Prediction of pediatric sepsis mortality within 1 h of intensive care admission

Purpose

The definitions of sepsis and septic shock have recently been revised in adults, but contemporary data are needed to inform similar approaches in children.

Methods

Multicenter cohort study including children <16 years admitted with sepsis or septic shock to ICUs in Australia and New Zealand in the period 2012–2015. We assessed septic shock criteria at ICU admission to define sepsis severity, using 30-day mortality as outcome. Through multivariable logistic regression, a pediatric sepsis score was derived using variables available within 60 min of ICU admission.

Results

Of 42,523 pediatric admissions, 4403 children were admitted with invasive infection, including 1697 diagnosed as having sepsis/septic shock on admission. Mortality was 8.5% (144/1697) and 50.7% of deaths occurred within 48 h of admission. The presence of septic shock as defined by the 2005 consensus was sensitive but not specific in predicting mortality (AUC = 0.69; 95% CI 0.65–0.72). Combinations of hypotension, vasopressor therapy, and lactate >2 mmol/l discriminated poorly (AUC <0.60). Multivariate models showed that oxygenation markers, ventilatory support, hypotension, cardiac arrest, serum lactate, pupil responsiveness, and immunosuppression were the best-performing predictors (0.843; 0.811–0.875). We derived a pediatric sepsis score (0.817; 0.779–0.855), and every one-point increase was associated with a 28.5% (23.8–33.2%) increase in the odds of death. Children with a score ≥6 had 19.8% mortality and accounted for 74.3% of deaths. The sepsis score performed comparably when applied to all children admitted with invasive infection (0.810; 0.781–0.840).

Conclusions

We observed mortality patterns specific to pediatric sepsis that support the need for specialized definitions of sepsis severity in children. We demonstrated the importance of lactate, cardiovascular, and respiratory derangements at ICU admission for the identification of children with substantially higher risk of sepsis mortality.

     

Incidence,treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study

Objective

To determine the incidence and outcome of severe sepsis in the adult Finnish population and to evaluate how treatment guidelines in severe sepsis are applied in clinical practice.

Study design

A prospective study in 24 closed multidisciplinary ICUs in 21 hospitals (4 university and 17 tertiary hospitals) in Finland.

Patients

All 4,500 consecutive ICU admission episodes were screened for severe sepsis during a 4-month period (1 November 2004 – 28 February 2005). The referral population was 3,743,225.

Results

The severe sepsis criteria were fulfilled in 470 patients, who had472 septic episodes. The incidence of severe sepsis in the ICUs in Finland was 0.38/1000 in the adult population (95% confidence interval 0.34–0.41). The mean ICU length of stay was 8.2?±?8.1?days. ICU, hospital, and 1-year mortality rates were 15.5%, 28.3%, and 40.9%, respectively. Respiratory failure requiring ventilation support was the most common organ failure (86.2%); septic shock was present in 77% and acute renal failure in 20.6% of cases. Activated protein C was given to only 15 of the 55 patients with indication (27%) and low-dose corticosteroids to 150 of 366 (41%) patients with septic shock.

Conclusions

This prospective study found the incidence of ICU-treated severe sepsis in Finland to be 0.38 per 1,000 of the population. The ICU and hospital mortalities were also lower than earlier reported in United States or Australia. Evidence-based sepsis therapies were not used as often as recommended.

     

Protein C zymogen in severe sepsis: a double-blinded,placebo-controlled,randomized study

Purpose

To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock.

Methods

This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality.

Results

The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072).

Conclusion

Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.

     

A retrospective comparison of helicopter transport versus ground transport in patients with severe sepsis and septic shock

Background

Helicopter emergency medical services (HEMS) extend the reach of a tertiary care center significantly. However, its role in septic patients is unclear. Our study was performed to clarify the role of HEMS in severe sepsis and septic shock.

