Reducing mortality in severe sepsis and septic shock

Severe sepsis is one of the most common reasons for critically ill patients to be admitted to an intensive care unit (ICU) and has very high associated morbidity and mortality. The Surviving Sepsis Campaign was initiated with the hope that mortality might be reduced by standardizing care informed by data from an increasing number of clinical trials. Important methods for reducing mortality identified by recent studies include aggressive fluid resuscitation, early goal-directed therapy (EGDT), early administration of antibiotics, and the administration of activated protein C to eligible patients.     

The effects of implementation of the Surviving Sepsis Campaign in the Netherlands

To reduce unintentional and avoidable adverse events in patients in hospitals in the Netherlands, a patient safety agency (VMS) programme was launched in 2008. Among the VMS topics, the programme 'optimal therapy in severe sepsis', according to the international Surviving Sepsis Campaign (SSC), aims to improve early diagnosis and treatment of sepsis to reduce sepsis mortality by 15% before the end of 2012. We analysed compliance data submitted to the international SSC database from the Netherlands and compared these data with published international SS C results. Data of 863 patients, representing 6% of the international data (n=14,209), were used for analysis. In the Netherlands, the resuscitation bundle compliance improved significantly from 7% at baseline to 27% after two years (p=0.002). Internationally, the resuscitation bundle compliance increased significantly from 11 to 31% (p.     

Cortisol levels and mortality in severe sepsis

OBJECTIVE: Serum cortisol levels rise in response to the stress of critical illness but the optimal range of serum cortisol in such settings is not clearly defined. The objectives of this study were to determine the range of serum cortisol levels in a group of medical intensive care unit patients with severe sepsis/septic shock using uniform criteria, and to correlate serum cortisol levels to mortality. DESIGN AND PATIENTS: In a prospective observational fashion, 100 medical intensive care unit patients at Northwestern Memorial Hospital in Chicago were enrolled within 48 h of developing severe sepsis/septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine. MEASUREMENTS: A serum cortisol level was measured during the morning hours in the first 48 h of developing severe sepsis/septic shock. The severity of critical illness was measured by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS: The average patient age was 63 +/- 17 years, 54 patients were men. The average APACHE II score for all patients was 23 +/- 7. In-hospital and 90-day mortality were 51% and 60%, respectively. Four patient groups were defined a priori based on morning serum cortisol levels and their in-hospital mortalities were as follows: group 1 (cortisol < or = 345 nmol/l), n = 11, mortality 54%; group 2 (cortisol 345-552 nmol/l), n = 19, mortality 53%; group 3 (cortisol 552-1242 nmol/l), n = 54, mortality 41%; and group 4 (cortisol > or = 1242 nmol/l), n = 16, mortality 81% (P < 0.01). CONCLUSIONS: Cortisol levels were elevated in most patients with septic shock. Cortisol levels less than 552 nmol/l occurred in 30% of patients with septic shock but the mortality in these patients was not significantly increased. Serum cortisol levels > or = 1242 nmol/l were associated with significantly higher mortality.     

Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality

Objective

Higher serum melatonin levels have previously been found in patients with severe sepsis who died within 30 days of diagnosis than in survivors. The objective of our study were to determine whether serum melatonin levels during the first seven days of severe sepsis diagnosis could be associated with sepsis severity and mortality.

Etomidate use in severe sepsis and septic shock patients does not contribute to mortality

