-functioning microcirculation.

Angus D, Linde-Zwirble W, Lidicker J, Clermont G, Carcillo J & Pinsky M. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med29: 1303-1310 10.1097/00003246-200107000-00002

Article

Jul 2001
CRIT CARE MED

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.

Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a reevaluation

Article

Jan 2000
CRIT CARE MED

Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies. Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes. An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways. Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course. This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.

Hypothermia and cytokines in septic shock

Article

Jun 2000

Background: Hypothermic patients with sepsis have a higher mortality than febrile patients. Since the pro-inflammatory cytokines play a crucial role in the genesis of fever we postulated that hypothermic patients would have lower circulating levels of these cytokines than febrile patients. Methods: Patients with septic shock who were enrolled into the placebo limb of the NORASEPT II study were analyzed. Body temperature, IL-6,TNF-α, sTNF-R55 and sTNF-R75 concentrations were measured at enrollment. The study population was divided into a hypothermic (temp, ≤ 35.6 oC) and a febrile group (temp, a 38.3oC) according to the core temperature at enrollment. Clinical and cytokine data was extracted allowing for comparisons between these two groups of patients. Results: A complete data set was available for 930 patients. 195 (21%)patients were hypothermic at enrollment. The 28 day survival of these patients was significantly lower than that of the febrile patients (34% vs 59%, p<0.001). The hypothermic patients had a higher incidence of organ dysfunction at enrollment.There was no significant differences in the cytokine profile between the two groups of patients (see table). In addition, there was no correlation between the core body temperature at enrollment and the circulating levels of cytokines measured. There was no difference in the spectrum of infecting pathogens between the two groups of patients. Conclusion: The hypothermia of sepsis cannot be explained by lower levels of circulating proinflammatory cytokines. We postulate hypothalamic dysfunction may lead to hypothermia in these patients. Cytokine levels at enrollment Hypothermic (n=195) Febrile (n=735) TNF (pg/ml) 385±355 413±502 IL-6 (ug/ml) 50.2±122.4 42.9±133.2 sTNF-R75 (ng/ml) 22.6±17.9 22.0±21.1 sTNF-R55 (ng/ml) 26.4±21.4 23.3±18.8.

Clinical and economic outcomes in critically ill patients with nosocomial catheter-related bloodstream infections

Article

Jan 2005

Background. Central venous catheters are universally used during the treatment of critically ill patients. Their use, however, is associated with a substantial infection risk, potentially leading to increased mortality and costs. We evaluate clinical and economic outcomes associated with nosocomial central venous catheter-related bloodstream infection (CR-BSI) in intensive care unit (ICU) patients.Methods. A retrospective (1992-2002), pairwise-matched (ratio of case patients to control subjects, 1 : 2 or 1 : 1), risk-adjusted cohort study was performed at a 54-bed general ICU at a university hospital. ICU patients with microbiologically documented CR-BSI (n=176) were matched with control subjects (n=315) on the basis of disease severity, diagnostic category, and length of ICU stay (equivalent or longer) before the onset of CR-BSI in the index case patient. Clinical outcome was principally evaluated by in-hospital mortality. Economic outcome was evaluated on the basis of duration of mechanical ventilation, length of ICU and hospital stays, and total hospital costs, as derived from the patient's hospital invoices.Results. The attributable mortality rate for CR-BSI was estimated to be 1.8% (95% confidence interval, -6.4% to 10.0%); in-hospital mortality rates for patients with CR-BSI and matched control subjects were 27.8% and 26.0%, respectively. CR-BSI was associated with significant excesses in duration of mechanical ventilation, duration of ICU and hospital stays, and a significant increase in total hospital cost. Linear regression analysis with adjustment for duration of hospitalization and clinical covariates, revealed that CR-BSI is independently associated with higher costs.Conclusions. In ICU patients, CR-BSI does not result in increased mortality. It is, however, associated with a significant economic burden, emphasizing the importance of continuous efforts in prevention.

