Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients

Introduction  

New challenges have arisen for the management of critically ill HIV/AIDS patients. Severe sepsis has emerged as a common cause of intensive care unit (ICU) admission for those living with HIV/AIDS. Contrastingly, HIV/AIDS patients have been systematically excluded from sepsis studies, limiting the understanding of the impact of sepsis in this population. We prospectively followed up critically ill HIV/AIDS patients to evaluate the main risk factors for hospital mortality and the impact of severe sepsis on the short- and long-term survival.     

Disease severity is a major determinant for the pharmacodynamics of propofol in critically ill patients

As oversedation is still common and significant variability between and within critically ill patients makes empiric dosing difficult, the population pharmacokinetics and pharmacodynamics of propofol upon long-term use are characterized, particularly focused on the varying disease state as determinant of the effect. Twenty-six critically ill patients were evaluated during 0.7-9.5 days (median 1.9 days) using the Ramsay scale and the bispectral index as pharmacodynamic end points. NONMEM V was applied for population pharmacokinetic and pharmacodynamic modeling. Propofol pharmacokinetics was described by a two-compartment model, in which cardiac patients had a 38% lower clearance. Severity of illness, expressed as a Sequential Organ Failure Assessment (SOFA) score, particularly influenced the pharmacodynamics and to a minor degree the pharmacokinetics. Deeper levels of sedation were found with an increasing SOFA score. With severe illness, critically ill patients will need downward titration of propofol. In patients with cardiac failure, the propofol dosages should be reduced by 38%.     

Disability is the major determinant of the severity of depressive symptoms in primary headaches but not in low back pain

Pain syndromes are often associated with depression. In a prospective study we analysed if determinants of depression differ among patients with different primary headaches and between headaches and non-headache pain. During a 2-year period between 1 February 2002 and 31 January 2004, 635 subjects (migraine n = 231; tension-type headache n = 176; cluster headache n = 11; patients with low back pain n = 103; and healthy subjects n = 114) seen by two neurologists filled in a questionnaire on pain characteristics, the MIDAS questionnaire and the Beck Depression Inventory. A multivariate general regression model was used to identify independent predictors of the severity of depressive symptoms. Pain was most frequent in chronic tension-type headache and most intense in the cluster subgroup (P < 0.001, Kruskal-Wallis ANOVA). In univariate tests gender, age, pain frequency, pain intensity and disability were all significantly associated with the severity of depressive symptoms. In the multivariate model disability was the most important independent determinant of the severity of depressive symptoms in the pooled headache group as well as in the migraine and tension-type headache subgroups. In contrast to patients with headache, pain frequency and pain intensity were the significant independent predictors of the severity of depressive symptoms in patients with low back pain. In a multivariate model, after controlling for other factors, determinants of the severity of depressive symptoms were different in headache and non-headache pain subjects, suggesting a different mechanism for developing depression in primary headaches and in other pain syndromes.     

Blood interleukin 10 levels parallel the severity of septic shock

The aim of this study was to investigate the relation between interleukin (IL) 10, tumor necrosis factor alpha (TNF), IL-1, and IL-6 levels in patients with septic shock and relate these cytokine levels to the development of organ failure.

In 11 patients with septic shock of recent onset, blood was sampled for determinations of TNF, IL-1, IL-6, and IL-10. The degree of organ failure was scored for four organ systems (respiratory, hepatic, renal, hematologic) in the first 48 hours of the study.

The APACHE II score was 21 ± 4. Three patients died. IL-10 levels were directly correlated with TNF levels (r = 0.73, P < .05) and IL-6 levels (r = 0.67, P < .05); and inversely correlated with total C3 (r = −0.73, P < .05) and CH50 (r = −0.68, P < .05). Both IL-10 and TNF levels were correlated to the organ failure score (r = 0.75 and r = 0.68, both P < .01). Six patients with high IL-10 levels (>60 pg/mL) had lower C3 (37 ± 11 v 62 ± 10 mg/dL) and CH50 (32 ± 7 v 68 ± 19%), and higher organ failure scores (5.7 ± 0.8 v 3.8 ± 1.3) than those with low IL-10 levels (all P < .05).

Although IL-10 has an inhibitory effect on the production of cytokines, it is released together with TNF and IL-6 in patients with septic shock. IL-10 blood levels are directly related to the severity of inflammation and the development of organ failure in septic shock.     

Sustained high serum malondialdehyde levels are associated with severity and mortality in septic patients

Introduction

There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week.

Methods

We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six -month mortality. The association between continuous variables was carried out using Spearman’s rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables.

Results

We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was lower in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure.

Conclusions

To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.     