Methods

This is a single-center retrospective cohort study. This study was performed at Mayo Clinic, Rochester, MN, in years 2007–2009. This study included a total of 181 consecutive adult patients admitted to the medical intensive care unit meeting criteria for severe sepsis or septic shock within 24 h of admission and transported from an acute care facility by a helicopter or ground ambulance. The primary predictive variable was the mode of transport. Multiple demographic, clinical, and treatment variables were collected and analyzed with univariate analysis followed by multivariate analysis.

Results

The patients transported by HEMS had a significantly faster median transport time (1.3 versus 1.7 h, p?<?0.01), faster time to meeting criteria for severe sepsis or septic shock (1.2 versus 2.9 h, p?<?0.01), a higher SOFA score (9 versus 7, p?<?0.01), higher incidence of acute respiratory distress syndrome (38 versus 18 %, p?=?0.013), higher need for invasive mechanical ventilation (60 versus 41 % p?=?0.014), higher ICU mortality (13.3 versus 4.1 %, p?=?0.024), and an increased hospital mortality (17 versus 30 %, p?=?0.04) when compared to those transported by ground. Distance traveled was not an independent predictor of hospital mortality on multivariate analysis.

Conclusions

HEMS transport is associated with faster transport time, carries sicker patients, and is associated with higher hospital mortality compared with ground ambulance services for patients with severe sepsis or septic shock.

     

The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study

Purpose

Sepsis and its progression are known to have a major influence on the coagulation system. Current coagulation tests are of limited use when assessing coagulation in sepsis patients. This study aims to assess the potential for a new functional biomarker of clot microstructure, fractal dimension, to identify changes in the mechanical properties of clot microstructure across the sepsis spectrum (sepsis, severe sepsis and septic shock).

Methods

A total of 100 patients that presented acutely to a large teaching hospital were included in this prospective observational study (50 sepsis, 20 severe sepsis and 30 septic shock) against a matched control of 44 healthy volunteers. Fractal analysis was performed, as well as standard markers of coagulation, and six plasma markers of inflammation.

Results

Fractal dimension was significantly higher in the sepsis and severe sepsis groups than the healthy control (1.78 ± 0.07 and 1.80 ± 0.05, respectively vs 1.74 ± 0.03) (p < 0.001), indicating a significant increase in mechanical clot strength and elasticity consistent with a hypercoagulable state. Conversely, fractal dimension was significantly lower in septic shock (1.66 ± 0.10, p < 0.001), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state. This corresponded with a significant increase in the inflammatory response.

Conclusions

This study confirms that clot microstructure is significantly altered through the various stages of sepsis. Of particular importance was the marked change in clot development between severe sepsis and septic shock, which has not been previously reported.

     

Predictors of early progression to severe sepsis or shock among emergency department patients with nonsevere sepsis

Background

Progression from nonsevere sepsis—i.e., sepsis without organ failure or shock—to severe sepsis or shock among emergency department (ED) patients has been associated with significant mortality. Early recognition in the ED of those who progress to severe sepsis or shock during their hospital course may improve patient outcomes. We sought to identify clinical, demographic, and laboratory parameters that predict progression to severe sepsis, septic shock, or death within 96 h of ED triage among patients with initial presentation of nonsevere sepsis.

Methods

This is a retrospective cohort of patients presenting to a single urban academic ED from November 2008 to October 2010. Patients aged 18 years or older who met criteria for sepsis and had a lactate level measured in the ED were included. Patients were excluded if they had any combination of the following: a systolic blood pressure <90 mmHg upon triage, an initial whole blood lactate level ≥4 mmol/L, or one or more of a set of predefined signs of organ dysfunction upon initial assessment. Disease progression was defined as the development of any combination of the aforementioned conditions, initiation of vasopressors, or death within 96 h of ED presentation. Data on predefined potential predictors of disease progression and outcome measures of disease progression were collected by a query of the electronic medical record and via chart review. Logistic regression was used to assess associations of potential predictor variables with a composite outcome measure of sepsis progression to organ failure, hypotension, or death.

