Rescue treatment with terlipressin in children with refractory septic shock: a clinical study

Introduction  

Refractory septic shock has dismal prognosis despite aggressive therapy. The purpose of the present study is to report the effects of terlipressin (TP) as a rescue treatment in children with catecholamine refractory hypotensive septic shock.     

Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign

Objective

The Surviving Sepsis Campaign (SSC) developed guidelines and treatment bundles for the administration of steroids in adult septic shock. However, it is not clear how this has affected clinical practice or patient outcome.

Design and setting

The SSC has developed an extensive database to assess the overall effect of its guidelines on clinical practice and patient outcome. This analysis focuses on one particular element of the SSC’s management bundle, namely, the administration of low-dose steroids in adult septic shock. This analysis was conducted on data submitted from January 2005 through March 2010 including 27,836 subjects at 218 sites.

Main results

A total of 17,847 (of the total 27,836) patients in the database required vasopressor therapy despite fluid resuscitation and therefore met the eligibility criteria for receiving low-dose steroids. A total of 8,992 patients (50.4?%) received low-dose steroids for their septic shock. Patients in Europe (59.4?%) and South America (51.9?%) were more likely to be prescribed low-dose steroids compared to their counterparts in North America (46.2?%, p?<?0.001). The adjusted hospital mortality was significantly higher (OR 1.18, 95?% CI 1.09–1.23, p?<?0.001) in patients who received low-dose steroids compared to those who did not. There was still an association with increased adjusted hospital mortality with low-dose steroids even if they were prescribed within 8?h (OR 1.23, 95?% CI 1.13–1.34, p?<?0.001).

Conclusions

Steroids were commonly administered in the treatment of septic shock in this subset analysis of the Surviving Sepsis Campaign database. However, this was associated with an increase in adjusted hospital mortality.     

Vasopressin in septic shock: effects on pancreatic,renal, and hepatic blood flow

Introduction  

Vasopressin has been shown to increase blood pressure in catecholamine-resistant septic shock. The aim of this study was to measure the effects of low-dose vasopressin on regional (hepato-splanchnic and renal) and microcirculatory (liver, pancreas, and kidney) blood flow in septic shock.     

Mortality benefit of vasopressor and inotropic agents in septic shock: A Bayesian network meta-analysis of randomized controlled trials

Objective

The choice of vasopressor in septic shock has been a matter of debate. The purpose of this study was to systematically review overall evidence of vasopressor and inotropic agents in septic shock using a Bayesian network meta-analysis.

Methods

Databases, including Medline, Scopus, CINAHL, and Google Scholar were searched to identify relevant studies. Eligible studies were randomized controlled trials that reported mortality rates on the use of vasopressors and inotropes in patients with septic shock. We chose to use 28-day mortality as the outcome assessment criterion.

Results

Fourteen studies with a total of 2811 patients were included in the analysis. Norepinephrine (NE) and NE + low-dose vasopressin but not epinephrine (EPI) were associated with significantly reduced mortality compared with dopamine. (Odds ratio, 0.80 [95% credibility interval, 0.65-0.99], 0.69 [0.48-0.98], and 0.56 [0.26-1.18], respectively). The addition of an inotropic agent such as dobutamine or dopexamine did not reduce mortality compared with EPI or NE alone.

Conclusions

Our results support the use of NE with or without low-dose vasopressin as the first-line vasopressor therapy in septic shock. No concrete evidence exists to support the use of EPI over dopamine as the second-line agent or the addition of an inotropic agent.     

Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies

Purpose  

Low-dose steroids have shown contradictory results in trials and three recent meta-analyses. We aimed to assess the efficacy and safety of low-dose steroids for severe sepsis and septic shock by Bayesian methodology.     

Response to the high-dose corticotrophin stimulation test depends on plasma adrenocotropin hormone levels in septic shock

Purpose

The use of the high-dose corticotrophin stimulation test (HDCST) as a guide to use low-dose steroid therapy in septic shock is controversial. The adrenocotropin hormone (ACTH) constitutes the immediate stimuli to produce cortisol. We evaluated the correlation of the response to the HDCST with plasma ACTH levels in patients with septic shock.

Methods

This is a retrospective review of 102 patients with septic shock in which adrenal function was evaluated using the HDCST and plasma ACTH levels were measured. Patients with a δ cortisol of 9 μg/dL or less were considered as nonresponders or with subnormal response. The association between plasma ACTH levels and the response to the HDCST was investigated.

Results

Sixty-four patients (62.7%) had a subnormal response. Plasma ACTH levels were higher in patients with subnormal response (19.8 [11.7-31.4] vs 10.0 [7.0-21.2] pg/mL; P = .002). Patients in the highest quartile of plasma ACTH had lower δ cortisol (P = .014) and higher percentage of subnormal response (P = .005). The optimal cutoff point of plasma ACTH level with fewest false classifications was 10 pg/mL (sensitivity, 0.83 [95% confidence interval, 074-0.90] and specificity, 0.50 [95% confidence interval, 0.74-0.90]).