Sepsis and septic shock in pregnancy

Sepsis is the leading cause of death in critically ill patients in the United States. Improvements in the critical care management of septic shock have led to a decrease in the mortality rate in the past decade. Septic shock in obstetric patients is rare. Pregnant women as a group are younger and have fewer comorbid conditions. Though little is known regarding the treatment of sepsis and septic shock in pregnancy, the same principles and treatment modalities discussed in this article should govern the management of pregnant women.     

Ranitidine is unable to maintain gastric pH levels above 4 in septic patients

Purpose

The study aimed to evaluate whether ranitidine and pantoprazole are able to maintain gastric pH ≥4 in septic patients.

Materials and methods

Twenty intensive care unit patients from a university teaching hospital with sepsis were included in this study. Ten patients received ranitidine (50 mg as an intermittent bolus 3 times a day) and 10 received pantoprazole (40 mg as an intermittent bolus twice a day). Gastric pH was measured continuously for 48 hours. Endoscopy of the upper digestive tract, gastric biopsy, and investigation for Helicobacter pylori were carried out before and at the end of the study.

Results

pH values ≥4 were maintained for 46.27% ± 38.21% and 81.57% ± 19.65% of study time in the ranitidine and pantoprazole groups, respectively (P = .04).

Conclusions

Intravenous ranitidine was unable to maintain gastric pH above 4 in septic patients. All cases in the ranitidine group in whom pH remained above 4 had gastric hypotrophy or atrophy. Pantoprazole successfully maintained pH levels above 4.     

Endothelial lipase is a major determinant of HDL level

A new member of the lipase gene family, initially termed endothelial lipase (gene nomenclature, LIPG; protein, EL), is expressed in a variety of different tissues, suggesting a general role in lipid metabolism. To assess the hypothesis that EL plays a physiological role in lipoprotein metabolism in vivo, we have used gene targeting of the native murine locus and transgenic introduction of the human LIPG locus in mice to modulate the level of EL expression. Evaluation of these alleles in a C57Bl/6 background revealed an inverse relationship between HDL cholesterol level and EL expression. Fasting plasma HDL cholesterol was increased by 57% in LIPG(-/-) mice and 25% in LIPG(+/-) mice and was decreased by 19% in LIPG transgenic mice as compared with syngeneic controls. Detailed analysis of lipoprotein particle composition indicated that this increase was due primarily to an increased number of HDL particles. Phospholipase assays indicated that EL is a primary contributor to phospholipase activity in mouse. These data indicate that expression levels of this novel lipase have a significant effect on lipoprotein metabolism.     

Plasma endothelin-1 levels in septic patients

Dysfunction of the vascular endothelium (ET) causes an increase in serum ET-1 concentration, as observed in septic patients. It was assumed that in this patient population the ET-1 level correlates with the degree of sepsis severity, including the level of organ dysfunction and, in particular, the level of circulatory dysfunction. The aim of the present study was to assess the relationship between levels of ET-1 and levels of N-terminal brain natriuretic propeptide (NT-proBNP), procalcitonin (PCT), and C-reactive protein (CRP), as well as the Sepsis-related Organ Failure Assessment (SOFA) score in septic patients. PCT and CRP were used to estimate the level of sepsis severity; the SOFA score was used to estimate multiorgan dysfunction; and NT-proBNP was used as a marker of cardiac dysfunction. Twenty patients with sepsis and severe sepsis were included in the study. Blood serum ET-1, NT-proBNP, PCT, and CRP concentrations were determined at specific time intervals, and the SOFA score was calculated. Mean ET-1, NT-proBNP, PCT, and CRP concentrations were 8.39 pg/ml +/- 6.39 pg/mL, 140.80 pg/mL +/- 84.65 pg/mL, 22.32 ng/mL +/- 97.41 ng/mL, and 128.51 mg/L +/- 79.05 mg/L, respectively. Correlation between ET-1 levels and levels of NT-proBNP, PCT, and CRP was .3879 (P < .001), .358 (P < .001), and .225 (P = .011), respectively. Mean SOFA score was 6.31 pts +/- 3.75 pts. Correlation between the ET-1 levels and SOFA score was .470 (P < .001). Six patients (30%) died during the observation period of 28 days. ET-1 levels correlate with levels of NT-proBNP, PCT, and CRP, as well as the SOFA score in septic patients.     

Pronounced elevation in circulating calcitonin in critical care patients is related to the severity of illness and survival

Objective

To study circulating levels of calcitonin in critically ill patients in relation to the severity of illness and survival.

Design

Cross-sectional and prospective.

Setting

The ICU in Gävle hospital, a secondary non-teaching hospital.

Patients

37 consecutive ICU patients.