Use of etomidate in severe sepsis and septic shock has been challenged in recent literature due to its link to adrenal insufficiency and suspected increased mortality. We hypothesized that etomidate does not contribute to mortality in this patient population. A retrospective chart review of 230 intubated, severe sepsis/septic shock patients at two university tertiary care referral centers was conducted for patients receiving treatment between 12/2001 and 10/2009. The primary endpoint was in-hospital mortality. Additional investigated variables included the use of corticosteroids, hospital and intensive care unit (ICU) length of stay, mechanical ventilation days and patient demographics. One hundred seventy-three patients received etomidate and fifty-seven patients received either no medication or an alternative drug. Use of etomidate in this patient cohort did not worsen mortality. Mortality in the etomidate group was 43.9% (76/173). Mortality in the non-etomidate cohort was 45.6% (26/57) (p = 0.48). APACHE II scores were 22 ± 7.2 and 23 ± 7.1 for the etomidate group and the non-etomidate group, respectively, (p = 0.36). There was no significant difference in mortality between etomidate and non-etomidate cohorts in this study. This large retrospective multi-center study further supports the safety of etomidate use in severe sepsis and septic shock.     

Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis

Inter-alpha inhibitor protein (IalphaIp) is an endogenous serine protease inhibitor in human plasma. Circulating IalphaIp levels were lower in 51 patients with severe sepsis than in healthy volunteers. Mean levels were 688+/-295 mg/L in patients with severe sepsis who survived (n=32), 486+/-193 mg/L in patients with sepsis who died (n=19), and 872+/-234 mg/L in control subjects (n=25). IalphaIp levels were lower in patients with shock versus those without (540+/-246 [n=33] vs. 746+/-290 [n=18] mg/L; P=.0102). IalphaIp levels were inversely correlated with 28-day mortality rates and Acute Physiology and Chronic Health Evaluation II scores and directly correlated with antithrombin III, protein C, and protein S levels. The administration of IalphaIp (30 mg/kg body weight intravenously) increased the 50% lethal dose in mice by 100-fold after an intravenous challenge of Escherichia coli. Thus, human IalphaIp may be a useful predictive marker and potential therapeutic agent in sepsis.     

Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis

The enzyme group of matrix metalloproteinases (MMPs) and their inhibitors, so-called tissue inhibitors of matrix-metalloproteinases (TIMPs), are crucial mediators responsible for wound repair after parenchymal damage. Little is known about the role of MMPs and TIMPs in severe sepsis. The aim of the present study was therefore to investigate their levels in patients with severe sepsis and to examine their association with prognosis. MMP-2, MMP-9, TIMP-1, TIMP-2 and interleukin-6 (IL-6) plasma levels were measured by ELISA methods in 37 patients on day 1 of severe sepsis. 37 healthy volunteers served as controls. Levels of MMP-9, TIMP-1, TIMP-2 and IL-6 in septic patients were significantly higher compared to healthy controls (p<0.001), whereas MMP-2 levels were not different in patients and controls. TIMP-1 levels were significantly higher in non-survivors (4675+/-435 ng/ml, mean+/-SEM) compared to survivors of severe sepsis (3201+/-249 ng/ml; p<0.01). Septic patients with TIMP-1 values >3200 ng/ml were 4.5 times more likely to die than patients with lower values (RR = 4.5; 95% CI 1.14-17.6, p = 0.014). Our results indicate that MMP-9, TIMP-2 and TIMP-1 are elevated in severe sepsis. Furthermore, TIMP-1 may serve as a useful laboratory marker to predict the clinical outcome of patients presenting with severe sepsis.     

Surviving sepsis in low-income and middle-income countries: new directions for care and research

Sepsis is a disorder characterised by systemic inflammation secondary to infection. Despite recent progress in the understanding and treatment of sepsis, no data or recommendations exist that detail effective approaches to sepsis care in resource-limited low-income and middle-income countries (LMICs). Although few data exist on the burden of sepsis in LMICs, the prevalence of HIV and other comorbid conditions in some LMICs suggest that sepsis is a substantial contributor to mortality in these regions. In well-resourced countries, sepsis management relies on protocols and complex invasive technologies not widely available in most LMICs. However, the key concepts and components of sepsis management are potentially translatable to resource-limited environments. Health personnel in LMICs should be educated in the recognition of sepsis and the importance of early and appropriate antibiotic use. Simple and low-cost standardised laboratory testing should be emphasised to allow accurate diagnosis, prognosis, and monitoring of treatment response. Evidence-based interventions and treatment algorithms tailored to LMIC ecology and resources should thus be developed and validated.     