The Ventilatory Response in Severe Metabolic Acidosis

Article

Jun 1976
Clin Sci Mol Med

M Fulop

1. The ventilatory response to severe metabolic acidosis was studied by measuring arterial blood carbon dioxide tension and pH in sixty-seven patients with blood pH < 7·10, none of whom had hypercapnia, pulmonary oedema, or chronic pulmonary insufficiency. The results were compared with those previously found in patients with uncomplicated diabetic ketoacidosis. 2. By that comparison, fifty-two of the sixty-seven patients with blood pH < 7·10 were judged to have ‘appropriate hypocapnia’, and fifteen had ‘submaximal hypocapnia’. Thirteen of the latter fifteen had circulatory failure and/or acute hypoxia, and seven of nine in whom it was measured had plasma lactate >9 mmol/l. 3. Hyperventilation was therefore usually well sustained in these patients with severe metabolic acidosis, except in most of those with acute tissue hypoxia. The latter may have had insufficient time to achieve maximum hyperventilation in response to their acidosis, or perhaps their submaximal hypercapnia presaged imminent failure of the hyperventilatory response.

The ACCP-SCCM consensus conference on sepsis and organ failure

Article

Jul 1992

Difficulty in predicting bacteremia in elderly emergency patients

Article

Aug 1992
ANN EMERG MED

To characterize the clinical presentation and identify factors predictive of bacteremia in elderly patients. Retrospective review of emergency department charts, hospital records, and microbiology reports. Community teaching hospital with annual ED census of 65,000 adults. Seven hundred fifty elderly patients (aged 65 to 99 years) who were evaluated by the emergency physician, had blood cultures obtained in the ED, and were hospitalized with a suspected infectious process during a 12-month period. Records were analyzed for demographic information, underlying diseases, clinical presentation, laboratory findings, sources of infection, and causative organisms. Using contingency tables, 79 patients with positive blood cultures were compared with a random sample of 136 patients with sterile blood cultures to identify clinical variables significantly (P less than .05) associated with bacteremia. Logistic regression analysis was performed with significant factors to develop a model to predict bacteremia. Sensitivity, specificity, and predictive values were calculated for the model. The prevalence of bacteremia was 10.6%. Escherichia coli was the most commonly isolated pathogen (29% of cases), and the urinary tract was the most common source of infection (44.3% of cases). Logistic regression analysis showed that altered mental status (odds ratio, 2.88; 95% confidence interval [Cl], 1.52 to 5.50), vomiting (odds ratio, 2.63; 95% Cl, 1.16 to 6.15), and WBC band forms of more than 6% (0.06) (odds ratio, 3.50; 95% Cl, 1.58 to 5.27) were independent predictors of bacteremia. The presence of at least one of these three factors had a sensitivity of 0.85 (95% Cl, 0.75 to 0.92) and a specificity of 0.46 (95% Cl, 0.38 to 0.55) for predicting bacteremia in the study group. The positive predictive value was 0.16 (95% Cl, 0.12 to 0.19) and the negative predictive value was 0.96 (95% Cl, 0.94 to 0.98) for the ED patient group that met inclusion criteria. Elderly patients fail to manifest identifiable clinical features indicative of bloodstream infection. The sensitivity and specificity of the best statistical model for identifying bacteremic elderly patients suggest that clinical indicators alone are unreliable predictors of bacteremia in the geriatric ED population studied.

Sepsis, the Sepsis Syndrome, Multi-Organ Failure: A Plea for Comparable Definitions

Article

Mar 1991

Roger C. Bone

The terms bacteremia, sepsis, septicemia, sepsis syndrome, and septic shock are used in various contexts. Because imprecise meanings are often misinterpreted, standardized terminology is advocated. Positive blood culture constitutes the diagnostic criterion for bacteremia. The term septicemia should be discarded. Sepsis should be defined as clinical evidence of infection plus the systemic response to it (tachypnea, tachycardia, and hypothermia or hyperthermia). The sepsis syndrome is sepsis with evidence of altered organ perfusion. Septic shock and refractory septic shock are defined as the sepsis syndrome with responsive and refractory hypotension, respectively. Early recognition of sepsis may improve survival through prompt and aggressive therapeutic intervention.

Occult bacterial infection in adults with unexplained fever. Validation of a diagnostic index

Article

Jul 1990
ARCH INTERN MED

We tested the performance of a previously developed index to diagnose occult bacterial infection and bacteremia in febrile patients. A total of 113 patients consecutively hospitalized because of an acute febrile disease, without a recognizable source of fever, were divided into four groups, with increasing probability of bacterial infection and bacteremia. None of the patients in the first group had bacterial infection or bacteremia. The incidence of bacterial infection and bacteremia was 27% and 11% in the second group, 32% and 17% in the third group, and 53% and 35% in the fourth group. No patient in the first group died, as opposed to 29% of patients in the fourth group. The use of the index at admission would have probably changed the treatment of 11% of patients. Thus, the index could be used to identify patients to be discharged from the emergency department (first group) or hospitalized and treated empirically (fourth group).

Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: Incidence, morbidities and outcomes in surgical ICU patients

Article

Apr 1995

To determine the incidence of systemic inflammatory response syndrome (SIRS), sepsis and severe sepsis in surgical ICU patients and define patient characteristics associated with their acquisition and outcome. One-month prospective study of critically ill patients with a 28 day in-hospital follow up. Surgical intensive care unit (SICU) at a tertiary care institution. All patients (n = 170) admitted to the SICU between April 1 and April 30, 1992 were prospectively followed for 28 days. Daily surveillance was performed by two dedicated, specifically-trained research nurses. Medical and nursing chart reviews were performed, and follow up information at six and twelve months was obtained. The in-hospital surveillance represented 2246 patient-days, including 658 ICU patient-days. Overall, 158 patients (93%) had SIRS for an incidence of 542 episodes/1000 patients-days. The incidence of SIRS in the ICU was even higher (840 episodes/1000 patients-days). A total of 83 patients (49%) had sepsis; among them 28 developed severe sepsis. Importantly, 13 patients had severe sepsis after discharge from the ICU. Patient groups were comparable with respect to age, sex ratio, and type of surgery performed. Apache II score on admission to the ICU and ASA score at time of surgery were significantly higher (p < 0.05) only for patients who subsequently developed severe sepsis. The crude mortality at 28 days was 8.2% (14/170); it markedly differed among patient groups: 6% for those with SIRS vs. 35% for patients with severe sepsis. Patients with sepsis and severe sepsis had a longer mean length of ICU stay (2.1 +/- 0.2 and 7.5 +/- 1.5, respectively) than those with SIRS (1.45 +/- 0.1) or control patients (1.16 +/- 0.1). Total length of hospital stay also markedly differed among groups (35 +/- 9 (severe sepsis), 24 +/- 2 (sepsis), 11 +/- 0.8 (SIRS), and 9 +/- 0.1 (controls, respectively). Almost everyone in the SICU had SIRS. Therefore, because of its poor specificity, SIRS was not helpful predicting severe sepsis and septic shock. Patients who developed sepsis or severe sepsis had higher crude mortality and length of stay than those who did not. Studies designed to identify those who develop complications of SIRS would be very useful.

The Natural History of the Systemic Inflammatory Response Syndrome (SIRS)

Article

Feb 1995

Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. Prospective cohort study with a follow-up of 28 days or until discharge if earlier. Three intensive care units and three general wards in a tertiary health care institution. Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count. Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death. During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations. This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.

An overview of mortality prediction in sepsis

Article

Mar 1995
CRIT CARE MED

To review the evolution and development of mortality risk prediction methods as they have been applied to the management of septic patients. Selected relevant articles from the pertinent literature. Theoretical and clinical data on the mortality risk identification, severity of illness scoring systems, and cytokine levels as they relate to mortality in patients with sepsis. All concepts relating to mortality risk prediction, cytokines, severity of illness, and intensive care unit (ICU) mortality were explored and interrelated accordingly. In order to improve the precision of the evaluation of new therapies for the treatment of sepsis, to monitor their utilization and to refine their indications, it has been recommended that mortality risk stratification or severity of illness scoring systems be utilized in clinical trials and in practice. With the increasing influence of managed care on healthcare delivery, there will be an increased demand for techniques to stratify patients for cost-effective allocation of care. Severity of illness scoring systems are widely utilized for patient stratification in the management of cancer and heart disease. However, the use of such systems in patients with sepsis has been limited to application in clinical trial design for assurance of balance among treatment groups. Mortality risk prediction in sepsis has evolved from identification of risk factors, and simple counts of failing organs, to sophisticated techniques that mathematically transform a raw score, comprised of physiologic and/or clinical data, into a predicted risk of death. Most of the developed systems are based on global ICU populations rather than upon sepsis patient databases. A few, newer systems are derived from such databases. However, the overall discriminating ability of the various methods is similar. Mortality prediction has also been carried out from assessments of endotoxin or cytokine (interleukin-1, interleukin-6, tumor necrosis factor) plasma concentrations. While increased levels of these substances have been correlated with increased mortality, difficulties with bioassay and their sporadic appearance in the bloodstream prevent these measurements from being practically applied. The calibration of risk prediction methods comparing predicted with actual mortality across the breadth of risk for a population of patients is excellent, but overall accuracy in individual patient predictions is such that clinical judgment must remain a major part of decision-making. However, as databases of appropriate patient information increase in size and complexity, it may be possible in the future to devise a scoring system that can be relied on to assist in clinical decision-making. Severity of illness scoring systems are widely used in critically ill patients. However, their use in patients with sepsis has largely been limited to a means of stratification in clinical trials. As newer sepsis therapies become available, it may be possible to use such systems for refining their indications, and monitoring their utilization. Finally, as the databases supporting the systems increase in size and complexity, it may be possible to utilize them in clinical decision-making.