Measurements and results

Serum calcium and immunoreactive calcitonin (iCT) were measured and the Apache II and the Multiple Organ Failure (MOF) scores were recorded during the first 24 h in the ICU. Patients were followed for hospital survival. Profound increase in circulating iCT was seen (mean 591, median 184, range 8–3445 pg/ml) in the studied sample and only 11% of the patients showed normal levels (<40 pg/ml). iCT was higher in septic than non-septic patients (p<0.004) and was correlated to two indices of severity of illness (r=0.50,p<0.006 versus the Apache II score andp=0.55,p<0.003 versus the MOF score). Furthermore, iCT was correlated to the length of stay in the intensive care unit (r=0.56,p<0.001) and was elevated in the patients who did not survive when compared to survivors (p<0.03). iCT was not significantly related to the degree of serum calcium (mean 2.22±0.15 SD mmol/l). Gel chromatography in a fast protein liquid chromatography (FPLC) system of serum from 4 patients with elevated iCT disclosed that a majority of the measured CT was not due to monomeric CT, but high molecular CT.

Conclusions

Pronounced elevations in circulating iCT were seen during the first 24 h critically ill patients. As the major part of the iCT consisted of high molecular weight CT this would not induce hypocalcemia. Rather, the elevated iCT would be regarded as a part of the metabolic responses to illness.     

Effect of hemofiltration filter adsorption on circulating IL-6 levels in septic rats

Introduction  

Hemofiltration may modulate the inflammatory response in sepsis through a variety of mechanisms. We sought to distinguish clearance from adsorption as the principal mechanism responsible for reducing circulating IL-6 levels with hemofiltration.     

Plasma-induced endothelial oxidative stress is related to the severity of septic shock

OBJECTIVE: To estimate the capacity of plasma from septic shock patients to induce in vitro reactive oxygen species (ROS) production by endothelial cells and to analyze whether ROS production is related to the severity of the septic shock. DESIGN: Prospective, observational study. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Twenty-one patients with septic shock. INTERVENTIONS: The in vitro capacity of plasma from septic shock patients to induce ROS production by naive human umbilical vein endothelial cells (HUVEC) was quantified by using a fluorescent probe (2',7'-dichlorodihydrofluorescein diacetate). MEASUREMENTS AND MAIN RESULTS: Blood samples were collected on day 1, day 3, and day 5 from 21 consecutive septic shock adult patients and from ten healthy volunteers. Patients mean age was 58 yrs old, mean Sequential Organ Failure Assessment (SOFA) score at admission was 12, mean severity illness assessed by Simplified Acute Physiology Score (SAPS) II was 53, and the mortality rate was 47%. In addition to assessment of in vitro ROS generation by HUVEC, oxidative stress in blood was evaluated by measuring lipid peroxidation products and enzymatic and nonenzymatic antioxidants. Septic shock was associated with oxidative stress and an imbalance in antioxidant status. As compared with controls, plasma-induced ROS production by naive HUVEC was significantly higher in septic shock. Moreover ROS production was significantly correlated with SAPS II (p = .028) and SOFA values (p = .0012) and was higher in nonsurvivors than in survivors. In contrast, no correlation was found between the severity of the septic shock and any of the levels of lipid peroxidation products or enzymatic and nonenzymatic antioxidants. CONCLUSION: Plasma from septic shock patients induces ROS formation by naive HUVEC, and the extent of ROS formation correlates with mortality and with criteria of the severity of septic shock as SOFA score and SAPS II.     

Evaluation of the Mortality in Emergency Department Sepsis score combined with procalcitonin in septic patients

Objective

To determine an effective method for predicting severity of sepsis and 28-day mortality of emergency department (ED) patients, we compared the Mortality in Emergency Department Sepsis (MEDS) score with procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) and evaluated the MEDS score combined with relevant biomarkers.

Methods

A total of 501 adult ED patients with sepsis were selected for this prospective clinical study. The optimal combination was assessed by logistic regression. All cases were divided into the sepsis group (319 cases) and the severe sepsis and septic shock group (182 cases) according to the severity of sepsis, as well as the survivor group (367 cases) and nonsurvivor group (134 cases) according to the 28-day outcomes.

Results

The area under the curve of the MEDS score, PCT, IL-6, and CRP was 0.793, 0.712, 0.695, and 0.681 for severity of sepsis and 0.776, 0.681, 0.692, and 0.661 for 28-day mortality, respectively. Only PCT was an independent predictor when combined with the MEDS score. The new combination of the MEDS score with PCT improved the area under the curve for severity (0.852) and mortality (0.813). This new combination for evaluation of severity had better sensitivity (63.2%), specificity (92.2%), and positive predictive (82.1%) and negative predictive (81.4%) values.

Conclusions

The predictive ability of the MEDS score for severity and 28-day mortality of septic ED patients is better than PCT, IL-6, and CRP levels. The MEDS score combined with PCT enhances the ability of risk stratification and prognostic evaluation.     

Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock

Purpose

Septic shock induces a decrease in dendritic cells (DCs) that may contribute to sepsis-induced immunosuppression. We analyzed the time course of circulating DCs in patients with septic shock and its relation to susceptibility to intensive care unit (ICU)-acquired infections.