Results

In this cohort of 582 ED patients with nonsevere sepsis, 108 (18.6 %) experienced disease progression. Initial serum albumin <3.5 mg/dL (OR 4.82; 95 % CI 2.40–9.69; p?<?0.01) and a diastolic blood pressure <52 mmHg at ED triage (OR 4.59; 95 % CI 1.57–13.39; p?<?0.01) were independently associated with disease progression to severe sepsis or shock within 96 h of ED presentation. There were no deaths within 96 h of ED presentation.

Conclusions

In our patient cohort, serum albumin <3.5 g/dL and an ED triage diastolic blood pressure <52 mmHg independently predict early progression to severe sepsis or shock among ED patients with presumed sepsis.

     

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).

     

Improved short- and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of 942 patients

Purpose

Intensive care unit (ICU) admission of allogeneic hematopoietic stem cell transplant (HSCT) recipients is associated with relatively poor outcome. Since longitudinal data on this topic remains scarce, we analyzed reasons for ICU admission as well as short- and long-term outcome of critically ill HSCT recipients.

Methods

A total of 942 consecutive adult patients were transplanted at Hannover Medical School from 2000 to 2013. Of those, 330 patients were at least admitted once to the ICU and included in this retrospective study. To analyze time-dependent improvements, we separately compared patient characteristics as well as reasons and outcome of ICU admission for the periods 2000–2006 and 2007–2013.

Results

The main reasons for ICU admission were acute respiratory failure (ARF) in 35%, severe sepsis/septic shock in 23%, and cardiac problems in 18%. ICU admission was clearly associated with shortened survival (p?<?0.001), but survival of ICU patients after hospital discharge reached 44% up to 5 years and was comparable to that of non-ICU HSCT patients. When ICU admission periods were compared, patients were older (48 vs. 52 years; p?<?0.005) and the percentage of ARF as leading cause for ICU admission decreased from 43% in the first to 30% in the second period. Over time ICU and hospital survival improved from 44 to 60% (p?<?0.01) and from 26 to 43% (p?<?0.01), respectively. The 1- and 3-year survival rate after ICU admission increased significantly from 14 to 32% and from 11 to 23% (p?<?0.01).

Conclusions

Besides ARF and septic shock, cardiac events were especially a major reason for ICU admission. Both short- and long-term survival of critically ill HSCT patients has improved significantly in recent years, and survival of HSCT recipients discharged from hospital is not significantly affected by a former ICU stay.

     

Septic shock in chronic dialysis patients: clinical characteristics,antimicrobial therapy and mortality

Objectives

To describe the clinical characteristics and in-hospital mortality of chronic dialysis-dependent end-stage kidney disease patients with septic shock in comparison to septic shock patients not receiving chronic dialysis.

Methods

Using an international, multicenter database, we conducted a retrospective analysis of data collected from 10,414 patients admitted to the intensive care unit (ICU) with septic shock from 1989 to 2013, of which 800 (7.7 %) were chronic dialysis patients. Data on demographic characteristics, sites of infection, microbial pathogens, antimicrobial usage patterns, and in-hospital mortality were aggregated and compared for chronic dialysis and non-dialysis patients. Multivariate time-varying Cox models with and without propensity score matching were constructed to determine the association between dialysis and in-hospital death.

Results

Septic shock secondary to central venous catheter infection, peritonitis, ischemic bowel, and cellulitis was more frequent in chronic dialysis patients. The isolation of resistant organisms (10.7 vs. 7.1 %; p = 0.005) and delays in receiving antimicrobials (6.0 vs. 5.0 h) were more common in chronic dialysis patients than in non-dialysis patients. Delayed appropriate antimicrobial therapy was associated with an increased risk of death in chronic dialysis patients (p < 0.0001). In-hospital death occurred in 54.8 and 49.0 % of chronic dialysis and non-dialysis patients, respectively. After propensity score matching, there was no difference in overall survival between chronic dialysis and non-dialysis patients, but survival in chronic dialysis patients decreased over time compared to non-dialysis patients.

Conclusions

The demographic and clinical characteristics of chronic dialysis patients with septic shock differ from those of similar non-dialysis patients. However, there was no significant difference in mortality between the chronic dialysis and non-dialysis patients with septic shock enrolled in this analysis.