Conclusion

Patients with septic shock with higher plasma ACTH values presented a subnormal response to the HDCST. The number of patients who failed to the HDCST was higher as plasma ACTH increased.     

Do Low-dose Corticosteroids Improve Mortality or Shock Reversal in Patients with Septic Shock? A Systematic Review and Position Statement Prepared for the American Academy of Emergency Medicine

Background

The management of septic shock has undergone a significant evolution in the past decade. A number of trials have been published to evaluate the efficacy of low-dose corticosteroid administration in patients with septic shock.

Methods

The Sepsis Sub-committee of the American Academy of Emergency Medicine Clinical Practice Committee performed an extensive search of the contemporary literature and identified seven relevant trials.

Results

Six of the seven trials reported a mortality outcome of patients in septic shock. Analysis of the data revealed that the relative risk (RR) of 28-day all-cause mortality in septic shock patients who received low-dose corticosteroids was 0.92 (95% confidence interval [CI] 0.79–1.07). All seven trials reported data concerning shock reversal or the withdrawal of vasopressors. Pooled results revealed that the RR of shock reversal is 1.17 (95% CI 1.07–1.28), which suggests that there may be significant improvement in shock reversal after corticosteroid administration. It is important to understand that two of the seven studies reviewed were disproportionately represented and accounted for 799 of 1005 patients (80%) considered for this recommendation.

Conclusions

The evidence suggests that low-dose corticosteroids may reverse shock faster; however, mortality is not improved for the overall population.     

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

Introduction  

Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.     

Low-dose steroid therapy does not affect hemodynamic response in septic shock patients

PURPOSE: Several studies showed that low-dose steroid therapy (LDST) in patients with septic shock leads to a significantly shorter duration of shock and a decreased mortality. However, these results have been criticized. Our purpose was to evaluate the effects of LDST on time to shock reversal and mortality in septic shock. MATERIALS AND METHODS: We retrospectively studied 203 patients with septic shock admitted to the intensive care unit of our tertiary hospital. A short corticotropin test was performed in all patients within 72 hours of septic shock onset. We performed a propensity score analysis through a logistic regression model with baseline relevant characteristics, and evaluated the influence of LDST on time to shock reversal and inhospital mortality. RESULTS: One hundred twenty-four patients were treated with LDST (steroid group) and 79 without LDST (control group). Patients treated with steroids presented higher Simplified Acute Physiology Score II and maximum Sepsis-Related Organ Failure Assessment scores. Both groups presented similar baseline and stimulated cortisol values. The hazard ratio of remaining on shock adjusted by severity of illness, inadequate antibiotic, and propensity score was 1.15 (95% confidence interval 0.71-1.86) for patients treated with steroids. Inhospital mortality was 62% in the steroid group and 52% in the control group (P = .84). Logistic regression analysis with propensity score neither showed differences between steroid and control group in the inhospital mortality. Predictors of inhospital mortality were age, maximum Sepsis-Related Organ Failure Assessment score, and inadequate antibiotics. CONCLUSION: In our study, treatment with low-dose steroid therapy was not associated to a reduction in time to shock reversal or mortality.     

Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock

Introduction  

Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo.     

Comparing hydrocortisone and methylprednisolone in patients with septic shock

Introduction  Intravenous hydrocortisone of 200–300 mg/day for 7 days is suggested for patients with septic shock who require vasopressors to maintain mean artery pressure ≥65 mmHg, despite adequate fluid resuscitation. No study to date has compared the effects between physiologic doses of hydrocortisone and methylprednisolone in patients with septic shock. Methods  From July 2007 to June 2008, patients who were admitted to the intensive care unit at Chang Gung Memorial Hospital, Keelung, Taiwan, with low-dose steroid therapy due to septic shock were enrolled in this study. The typical steroid therapy included 7 days of intravenous hydrocortisone 50 mg every 6 hours. Methylprednisolone (20 mg every 12 hours) was replaced in these patients from January 2008 because no hydrocortisone could be prescribed. Results  A total of 21 patients were prescribed hydrocortisone and 19 patients were prescribed methylprednisolone. The survival rates for patients receiving hydrocortisone were relatively higher compared with those receiving methylprednisolone, but the difference was not significant. There were no significant differences in the Kaplan-Meier curves for the time to reverse shock between patients who received hydrocortisone, or methylprednisolone. Further regression analysis showed no significant independent factors associated with the survival rates and the time to reverse shock among age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, histories, and adverse events. Conclusions  Low-dose methylprednisolone and hydrocortisone might have a similar effect for the treatment of patients with septic shock.     

Increased survival of cirrhotic patients with septic shock

Introduction

The overall outcome of septic shock has been recently improved. We sought to determine whether this survival gain extends to the high-risk subgroup of patients with cirrhosis.