Is presentation of bacteremia in the elderly the same as in younger patients?

Article

Jan 1996
AM J MED

To compare the presentation of bacteremia in young and elderly patients. Seventy-one elderly (mean age 80.4 years) and 34 younger inpatients (mean age 45.7 years) with bacteremia were prospectively studied. These were compared with a control group of 187 geriatric patients (mean age 81.3 years) with clinical signs of bacteremia but in whom blood cultures were negative. Bacteremia was defined as one or more positive blood cultures showing a pathogenic bacteria in patients with clinical signs of bacteremia. In all 105 patients with bacteremia, 16 common clinical or biological signs of the disease were immediately investigated after blood culture. Patients were classified into three groups: elder patients and young patients with bacteremia and elderly patients without bacteremia. Only three clinical findings of the 16 studied were found in at least 70% of the bacteremic elderly patients: fever, increased erythrocyte sedimentation rate, and a clinical indication of the source of infection. These three signs were found statistically more often in bacteremic elderly compared with nonbacteremic elderly patients (P < 0.01). Seven other signs (hypothermia, altered mental state, leukopenia, and lymphopenia) had a specificity above 80%. On a logistic regression analysis, four variables were significantly and independently associated with bacteremia in the elderly: rapid onset of infection (defined as a period < or = 48 hours between the earliest manifestation of bacteremia and the time of blood blood sample), fever, altered general state, and clinical indication of the source of infection. Younger infected patients had more chills, sweating, alter general state, altered mental state or lymphopenia than did the bacteremic elderly patients. Bacteremic elderly patients had statistically few symptoms than the young infected patients (P < 0.001). In elderly patients with early stage bacteremia, most of the signs or symptoms that are considered typical in the literature appear irregularly. None appeared pathognomonic. Elderly patients with bacteremia had fewer signs or symptoms than younger infected patients.

Sepsis/septic shock: participation of the microcirculation: an abbreviated review

Article

Jul 1996
CRIT CARE MED

L B Hinshaw

An overview of the importance of understanding mechanisms occurring in the microcirculation during septic and endotoxic shock. The thesis of the paper is to place emphasis on this important vascular network to ultimately benefit the patient. Early descriptions of vascular reactions to endotoxin which suggest that the microcirculation is a major site of attack during shock. More recent studies were sought out and examined as to their possible impacts on the microcirculation. Early comprehensive studies concerning vascular reactions in the microcirculation during shock were selected. Subsequent studies identified from the mainstream scientific medical literature describe the actions of blood, cells, and the emerging significant role of the vascular endothelium among other factors. A consensus view is identified, pointing to the causes of a malfunctioning microcirculation during shock. Data gathered from reports in the mainstream, well-established basic and clinical literature, from reviews and forum reports, from studies by well-established investigators, and from more recent reports of excellent quality. The microcirculation undergoes massive alterations during sepsis/septic shock. There are numerous changes, including slowing of capillary blood flow due to depressed perfusion pressure as a result of systemic pressure reduction and local arteriolar constriction. Observations suggest that the microcirculation is shut off early in severe sepsis, allowing the effects of hypoperfusion and attacks by microorganisms to prevail in their destructive capabilities. Widespread capillary dilation may ultimately occur. However, with blood flow diverted through some arteriovenous channels, important areas of capillary exchange are bypassed. Decreased capillary blood flow during shock results from failure to allow normal passage of cellular elements, including erythrocytes and neutrophils. This defect occurs, in part, because of decreased perfusion pressure, decreased deformability of red and white cells, constricted arterioles, circulating obstructive fragments (including hemoglobin), and plugging of microvessels with "sludge." Other factors are adherence of cells to capillary and venular epithelial membranes creating increased resistance to flow, loss of fluid through abnormal transcapillary exchange, differential vascular resistance changes between various beds (e.g., intestinal vs. muscle), and the relative absence of regulatory neurohumoral control of small vessel segments of the circulation. During sepsis/septic shock, endothelial cells are reported to modulate vascular tone, control local blood flow, influence the rate of leakage of fluids and plasma proteins into tissues, modulate the accumulation and extravasation of white cells into tissues, and influence white cell activation. As a result of the predominance of many destructive factors, a subsequent round of tissue damage may occur. Because of prolonged capillary vascular stasis, deficient flow, and factors released from injured cells, the microcirculation becomes a trap for uncontrolled bacterial growth enhanced by sustained hypoxemia, acidosis and toxemia. These events may combine to contribute to the loss of normal cell integrity and death of the host. The purpose of this review is to draw the readers' attention to the growing list of adverse factors occurring in the microcirculation during sepsis/septic shock. A further aim is to point to the realization of the complexity of factors which may contribute to the importance of a well-functioning microcirculation.