Methods

We enrolled adult patients with septic shock (n?=?43), non-septic shock (n?=?29), and with sepsis without organ dysfunction (n?=?16). Healthy controls (n?=?16) served as reference. Blood samples were drawn on the day of shock (day 1), then after 3 and 7?days. Myeloid (mDC) and plasmacytoid (pDC) DCs were counted by flow cytometry. Cell surface HLA-DR expression was analyzed in both DC subsets.

Results

At day 1, median mDC and pDC counts were dramatically lower in septic shock patients as compared to healthy controls (respectively, 835?mDCs and 178?pDCs/ml vs. 19,342?mDCs and 6,169?pDCs/ml; P?P?Conclusion Septic shock is associated with profound and sustained depletion of circulating DCs. The persistence of low mDC counts is associated with the development of ICU-acquired infections, suggesting that DC depletion is a functional feature of sepsis-induced immunosuppression.     

Plasma cortisol levels in patients with septic shock

To investigate the endogenous adrenocortical response to sepsis, plasma cortisol concentrations were measured in 37 patients (53 +/- 3 yr of age) with septic shock. Patients were studied 11 +/- 2 h after shock commenced. Vasopressor therapy was required in 35 of 37 patients (median dopamine infusion rate of 11 micrograms/kg.min, range 3 to 74). Plasma cortisol concentrations were increased markedly (median 50.7 micrograms/dl, range 15.6 to 400) above normal values (10 to 20 micrograms/dl) in patients with septic shock. Neither patients who reversed their shock nor those who survived to hospital discharge had significantly different plasma cortisol concentrations from those who did not. Patients with Gram-positive infections had increased cortisol levels compared with those who had Gram-negative infections (median 83 micrograms/dl, range 32 to 400 vs. median 44 micrograms/dl, range 16 to 81, respectively; p less than .05). The source of infection, amount of vasopressors infused, and severity of shock were not associated with differences in cortisol concentrations. The length of time in shock before collection of the blood sample for measurements of cortisol and mean arterial pressure at the time of blood collection had significant but weak negative correlations with cortisol concentrations (p less than .05, rs = .37 and p less than .05, rs = -.40, respectively). We conclude that plasma cortisol concentrations are increased in patients with septic shock, but that the degree of increase is variable. This variability may, in part, be related to type of infection, length of time in shock, and BP at the time of blood sampling.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uptake of extracellular enzyme by a novel pathway is a major determinant of cathepsin L levels in human macrophages.

The phorbol myristate acetate (PMA)-differentiated myelomonocytic cell line, THP-1, and human alveolar macrophages contain the cysteine proteinase cathepsin L. This enzyme is synthesized as a 43-kD proenzyme and processed to the active 25-kD form. Differentiation of THP-1 cells in the presence of human serum resulted in an increase in the size of the vacuolar compartment and the accumulation of more 25-kD cathepsin L antigen, as compared with THP-1 cells differentiated in the presence of fetal calf serum. Cells cultured in both types of sera have equivalent levels of cathepsin L mRNA. Metabolic labeling experiments demonstrated equivalent rates of synthesis, processing to the active form, and persistence in both culture conditions. An extracellular source of enzyme was documented by immunoblotting human serum which demonstrated 25-kD cathepsin L antigen; furthermore, we demonstrated that both THP-1 cells, differentiated in human serum, and human alveolar macrophages take up the 43-kD proenzyme and process it to the 25-kD form. Thus, human serum contains a factor(s) that induces both a marked increase in the size of the vacuolar compartment in differentiated THP-1 cells and a novel pathway that is responsible for the uptake and processing of extracellular cathepsin L. The activity of this inducible pathway is a major determinant of levels of intracellular cathepsin L. Cathepsin L is a potent elastase and the regulation of its uptake and processing may play a role in the pathogenesis of disease processes characterized by the destruction of elastin, such as pulmonary emphysema.     

Lipoplex size is a major determinant of in vitro lipofection efficiency.

The inhibition effect of serum on the transfection efficiency of cationic liposome-DNA complexes (lipoplexes) is a major obstacle to the application of this gene delivery vector both in vitro and in vivo. The size of the lipoplexes, as they are presented to targeted cells, is found to be the major determinant of their effectiveness in transfection. The transfection efficiency and the cell association and uptake of lipoplexes with CHO cells was found to increase with increasing lipoplex size. The influence on the transfection efficiency of lipoplexes by their cationic lipid:DNA ratios, types of liposomes, incubation time in polyanion containing media, and time of serum addition, are mediated mainly through size. Lipoplexes at a 2:1 charge ratio grow in size in media containing polyanions. The size growth may be arrested by adding serum to the incubation media. By using large lipoplexes, especially those made from multilamellar vesicles, the serum inhibition effect may be overcome.