Control groups in recent septic shock trials: a systematic review

Purpose

The interpretation of septic shock trial data is profoundly affected by patients, control intervention, co-interventions and selected outcome measures. We evaluated the reporting of control groups in recent septic shock trials.

Methods

We searched for original articles presenting randomized clinical trials (RCTs) in adult septic shock patients from 2006 to 2016. We included RCTs focusing on septic shock patients with at least two parallel groups and at least 50 patients in the control group. We selected and evaluated data items regarding patients, control group characteristics, and mortality outcomes, and calculated a data completeness score to provide an overall view of quality of reporting.

Results

A total of 24 RCTs were included (mean n = 287 patients and 71 % of eligible patients were randomized). Of the 24 studies, 14 (58 %) presented baseline data on vasopressors and 58 % the proportion of patients with elevated lactate values. Five studies (21 %) provided data to estimate the proportion of septic shock patients fulfilling the Sepsis-3 definition. The mean data completeness score was 19 out of 36 (range 8–32). Of 18 predefined control group characteristics, a mean of 8 (range 2–17) were reported. Only 2 (8 %) trials provided adequate data to confirm that their control group treatment represented usual care.

Conclusions

Recent trials in septic shock provide inadequate data on the control group treatment and hemodynamic values. We propose a standardized trial dataset to be created and validated, comprising characteristics of patient population, interventions administered, hemodynamic values achieved, surrogate organ dysfunction, and mortality outcomes, to allow better analysis and interpretation of future trial results.

     

Gender differences in mortality and quality of life after septic shock: A post-hoc analysis of the ARISE study

PurposeTo assess the impact of gender and pre-menopausal state on short- and long-term outcomes in patients with septic shock.Material and methodsCohort study of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial, an international randomized controlled trial comparing early goal-directed therapy (EGDT) to usual care in patients with early septic shock, conducted between October 2008 and April 2014. The primary exposure in this analysis was legal gender and the secondary exposure was pre-menopausal state defined by chronological age (≤ 50 years).Results641 (40.3%) of all 1591 ARISE trial participants in the intention-to-treat population were females and overall, 337 (21.2%) (146 females) patients were 50 years of age or younger. After risk-adjustment, we could not identify any survival benefit for female patients at day 90 in the younger (≤50 years) (adjusted Odds Ratio (aOR): 0.91 (0.46–1.89), p = .85) nor in the older (>50 years) age-group (aOR: 1.10 (0.81–1.49), p = .56). Similarly, there was no gender-difference in ICU, hospital, 1-year mortality nor quality of life measures.ConclusionsThis post-hoc analysis of a large multi-center trial in early septic shock has shown no short- or long-term survival effect for women overall as well as in the pre-menopausal age-group.     

Timing of vasopressor initiation and mortality in septic shock: a cohort study

Introduction

Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock.

Methods

Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis.

Results

In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P <0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors.

Conclusion

Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.     

Efficacy and safety of Shenfu injection for septic shock: A systematic review and meta-analysis of randomized controlled trials

ObjectiveTo evaluate the efficacy and safety of Shenfu injection (SFI) combined with standard therapy versus standard therapy for septic shock, three groups of patients with septic shock were analyzed based on the level of mean arterial lactate. They were mean arterial lactate level < 4.5 mmol/L, 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L and mean arterial lactate level ≥ 7 mmol/L.MethodsRandomized controlled trials (RCT) from PubMed, Cochrane library, Embase, CENTRAL, SinoMed, Wanfang, CNKI, and Weipu (VIP) databases from the inception to September 2018 were searched. Relative risks (RR), weighted mean difference (WMD), along with 95% confidence interval (95%CI) were used to analyze the main outcomes. Statistical analysis was performed using Rev.Man 5.3. The qualities of the involved studies were accessed by the ROB according to the Cochrane handbook.Results19 randomized controlled trials with 1505 participants were included. Compared with standard therapy, SFI plus standard therapy cannot decrease the 28-day mortality for all of the three groups. Compared with the other two subgroups (mean arterial lactate level < 4.5 mmol/L and mean arterial lactate level ≥ 7 mmol/L), the 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L group has a trend to decrease 28-day mortality (RR: 0.67; 95% CI: 0.38–1.19; P = 0.17). In addition, adding SFI could have further increased mean arterial pressure (MAP) at 6-hours (RR: 7.05; 95% CI: 4.14–9.97) and further normalized heart rate (HR) when compared with standard therapy (RR: –17.48; 95% CI: [?19.39–(?15.57)].ConclusionFor septic shock patients with 4.5 mmol/L ≤ mean arterial lactate level < 7 mmol/L, when the Traditional Chinese Medicine syndrome meet Yang-Qi deficiency, clinicians could choose SFI as a supplementary drug. But further high-quality and large-scale RCT should be performed to verify it.PROSPERO registration numberCRD42018090320.     