Coagulation inhibitors in severe sepsis: state of the art

OBJECTIVE: To present and discuss the rationale and the results of clinical trials using supplementation with physiologic anticoagulants (Tissue Factor Pathway Inhibitor (TFPI), AntiThrombin (AT), and Protein C (PC) in patients with severe sepsis. RATIONALE: An early activation of the coagulation cascade occurs in severe sepsis. TFPI, AT, and PC are major inhibitors of the coagulation cascade, and additionally modulate inflammatory and vascular reactions. They are consumed or inhibited in the sepsis pathologic process. Therapeutic supplementation with these inhibitors could improve the sepsis-induced organ failures and mortality. CLINICAL RESULTS: Randomized controlled studies were recently completed. No effect on the mortality rate could be documented after treatment with recombinant TFPI. AT concentrates neither improve mortality, but a biological interaction with heparin therapy could have biased the study results. Treatment with recombinant activated PC (alpha-drotrecogin) was associated with a significant reduction in the mortality rate of severely ill patients and received recently the approval from FDA and EC authorities in this indication. An increase in the rate of hemorrhagic adverse effects has been observed with these compounds, justifying a strict observance of contraindications and of patients selection. PROSPECTIVE: Additional studies are needed to give confirmation of the positive effects of activated PC supplementation in less severely ill patients, children and specific clinical situations. The effects of new anticoagulant compounds are currently evaluated in preclinical studies.     

Platelet aggregation in severe sepsis

Severe sepsis and multiple organ distress syndrome remain a diagnostic and therapeutic challenge for intensive therapy. Platelet activating factor forms a bridge between inflammation and clot formation. Our study surveys the effect of severe sepsis on platelet function and focuses on spontaneous aggregation in severely ill patients. Daily arterial blood samples were collected from 45 patients (average age of 60.7 ± 13) for five consecutive days following admission and 30 healthy controls. Platelet aggregation was measured using adrenaline (ADR), adenosine diphosphate (ADP), collagen (COL) and normal saline (SAL). Clinical status was observed using Multiple Organ Dysfunction Score (MODS) and Sequential Organ Failure Assessment (SOFA) score systems. Inducible aggregation deteriorated in septic patients in all 5 days with ADR, ADP and COL (P < 0.05) while SAL aggregation was increased during intensive care. Low platelet patients showed weak inducible aggregation with ADP throughout, with ADR on the 2nd, 3rd, 4th and 5th days and with COL on the 1st, 2nd and 3rd days. SAL aggregation showed no significance. No significant difference was seen between platelet functions comparing survivors and non-survivors. In the spontaneous aggregative group, platelet count was insignificantly higher, while procalcitonin levels were lower in 1st, 3rd and 4th days and no significant difference was observed in lactate levels. We demonstrated the presence of spontaneous platelet activity while overall inducible platelet aggregation is significantly deteriorated in septic patients. There were significant differences in inducible aggregation between normal and low platelet count groups. Inducible platelet function had no predictive value in the outcome.     

Dysregulation of the immune response in severe sepsis

Sepsis is systemic expression of a generalized activation of the host's innate immunity as a result of varied types of insults. This expression involves a cellular inflammatory response that has both proinflammatory and antiinflammatory components, the primary trigger for which is an intracellular oxidative stress, induced by receptor-mediated transmembrane signal transduction or direct noxious injury. Sepsis reflects the interaction between pro- and anti-inflammatory intracellular mechanisms, the uncontrolled activation of which leads to cell exhaustion, organ dysfunction, and death. Successful clinical trials of novel treatments for the management of severe sepsis share a common ability to down-regulate this overall response, restoring normal proinflammatory responsiveness and mitochondrial energetic function.