     

Severe hyperlactatemia,lactate clearance and mortality in unselected critically ill patients

Purpose

Hyperlactatemia may occur for a variety of reasons and is a predictor of poor clinical outcome. However, only limited data are available on the underlying causes of hyperlactatemia and the mortality rates associated with severe hyperlactatemia in critically ill patients. We therefore aimed to evaluate the etiology of severe hyperlactatemia (defined as a lactate level >10 mmol/L) in a large cohort of unselected ICU patients. We also aimed to evaluate the association between severe hyperlactatemia and lactate clearance with ICU mortality.

Methods

In this retrospective, observational study at an University hospital department with 11 ICUs during the study period between 1 April 2011 and 28 February 2013, we screened 14,040 ICU patients for severe hyperlactatemia (lactate >10 mmol/L).

Results

Overall mortality in the 14,040 ICU patients was 9.8 %. Of these, 400 patients had severe hyperlactatemia and ICU mortality in this group was 78.2 %. Hyperlactatemia was associated with death in the ICU [odds ratio 1.35 (95 % CI 1.23; 1.49; p < 0.001)]. The main etiology for severe hyperlactatemia was sepsis (34.0 %), followed by cardiogenic shock (19.3 %), and cardiopulmonary resuscitation (13.8 %). Patients developing severe hyperlactatemia >24 h of ICU treatment had a significantly higher ICU mortality (89.1 %, 155 of 174 patients) than patients developing severe hyperlactatemia ≤24 h of ICU treatment (69.9 %, 158 of 226 patients; p < 0.0001). Lactate clearance after 12 h showed a receiver-operating-characteristics area under the curve (ROC-AUC) value of 0.91 to predict ICU mortality (cut-off showing highest sensitivity and specifity was a 12 h lactate clearance of 32.8 %, Youden Index 0.72). In 268 patients having a 12-h lactate clearance <32.8 % ICU mortality was 96.6 %.

Conclusions

Severe hyperlactatemia (>10 mmol/L) is associated with extremely high ICU mortality especially when there is no marked lactate clearance within 12 h. In such situations, the benefit of continued ICU therapy should be evaluated.

     

Fluid administration in severe sepsis and septic shock,patterns and outcomes: an analysis of a large national database

Purpose

The optimal strategy of fluid resuscitation in the early hours of severe sepsis and septic shock is controversial, with both an aggressive and conservative approach being recommended.

Methods

We used the 2013 Premier Hospital Discharge database to analyse the administration of fluids on the first ICU day, in 23,513 patients with severe sepsis and septic shock, who were admitted to an ICU from the emergency department. Day 1 fluid was grouped into categories 1 L wide, starting with 1–1.99 L up to ≥9 L, to examine the effect of day 1 fluids on patient mortality. We built binary response models for hospital mortality and the propensity for receiving more than 5 L of fluids on day 1, using patient age and acute conditions present on admission. Patients were grouped by the requirement for mechanical ventilation and the presence or absence of shock. We assessed trends in the difference between actual and expected mortality, in the low fluid range (1–5 L day 1 fluids) and the high fluid range (5 to ≥9 L day 1 fluids) categories, using weighted linear regression controlling for the effects of sample size and variation within the day 1 fluid category.

Results

Day 1 fluid administration averaged 4.4 L being lowest in the group with no mechanical ventilation and no shock (3.6 L) and highest (5.4 L) in the group receiving mechanical ventilation and in shock. The administration of day 1 fluids was remarkably consistent on the basis of hospital size, teaching status, rural/urban location, and region of the country. The hospital mortality in the entire cohort was 25.8%, with a mean ICU and hospital length of stay of 5.1 and 9.1 days, respectively. In the entire cohort, low volume resuscitation (1–4.99 L) was associated with a small but significant reduction in mortality, of ?0.7% per litre (95% CI ?1.0%, ?0.4%; p = 0.02). However, in patients receiving high volume resuscitation (5 to ≥9 L), the mortality increased by 2.3% (95% CI 2.0, 2.5%; p = 0.0003) for each additional litre above 5 L. Total hospital cost increased by $999 for each litre of fluid above 5 L (adjusted R ² = 92.7%, p = 0.005).