Polymyxin B-immobilized hemoperfusion and mortality in critically ill adult patients with sepsis/septic shock: a systematic review with meta-analysis and trial sequential analysis

Purpose

Polymyxin B-immobilized hemoperfusion (PMX-HP) is an adjuvant therapy for sepsis or septic shock that clears circulating endotoxin. Prior trials have shown that PMX-HP improves surrogate endpoints. We aimed to conduct an evidence synthesis to evaluate the efficacy and safety of PMX-HP in critically ill adult patients with sepsis or septic shock.

Methods

We searched for randomized controlled trials (RCTs) in MEDLINE, EMBASE, the Cochrane Library, the Health Technology Assessment Database, CINAHL, “Igaku Chuo Zasshi”, the National Institute of Health Clinical Trials Register, the World Health Organization International Clinical Trials Registry Platform, the University Hospital Medical Information Network Clinical Trials Registry, the reference lists of retrieved articles, and publications by manufacturers of PMX-HP. The primary outcomes were 28-day all-cause mortality, the number of patients with at least one serious adverse event, and organ dysfunction scores. The GRADE methodology for the certainty of evidence was used.

Results

Six trials (857 participants; weighted mean age 62.5 years) proved eligible. Patient-oriented primary outcomes were assessed. The pooled risk ratio (RR) for 28-day mortality associated with PMX-HP was 1.03 [95% confidence interval (CI) 0.78–1.36; I ² = 25%; n = 797]. The pooled RR for adverse events was 2.17 (95% CI 0.68–6.94; I ² = 0%; n = 717). Organ dysfunction scores over 24–72 h after PMX-HP treatment did not change significantly (standardized mean difference ? 0.26; 95% CI ? 0.64 to 0.12; I ² = 78%; n = 797). The certainty of the body of evidence was judged as low for both benefit and harm using the GRADE methodology.

Conclusions

There is currently insufficient evidence to support the routine use of PMX-HP to treat patients with sepsis or septic shock.

Registration

PROSPERO International Prospective Register of Systematic Reviews (CRD42016038356).

     

Cancer patients with septic shock: mortality predictors and neutropenia

Goals of work To study outcome and its predictive factors in cancer patients admitted to the ICU with septic shock, and the implications of neutropenia as a risk factor in this advanced stage of systemic inflammatory response.Patients and methods A prospective consecutive observational cohort study was conducted in 73 adults with cancer and septic shock admitted to the ICU at the Cancer Medical Center associated with the University of Buenos Aires.Main results The mortality rate from septic shock was 53.4% (95%CI 41.9 to 64.8%). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission, the mean number of organ dysfunctions on admission or during the ICU stay, liver dysfunction, respiratory dysfunction, and the need for mechanical ventilation were predictive of mortality in a univariate analysis. Neutropenia was not associated with a worse prognosis in terms of mortality (56%) or mean days of ICU stay (6.64 days) in comparison with nonneutropenic patients (52.1% and 6.8 days) in the univariate analysis. In the logistic regression model only the need for mechanical ventilation and liver dysfunction remained independent predictors of mortality.Conclusions Septic shock among cancer patients admitted to the ICU has a mortality rate similar to that reported for mixed populations, and it is particularly increased when hepatic or respiratory dysfunction develop. Neutropenia on admission does not seem to modify outcome.     

Long-term mortality and quality of life after septic shock: a follow-up observational study

Purpose

In septic shock, short-term outcomes are frequently reported, while long-term outcomes are not. The aim of this study was to evaluate mortality and health-related quality of life (HRQOL) in survivors 6 months after an episode of septic shock.

Methods

This single-centre observational study was conducted in an intensive care unit in a university hospital. All patients with septic shock were included. Mortality was assessed 6 months after the onset of septic shock, and a comparison between patients who survived and those who died was performed. HRQOL was assessed using the MOS SF-36 questionnaire prior to hospital admission (baseline) and at 6 months in survivors. HRQOL at baseline and at 6 months were compared to the general French population, and HRQOL at baseline was compared to 6-month HRQOL.