Methods

Cirrhotic patients with septic shock admitted to a medical intensive care unit (ICU) during two consecutive periods (1997-2004 and 2005-2010) were retrospectively studied.

Results

Forty-seven and 42 cirrhotic patients presented with septic shock in 1997-2004 and 2005-2010, respectively. The recent period differed from the previous one by implementation of adjuvant treatments of septic shock including albumin infusion as fluid volume therapy, low-dose glucocorticoids, and intensive insulin therapy. ICU and hospital survival markedly improved over time (40% in 2005-2010 vs. 17% in 1997-2004, P = 0.02 and 29% in 2005-2010 vs. 6% in 1997-2004, P = 0.009, respectively). Furthermore, this survival gain in the latter period was sustained for 6 months (survival rate 24% in 2005-2010 vs. 6% in 1997-2004, P = 0.06). After adjustment with age, the liver disease stage (Child-Pugh score), and the critical illness severity score (SOFA score), ICU admission between 2005 and 2010 remained an independent favorable prognostic factor (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02-0.4, P = 0.004). The stage of the underlying liver disease was also independently associated with hospital mortality (Child-Pugh score: OR 1.42 per point, 95% CI 1.06-1.9, P = 0.018).

Conclusions

In the light of advances in management of both cirrhosis and septic shock, survival of such patients substantially increased over recent years. The stage of the underlying liver disease and the related therapeutic options should be included in the decision-making process for ICU admission.     

Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality

Purpose  

To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients.     

De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock

Purposes

We set out to assess the safety and the impact on in-hospital and 90-day mortality of antibiotic de-escalation in patients admitted to the ICU with severe sepsis or septic shock.

Methods

We carried out a prospective observational study enrolling patients admitted to the ICU with severe sepsis or septic shock. De-escalation was defined as discontinuation of an antimicrobial agent or change of antibiotic to one with a narrower spectrum once culture results were available. To control for confounding variables, we performed a conventional regression analysis and a propensity score (PS) adjusted-multivariable analysis.

Results

A total of 712 patients with severe sepsis or septic shock at ICU admission were treated empirically with broad-spectrum antibiotics. Of these, 628 were evaluated (84 died before cultures were available). De-escalation was applied in 219 patients (34.9 %). By multivariate analysis, factors independently associated with in-hospital mortality were septic shock, SOFA score the day of culture results, and inadequate empirical antimicrobial therapy, whereas de-escalation therapy was a protective factor [Odds-Ratio (OR) 0.58; 95 % confidence interval (CI) 0.36–0.93). Analysis of the 403 patients with adequate empirical therapy revealed that the factor associated with mortality was SOFA score on the day of culture results, whereas de-escalation therapy was a protective factor (OR 0.54; 95 % CI 0.33–0.89). The PS-adjusted logistic regression models confirmed that de-escalation therapy was a protective factor in both analyses. De-escalation therapy was also a protective factor for 90-day mortality.

Conclusions

De-escalation therapy for severe sepsis and septic shock is a safe strategy associated with a lower mortality. Efforts to increase the frequency of this strategy are fully justified.     

Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Introduction  

Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.     

Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients

Introduction  

Given the pivotal role of T lymphocytes in the immune system, patients with septic shock may show T cell abnormalities. We have characterised the T cell compartment in septic shock and assess its clinical implications.     

Effects of changes in arterial pressure on organ perfusion during septic shock

Introduction  

Septic shock is characterized by altered tissue perfusion associated with persistent arterial hypotension. Vasopressor therapy is generally required to restore organ perfusion but the optimal mean arterial pressure (MAP) that should be targeted is uncertain. The aim of this study was to assess the effects of increasing MAP using norepinephrine (NE) on hemodynamic and metabolic variables and on microvascular reactivity in patients with septic shock.     

Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated)

Introduction

In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC).

Methods

Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window.

Results

Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and drotrecogin alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and drotrecogin alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and drotrecogin alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).

Conclusion

Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with drotrecogin alfa (activated).     

Prediction of hospital outcome in septic shock: a prospective comparison of tissue Doppler and cardiac biomarkers

Introduction  

Diastolic dysfunction as demonstrated by tissue Doppler imaging (TDI), particularly E/e' (peak early diastolic transmitral/peak early diastolic mitral annular velocity) is common in critical illness. In septic shock, the prognostic value of TDI is undefined. This study sought to evaluate and compare the prognostic significance of TDI and cardiac biomarkers (B-type natriuretic peptide (BNP); N-terminal proBNP (NTproBNP); troponin T (TnT)) in septic shock. The contribution of fluid management and diastolic dysfunction to elevation of BNP was also evaluated.     

Heat stress is associated with decreased lactic acidemia in rat sepsis

Background  

Elevated plasma lactate has been shown to correlate with mortality in patients with septic shock. Heat stress prior to sepsis has resulted in reduction in acute lung injury and mortality. We investigated whether heat stress resulted in decreased plasma lactate concentration and protected the lung by decreasing the inflammatory response to sepsis.