Conclusion

The mean amount of fluid administered to patients with severe sepsis and septic shock in the USA during the first ICU day is less than that recommended by the Surviving Sepsis Campaign guidelines. The administration of more than 5 L of fluid during the first ICU day is associated with a significantly increased risk of death and significantly higher hospital costs.

     

Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised,parallel-group,multicentre feasibility trial

Purpose

We assessed the effects of a protocol restricting resuscitation fluid vs. a standard care protocol after initial resuscitation in intensive care unit (ICU) patients with septic shock.

Methods

We randomised 151 adult patients with septic shock who had received initial fluid resuscitation in nine Scandinavian ICUs. In the fluid restriction group fluid boluses were permitted only if signs of severe hypoperfusion occurred, while in the standard care group fluid boluses were permitted as long as circulation continued to improve.

Results

The co-primary outcome measures, resuscitation fluid volumes at day 5 and during ICU stay, were lower in the fluid restriction group than in the standard care group [mean differences ?1.2 L (95 % confidence interval ?2.0 to ?0.4); p < 0.001 and ?1.4 L (?2.4 to ?0.4) respectively; p < 0.001]. Neither total fluid inputs and balances nor serious adverse reactions differed statistically significantly between the groups. Major protocol violations occurred in 27/75 patients in the fluid restriction group. Ischaemic events occurred in 3/75 in the fluid restriction group vs. 9/76 in the standard care group (odds ratio 0.32; 0.08–1.27; p = 0.11), worsening of acute kidney injury in 27/73 vs. 39/72 (0.46; 0.23–0.92; p = 0.03), and death by 90 days in 25/75 vs. 31/76 (0.71; 0.36–1.40; p = 0.32).

Conclusions

A protocol restricting resuscitation fluid successfully reduced volumes of resuscitation fluid compared with a standard care protocol in adult ICU patients with septic shock. The patient-centred outcomes all pointed towards benefit with fluid restriction, but our trial was not powered to show differences in these exploratory outcomes.

Trial registration

NCT02079402.

     

Prognostic value of chromogranin A in severe sepsis: data from the FINNSEPSIS study

Purpose

To assess the prognostic information of chromogranin A (CgA), a marker associated with adrenergic tone and myocardial function, in patients with severe sepsis.

Methods

CgA levels were measured at the time of study inclusion and 72 h later in 232 patients with severe sepsis recruited from 24 ICUs in Finland (FINNSEPSIS study).

Results

Sixty-five patients (28 %) died during the index hospitalization. CgA levels at inclusion and after 72 h correlated with several established indices of risk in sepsis. Patients who died during the hospitalization had higher baseline CgA levels than hospital survivors: 14.0 (Q1–3, 7.4–27.4) versus 9.1 (5.9–15.8) nmol/l, P = 0.002, and after 72 h: 16.2 (9.0–31.1) versus 9.8 (6.0–18.0) nmol/l, P = 0.001. Prior cardiovascular disease (P = 0.04) and cardiovascular SOFA levels on day 3 (P = 0.03) were associated with higher CgA levels after 72 h by linear regression. CgA levels on study inclusion and after 72 h were independently associated with hospital mortality by logistic regression: OR (logarithmically transformed CgA levels) 1.95 (95 % CI 1.01–3.77), P = 0.046 and OR 2.03 (95 % CI 1.18–3.49), P = 0.01, respectively. The prognostic accuracy was comparable for CgA measurements and SAPS II score, and the addition of CgA measurements to the SAPS II score improved risk stratification of the patients as assessed by the category-free net reclassification index. A CgA level >6.6 nmol/l on study inclusion was associated with septic shock during the hospitalization.

Conclusion

CgA levels measured during hospitalization for severe sepsis are associated with cardiovascular dysfunction and may provide additional prognostic information in patients with severe sepsis.

     

Refractory septic shock in children: a European Society of Paediatric and Neonatal Intensive Care definition

Purpose

Although overall paediatric septic shock mortality is decreasing, refractory septic shock (RSS) is still associated with high mortality. A definition for RSS is urgently needed to facilitate earlier identification and treatment. We aim to establish a European society of paediatric and neonatal intensive care (ESPNIC) experts’ definition of paediatric RSS.

Methods

We conducted a two-round Delphi study followed by an observational multicentre retrospective study. One hundred and fourteen paediatric intensivists answered a clinical case-based, two-round Delphi survey, identifying clinical items consistent with RSS. Multivariate analysis of these items in a development single-centre cohort (70 patients, 30 % mortality) facilitated development of RSS definitions based on either a bedside or computed severity score. Both scores were subsequently tested in a validation cohort (six centres, 424 patients, 11.6 % mortality).

Results

From the Delphi process, the draft definition included evidence of myocardial dysfunction and high blood lactate levels despite high vasopressor treatment. When assessed in the development population, each item was independently associated with the need for extracorporeal life support (ECLS) or death. Resultant bedside and computed septic shock scores had high discriminative power against the need for ECLS or death, with areas under the receiver operating characteristics curve of 0.920 (95 % CI 0.89–0.94), and 0.956 (95 % CI 0.93–0.97), respectively. RSS defined by a bedside score equal to or higher than 2 and a computed score equal to or higher than 3.5 was associated with a significant increase in mortality.

Conclusions

This ESPNIC definition of RSS accurately identifies children with the most severe form of septic shock.

     

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.

     

Adrenocortical function during prolonged critical illness and beyond: a prospective observational study

Purpose

For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus–pituitary–adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.

Methods

Patients still in ICU on day 7 (N?=?392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.

Results

In all patients free of glucocorticoid treatment up until ICU day 28 (N?=?347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P?≤?0.002) explained by reduced binding proteins (P?≤?0.02) and suppressed cortisol breakdown (P?≤?0.001). Beyond ICU day 28 (N?=?64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P?≤?0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P?≤?0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N?=?45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.

Conclusions

Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.

     

Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates

Purpose

Although the definition of septic shock has been standardized, some variation in mortality rates among clinical trials is expected. Insights into the sources of heterogeneity may influence the design and interpretation of septic shock studies. We set out to identify inclusion criteria and baseline characteristics associated with between-trial differences in control group mortality rates.

Methods

We conducted a systematic review of RCTs published between 2006 and 2018 that included patients with septic shock. The percentage of variance in control-group mortality attributable to study heterogeneity rather than chance was measured by I². The association between control-group mortality and population characteristics was estimated using linear mixed models and a recursive partitioning algorithm.

Results

Sixty-five septic shock RCTs were included. Overall control-group mortality was 38.6%, with significant heterogeneity (I² = 93%, P < 0.0001) and a 95% prediction interval of 13.5–71.7%. The mean mortality rate did not differ between trials with different definitions of hypotension, infection or vasopressor or mechanical ventilation inclusion criteria. Population characteristics univariately associated with mortality rates were mean Sequential Organ Failure Assessment score (standardized regression coefficient (β) = 0.57, P = 0.007), mean serum creatinine (β = 0.48, P = 0.007), the proportion of patients on mechanical ventilation (β = 0.61, P < 0.001), and the proportion with vasopressors (β = 0.57, P = 0.002). Combinations of population characteristics selected with a linear model and recursive partitioning explained 41 and 42%, respectively, of the heterogeneity in mortality rates.

Conclusions

Among 65 septic shock trials, there was a clinically relevant amount of heterogeneity in control group mortality rates which was explained only partly by differences in inclusion criteria and reported baseline characteristics.

     

Chronic antiplatelet therapy is not associated with alterations in the presentation,outcome, or host response biomarkers during sepsis: a propensity-matched analysis

Purpose

Sepsis is a major health burden worldwide. Preclinical investigations in animals and retrospective studies in patients have suggested that inhibition of platelets may improve the outcome of sepsis. In this study we investigated whether chronic antiplatelet therapy impacts on the presentation and outcome of sepsis, and the host response.