Results

Ninety-six patients were included. Six-month mortality was 45 %. Survivors were significantly younger, had significantly lower lactate levels and SAPS II scores, required less renal support, received less frequent administration of corticosteroids, and had a longer length of hospital stay. At baseline (n = 39) and 6 months (n = 46), all of the components of the SF-36 questionnaire were significantly lower than those in the general population. Compared to baseline (n = 23), the Physical Component Score (CS) improved significantly at 6 months, the Mental CS did not differ.

Conclusions

Mortality 6 months after septic shock was high. HRQOL at baseline was impaired when compared to that of the general population. Although improvements were noted at 6 months, HRQOL remained lower than that in the general population.     

Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis

Purpose

To assess the effect of low dose corticosteroids on outcomes in adults with septic shock.

Methods

We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay.

Results

There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89–1.08, p?=?0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91–1.02, p?=?0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90–1.02, p?=?0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03–2.70, p?=?0.04, I²?=?78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) ?1.52 days; 95% CI ?1.71 to ?1.32, p?<?0.0001], duration of mechanical ventilation (MD ?1.38 days; 95% CI ?1.96 to ?0.80, p?<?0.0001), and ICU stay (MD ?0.75 days; 95% CI ?1.34 to ?0.17, p?=?0.01) were shorter with corticosteroids versus placebo.

Conclusions

In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced.PROSPERO registration no. CRD42017084037.

     

Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate

OBJECTIVE: Genetic differences in immune responses may affect susceptibility to and outcome of septic shock. CD14 seems to be an important part of the innate immune system, initiating antimicrobial response. We evaluated the frequency of a recently discovered CD14 promoter gene polymorphism (C to T transition at base pair -159) among patients with septic shock compared with those in a control group. DESIGN: Multiple-center study. SETTING: Hospital research department. PATIENTS: Ninety consecutive white patients with septic shock were included. The control group consisted of 122 age- and gender-matched white subjects. INTERVENTIONS: In both groups, the C-159T CD14 promoter genetic polymorphism was determined by using polymerase chain reaction and subsequent Hae III restriction enzyme digestion of the polymerase chain reaction products. MEASUREMENTS AND MAIN RESULTS: The C-159T polymorphism and the TT genotype were significantly overrepresented among septic shock patients compared with controls. Within the septic shock group, the mortality of patients with TT genotype (71%) was significantly higher than in patients with other genotypes (48%; Pearson chi-square, p =.008). In a multiple logistic regression model, the TT genotype was independently associated with an increased relative risk of death (odds ratio, 5.30; 95% confidence interval, 1.20-22.50, p =.02). CONCLUSIONS: The C-159T polymorphism affects susceptibility to septic shock and seems to be a new genetic risk factor for death.     

Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

Introduction  

It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock.     

Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis

Introduction  

The risk factors associated with poor outcome in generalized peritonitis are still debated. Our aim was to analyze clinical and bacteriological factors associated with the occurrence of shock and mortality in patients with secondary generalized peritonitis.     

Refractory septic shock and alternative wordings: A systematic review of literature

BackgroundWe reviewed the different studies using the terms “refractory septic shock” and/or “catecholamine resistance” and/or “high dose norepinephrine” so as to highlight the heterogeneity of the definitions used by authors addressing such concepts.MethodA systematic review was conducted assessing the papers reporting data on refractory septic shock. We used keywords as exact phrases and subject headings according to database syntax.ResultsOf 276 papers initially reviewed, we included 8 studies – 3 randomized controlled trials, 3 prospective studies and 2 retrospective studies, representing a total of 562 patients with septic shock. Catecholamine resistance was generally defined as “a decreased vascular responsiveness to catecholamine independently of the administered norepinephrine dose”. Refractory septic shock was broadly defined as “a clinical condition characterized by persistent hyperdynamic shock even though adequate fluid resuscitation (individualized doses) and high doses of norepinephrine (≥ 1 μg/kg/min)”. Reported “high doses” of norepinephrine were often ≥1 μg/kg/min. However, wide variability was found throughout the literature on the use of these terms.DiscussionMarked inconsistencies were identified in the usage of the terms for refractory septic shock. There is a pressing need to determine consensus definitions so as to establish a common language in the medical literature and to harmonize future studies.     

Activated protein C in septic shock: a propensity-matched analysis

Introduction  

The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC.