Small volume resuscitation with 20% albumin in intensive care: physiological effects

Purpose

We set out to assess the resuscitation fluid requirements and physiological and clinical responses of intensive care unit (ICU) patients resuscitated with 20% albumin versus 4–5% albumin.

Methods

We performed a randomised controlled trial in 321 adult patients requiring fluid resuscitation within 48 h of admission to three ICUs in Australia and the UK.

Results

The cumulative volume of resuscitation fluid at 48 h (primary outcome) was lower in the 20% albumin group than in the 4–5% albumin group [median difference ??600 ml, 95% confidence interval (CI) ??800 to ??400; P?<?0.001]. The 20% albumin group had lower cumulative fluid balance at 48 h (mean difference ??576 ml, 95% CI ??1033 to ??119; P?=?0.01). Peak albumin levels were higher but sodium and chloride levels lower in the 20% albumin group. Median (interquartile range) duration of mechanical ventilation was 12.0 h (7.6, 33.1) in the 20% albumin group and 15.3 h (7.7, 58.1) in the 4–5% albumin group (P?=?0.13); the proportion of patients commenced on renal replacement therapy after randomization was 3.3% and 4.2% (P?=?0.67), respectively, and the proportion discharged alive from ICU was 97.4% and 91.1% (P?=?0.02).

Conclusions

Resuscitation with 20% albumin decreased resuscitation fluid requirements, minimized positive early fluid balance and was not associated with any evidence of harm compared with 4–5% albumin. These findings support the safety of further exploration of resuscitation with 20% albumin in larger randomised trials.

Trial registration

http://www.anzctr.org.au. Identifier ACTRN12615000349549.

     

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.

     

Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised,double-blind,placebo-controlled trial

Objective

To investigate the effect of enteral Synbiotic 2000 FORTE^® (a mixture of lactic acid bacteria and fibre) on the incidence of ventilator associated pneumonia (VAP) in critically ill patients.

Design

Prospective, randomised, double blind, placebo controlled trial.

Setting

Tertiary referral centre, general Adult Intensive Care Unit (ICU).

Patients and participants

259 enterally fed patients requiring mechanical ventilation for 48 h or more were enrolled.

Intervention

All patients were enterally fed as per a standard protocol and randomly assigned to receive either synbiotic 2000 FORTE^® (twice a day) or a cellulose-based placebo for a maximum of 28 days.

Measurements and results

Treatment group (n = 130) was well matched with placebo group (n = 129) for age (mean 49.5 and 50 years, respectively) and APACHE II score (median 17 for both). Oropharyngeal microbial flora and colonisation rates were unaffected by synbiotics. The overall incidence of VAP was lower than anticipated (11.2%) and no statistical difference was demonstrated between groups receiving synbiotic and placebo in the incidence of VAP (9 and 13%, P = 0.42), VAP rate per 1,000 ventilator days (13 and 14.6, P = 0.91) or hospital mortality (27 and 33%, P = 0.39), respectively.

Conclusions

Enteral administration of Synbiotic 2000 FORTE^® has no statistically significant impact on the incidence of VAP in critically ill patients.

     

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.

     

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised,Double Blind,Placebo-Controlled,Phase III APEX Study and its Open-Label Extension

Introduction

The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS.

Methods

Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded.

Results

Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups.

Conclusion

The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports.

Trial Registration

ClinicalTrials.gov identifier NCT01838668.

Funding

Biogen Japan Ltd.

     

Spinal high-velocity low-amplitude manipulation with exercise in women with chronic temporomandibular disorders

Background

Evidence indicates that manual therapy alone or in combination with exercise can be beneficial for temporomandibular disorders (TMD). However, there is still insufficient information demonstrating the effectiveness of treatment directed to the cervical spine for the management of TMD.

Objective

To investigate the effects of spinal high-velocity low-amplitude (HVLA) manipulation with exercise compared to patient education in patients with chronic TMD. Another objective was to assess the effects of adding spinal HVLA manipulation to exercise.

Patients and methods

Sixty female patients with TMD were randomized to three groups: cervical spinal manipulation plus neck exercise (CSM?+?NE), sham manipulation plus neck exercise (SM?+?NE), and patient education only (PE). Scores on a numeric rating scale (NRS), pressure pain thresholds (PPT), pain-free maximum mouth opening (MMO), and Short Form 36 (SF-36) were evaluated at baseline, posttreatment, and 1?month follow-up after randomization. No further treatment of TMD (like dental correction) was applied during the study period.

Results

In terms of pain, significant differences were observed in the CSM?+?NE group vs. the SM?+?NE and PE groups posttreatment. Although PPT increased significantly in the CSM?+?NE group, no significant changes in any PPT were found in either the SM?+?NE or PE group. Regarding pain-free MMO and SF-36 scores, there were significant increases posttreatment in the CSM?+?NE and SM?+?NE groups compared to the PE group.

Conclusion

Our study suggests that HVLA manipulation of the upper cervical spine with neck exercise can be effective for treatment of pain and dysfunction in patients with chronic TMD, it is not the TMD treatment itself. Therefore, it seems reasonable to add cervical manipulation to the rehabilitation program.

     

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.

     

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.

     

Long-term outcomes in patients with septic shock transfused at a lower versus a higher haemoglobin threshold: the TRISS randomised,multicentre clinical trial

Purpose

We assessed the predefined long-term outcomes in patients randomised in the Transfusion Requirements in Septic Shock (TRISS) trial.

Methods

In 32 Scandinavian ICUs, we randomised 1005 patients with septic shock and haemoglobin of 9 g/dl or less to receive single units of leuko-reduced red cells when haemoglobin level was 7 g/dl or less (lower threshold) or 9 g/dl or less (higher threshold) during ICU stay. We assessed mortality rates 1 year after randomisation and again in all patients at time of longest follow-up in the intention-to-treat population (n = 998) and health-related quality of life (HRQoL) 1 year after randomisation in the Danish patients only (n = 777).

Results

Mortality rates in the lower- versus higher-threshold group at 1 year were 53.5 % (268/501 patients) versus 54.6 % (271/496) [relative risk 0.97; 95 % confidence interval (CI) 0.85–1.09; P = 0.62]; at longest follow-up (median 21 months), they were 56.7 % (284/501) versus 61.0 % (302/495) (hazard ratio 0.88; 95 % CI 0.75–1.03; P = 0.12). We obtained HRQoL data at 1 year in 629 of the 777 (81 %) Danish patients, and mean differences between the lower- and higher-threshold group in scores of physical HRQoL were 0.4 (95 % CI ?2.4 to 3.1; P = 0.79) and in mental HRQoL 0.5 (95 % CI ?3.1 to 4.0; P = 0.79).

Conclusions

Long-term mortality rates and HRQoL did not differ in patients with septic shock and anaemia who were transfused at a haemoglobin threshold of 7 g/dl versus a threshold of 9 g/dl. We may reject a more than 3 % increased hazard of death in the lower- versus higher-threshold group at the time of longest follow-up.

     

Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised,blinded, placebo-controlled trial

Purpose

The aim of the INSTINCT trial was to assess the effect of intravenous polyspecific immunoglobulin G (IVIG) compared with placebo on self-reported physical function in intensive care unit (ICU) patients with necrotising soft tissue infection (NSTI).

Methods

We randomised 100 patients with NSTI 1:1 to masked infusion of 25 g of IVIG (Privigen, CSL Behring) or an equal volume of 0.9% saline once daily for the first 3 days of ICU admission. The primary outcome was the physical component summary (PCS) score of the 36-item short form health survey (SF-36) 6 months after randomisation; patients who had died were given the lowest possible score (zero).

Results

Of the 100 patients randomised, 87 were included in the intention-to-treat analysis of the PCS score, 42 patients (84%) in the IVIG group and 45 patients (90%) in the placebo group. The two intervention groups had similar baseline characteristics with the exception of IVIG use before randomisation (1 dose was allowed) and rates of acute kidney injury. Median PCS scores were 36 (interquartile range 0–43) in the group assigned to IVIG and 31 (0–47) in the group assigned to placebo (mean adjusted difference 1 (95% confidence interval ?7 to 10), p = 0.81). The result was supported by analyses adjusted for baseline prognostics, those in the per protocol populations, in the subgroups (site of NSTI) and those done post hoc adjusted for IVIG use before randomisation.

Conclusions

In ICU patients with NSTI, we observed no apparent effects of adjuvant IVIG on self-reported physical functioning at 6 months. Trial registration: NCT02111161.

     

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.

     

Incidence of severe sepsis and septic shock in German intensive care units: the prospective,multicentre INSEP study

Purpose

To estimate the incidence density, point prevalence and outcome of severe sepsis and septic shock in German intensive care units (ICUs).

Methods

In a prospective, multicentre, longitudinal observational study, all patients already on the ICU at 0:00 on 4 November 2013 and all patients admitted to a participating ICU between 0:00 on 4 November 2013 and 2359 hours on 1 December 2013 were included. The patients were followed up for the occurrence of severe sepsis or septic shock (SEPSIS-1 definitions) during their ICU stay.

Results

A total of 11,883 patients from 133 ICUs at 95 German hospitals were included in the study, of whom 1503 (12.6 %) were diagnosed with severe sepsis or septic shock. In 860 cases (57.2 %) the infections were of nosocomial origin. The point prevalence was 17.9 % (95 % CI 16.3–19.7).The calculated incidence rate of severe sepsis or septic shock was 11.64 (95 % CI 10.51–12.86) per 1000 ICU days. ICU mortality in patients with severe sepsis/septic shock was 34.3 %, compared with 6 % in those without sepsis. Total hospital mortality of patients with severe sepsis or septic shock was 40.4 %. Classification of the septic shock patients using the new SEPSIS-3 definitions showed higher ICU and hospital mortality (44.3 and 50.9 %).

Conclusions

Severe sepsis and septic shock continue to be a frequent syndrome associated with high hospital mortality. Nosocomial infections play a major role in the development of sepsis. This study presents a pragmatic, affordable and feasible method for the surveillance of sepsis epidemiology. Implementation of the new SEPSIS-3 definitions may have a major effect on future epidemiological data.

     

Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre,randomised, outcome assessor-blinded EAT-ICU trial

Purpose

We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in adult intensive care unit (ICU) patients.

Methods

We randomised acutely admitted, mechanically ventilated ICU patients expected to stay longer than 3 days in the ICU. In the EGDN group we estimated nutritional requirements by indirect calorimetry and 24-h urinary urea aiming at covering 100% of requirements from the first full trial day using enteral and parenteral nutrition. In the standard of care group we aimed at providing 25 kcal/kg/day by enteral nutrition. If this was not met by day 7, patients were supplemented with parenteral nutrition. The primary outcome was physical component summary (PCS) score of SF-36 at 6 months. We performed multiple imputation for data of the non-responders.

Results

We randomised 203 patients and included 199 in the intention-to-treat analyses; baseline variables were reasonably balanced between the two groups. The EGDN group had less negative energy (p < 0.001) and protein (p < 0.001) balances in the ICU as compared to the standard of care group. The PCS score at 6 months did not differ between the two groups (mean difference 0.0, 95% CI ?5.9 to 5.8, p = 0.99); neither did mortality, rates of organ failures, serious adverse reactions or infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days.

Conclusions

EGDN did not appear to affect physical quality of life at 6 months or other important outcomes as compared to standard nutrition care in acutely admitted, mechanically ventilated, adult ICU patients. Clinicaltrials.gov identifier no. NCT01372176.

     

Olanzapine vs haloperidol: treating delirium in a critical care setting

Objective

To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to haloperidol in the treatment of delirium in the critical care setting.