Methods

We performed a prospective observational study in 972 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of them, 267 patients (27.5 %) were on antiplatelet therapy (95.9 % acetylsalicylic acid) before admission. To account for differential likelihoods of receiving antiplatelet therapy, a propensity score was constructed, including variables associated with use of antiplatelet therapy. Cox proportional hazards regression was used to estimate the association of antiplatelet therapy with mortality.

Results

Antiplatelet therapy was not associated with sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either unmatched or propensity-matched analyses. Antiplatelet therapy did not modify the values of 19 biomarkers providing insight into hallmark host responses to sepsis, including activation of the coagulation system, the vascular endothelium, the cytokine network, and renal function, during the first 4 days after ICU admission.

Conclusions

Pre-existing antiplatelet therapy is not associated with alterations in the presentation or outcome of sepsis, or the host response.

     

A multicenter multinational study of abdominal candidiasis: epidemiology,outcomes and predictors of mortality

Purpose

Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce.

Methods

We collected data from 13 hospitals in Italy, Spain, Brazil, and Greece over a 3-year period (2011–2013) including patients from ICU, medical, and surgical wards.

Results

A total of 481 patients were included in the study. Of these, 27 % were hospitalized in ICU. Mean age was 63 years and 57 % of patients were male. IAC mainly consisted of secondary peritonitis (41 %) and abdominal abscesses (30 %); 68 (14 %) cases were also candidemic and 331 (69 %) had concomitant bacterial infections. The most commonly isolated Candida species were C. albicans (n = 308 isolates, 64 %) and C. glabrata (n = 76, 16 %). Antifungal treatment included echinocandins (64 %), azoles (32 %), and amphotericin B (4 %). Septic shock was documented in 40.5 % of patients. Overall 30-day hospital mortality was 27 % with 38.9 % mortality in ICU. Multivariate logistic regression showed that age (OR 1.05, 95 % CI 1.03–1.07, P < 0.001), increments in 1-point APACHE II scores (OR 1.05, 95 % CI 1.01–1.08, P = 0.028), secondary peritonitis (OR 1.72, 95 % CI 1.02–2.89, P = 0.019), septic shock (OR 3.29, 95 % CI 1.88–5.86, P < 0.001), and absence of adequate abdominal source control (OR 3.35, 95 % CI 2.01–5.63, P < 0.001) were associated with mortality. In patients with septic shock, absence of source control correlated with mortality rates above 60 % irrespective of administration of an adequate antifungal therapy.

Conclusions

Low percentages of concomitant candidemia and high mortality rates are documented in IAC. In patients presenting with septic shock, source control is fundamental.

     

Challenges in assessing the burden of sepsis and understanding the inequalities of sepsis outcomes between National Health Systems: secular trends in sepsis and infection incidence and mortality in Germany

Purpose

Sepsis contributes considerably to global morbidity and mortality, while reasons for its increasing incidence remain unclear. We assessed risk adjusted secular trends in sepsis and infection epidemiology in Germany.

Methods

Retrospective cohort study using nationwide German hospital discharge data. We assessed incidence, outcomes and trends of hospital-treated sepsis and infections between 2010 and 2015. Sepsis was identified by explicit ICD-10 sepsis codes. As sensitivity analysis, results were compared with sepsis cases identified by implicit sepsis coding (combined infection and organ dysfunction codes).

Results

Among 18 664 877 hospital admissions in 2015, 4 213 116 (22.6%) patients had at least one infection code. There were 320 198 patients that had explicit sepsis codes including 136 542 patients with severe sepsis and septic shock; 183 656 patients were coded as sepsis without organ dysfunction. For patients with explicitly coded sepsis (including severe sepsis), or with severe sepsis alone, mortality rates over the period 2010–2015 decreased from 26.6 to 23.5%, and from 47.8 to 41.7%, respectively.

Conclusions

Sepsis and infection remain significant causes of hospital admission and death in Germany. Sepsis-related mortality is higher and has declined to a lesser degree than in other high-income countries. Although infection rates steadily increased, the observed annual increase of sepsis cases seems to result, to a considerable degree, from improved coding of sepsis.