Dear SIRS, I'm sorry to say that I don't like you

Article

Mar 1997
CRIT CARE MED

Jean-Louis Vincent

Cytokine profile and correlation to the APACHE III and MPM II scores in patients with sepsis

Article

Sep 1997

In 35 patients fulfilling the criteria of systemic inflammatory response syndrome (SIRS) of infectious origin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), tumor necrosis factor-soluble receptor (TNF-sR), and interleukin-12 (IL-12), C-reactive protein (CRP) levels and the Acute Physiology, and Chronic Health Evaluation III score (APACHE III) were determined on days 1 to 7, 14, 21, and 28. The Mortality Probability Models (MPM) II sepsis score was assessed at the time of admission into the study. The MPM II sepsis score correlated with IL-6 plasma levels on day 1. The APACHE III scores correlated with plasma levels of TNF-sR on days 2-7, with IL-6 levels on days 3-7, and with CRP levels on days 4-7 (p < 0.01). The MPM II sepsis score, the APACHE III score, and the IL-6, TNF-sR, and CRP levels were significantly different between survivors and nonsurvivors and between patients with and without shock (p < 0.05). A significant decrease of the APACHE III scores, IL-6, and CRP levels was observed over the study period in the survivor group only (p < 0.05), while neither the dynamics of TNF-alpha nor IL-12 plasma levels contributed to the risk estimation of mortality.

Predicting bacteremia in patients with sepsis syndrome. Academic Medical Center Consortium Sepsis Project Working Group

Article

Jan 1998

The Clinical Host Response to Microbial Infection in Medical Patients With Fever

Article

Sep 1999

Predictors among demographic, clinical, and laboratory variables for a microbial (nonviral/nonchlamydial) infection in hospitalized medical patients with new onset of fever (temperature > or =38.0 degrees C axillary or > or =38.3 degrees C rectal) were analyzed and compared with the criteria for the systemic inflammatory response syndrome (SIRS), including an abnormal body temperature and WBC count, tachypnea and tachycardia, and sepsis, defined as SIRS and the presence of a clinical infection. A prospective cohort study. Department of internal medicine at a university hospital. In 300 hospitalized medical patients with new onset of fever, demographic, clinical, and laboratory variables were obtained during the first 2 days after inclusion, and peak and nadir values, when appropriate, were taken. Microbiologic results for 7 days were collected. Clinical information was used to decide on the presence of a clinical infection. One hundred thirty-three of 300 patients (44%) had a microbial infection: 26% suffered from local microbial infection only, 9% from bacteremia only, and 9% had bloodstream plus local microbial infections. Patients with a microbial infection had a higher World Health Organization performance score at home (p<0.05), higher peak body temperature (p<0.001), higher nadir and peak WBC counts (p<0.05), lower nadir platelet count (p<0.01), higher peak alanine and aspartate aminotransferases (p<0.01), and lower nadir albumin (p<0.001) levels in blood during the first 2 days after inclusion than those without infection. Using multivariate techniques, predictors for microbial infection or bacteremia alone, independent of age, sex, underlying disease, and clinical infection, were peak temperature, peak WBC count, and nadir platelet count and albumin level. In contrast, conventional SIRS/sepsis definitions and criteria predicted microbial infection less well, mainly because tachypnea and tachycardia were of no predictive value. In febrile medical patients, microbial infection can be predicted with use of easily obtained clinical and laboratory variables, including peak temperature, peak WBC count, and nadir platelet count and albumin level within the first 2 days. The new model predicted microbial infection better than conventional SIRS/sepsis criteria. This may help to improve the clinical recognition of the systemic host response to microbial infection and to refine SIRS/sepsis definitions.

The value of sepsis definitions in daily ICU-practice

Abstract

No full-text available