Design

Prospective randomized trial

Setting

Tertiary care university affiliated critical care unit.

Patients

All admissions to a medical and surgical intensive care unit with a diagnosis of delirium.

Interventions

Patients were randomized to receive either enteral olanzapine or haloperidol.

Measurements

Patient’s delirium severity and benzodiazepine use were monitored over 5 days after the diagnosis of delirium.

Main results

Delirium Index decreased over time in both groups, as did the administered dose of benzodiazepines. Clinical improvement was similar in both treatment arms. No side effects were noted in the olanzapine group, whereas the use of haloperidol was associated with extrapyramidal side effects.

Conclusions

Olanzapine is a safe alternative to haloperidol in delirious critical care patients, and may be of particular interest in patients in whom haloperidol is contraindicated.

     

Non-invasive ventilation as a strategy for weaning from invasive mechanical ventilation: a systematic review and Bayesian meta-analysis

Purpose

A systematic review and meta-analysis was conducted to answer the question ‘In adults with respiratory failure requiring invasive ventilation for more than 24 h, does a weaning strategy with early extubation to non-invasive ventilation (NIV) compared to invasive ventilation weaning reduce all-cause hospital mortality?’

Methods

We included randomised and quasi-randomised controlled trials that evaluated the use of non-invasive ventilation, compared to invasive ventilation, as a weaning strategy in adults mechanically ventilated for at least 24 h. The EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) bibliographic databases were searched from inception to February 2018. Bayesian hierarchical models were used to perform the meta-analysis. The primary outcome was mortality at hospital discharge. Secondary outcomes included mortality (30, 60, 90 and 180 days), quality of life, duration of invasive ventilation, weaning failure, length of stay [intensive care unit (ICU) and hospital] and adverse events.

Results

Twenty-five relevant studies involving 1609 patients were included in the quantitative analysis. Studies had moderate to high risk of bias due to risk of performance and detection bias. Mortality at hospital discharge was lower in the NIV weaning group compared to the invasive weaning group [pooled odds ratio (OR) 0.58, 95% highest density interval (HDI) 0.29–0.89]. Subgroup analyses showed lower pooled mortality at hospital discharge rates in NIV weaning than those in the control group in chronic obstructive pulmonary disease (COPD) patients (pooled OR 0.43, 95% HDI 0.13–0.81) and the effect is less certain in the mixed ICU population (pooled OR 0.88, 95% HDI 0.25–1.48). NIV weaning reduced the duration of invasive ventilation in patients [standardised mean difference (SMD) ??1.34, 95% HDI ??1.92 to ??0.77] and ICU length of stay (SMD ??0.70, 95% HDI ??0.94 to ??0.46). Reported rates of ventilator associated pneumonia (VAP) were lower in the NIV group. NIV weaning did not reduce overall hospital length of stay or long-term mortality. There were insufficient data to compare other adverse events and health-related quality of life.

Conclusions

The use of NIV in weaning from mechanical ventilation decreases hospital mortality, the incidence of VAP and ICU length of stay. NIV as a weaning strategy appears to be most beneficial in patients with COPD.

     

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.

     

Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label,Multicenter Study

Introduction

Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.

Methods

In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.

Results

Mean maximum plasma concentration (C_max) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (T_max) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.

Conclusion

Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.

Trial Registration

ClinicalTrials.gov identifier, NCT02451150.

Funding

Takeda Pharmaceutical Co. Ltd.

     

Prevention of hospital infections by intervention and training (PROHIBIT): results of a pan-European cluster-randomized multicentre study to reduce central venous catheter-related bloodstream infections

Purpose

To test the effectiveness of a central venous catheter (CVC) insertion strategy and a hand hygiene (HH) improvement strategy to prevent central venous catheter-related bloodstream infections (CRBSI) in European intensive care units (ICUs), measuring both process and outcome indicators.

Methods

Adult ICUs from 14 hospitals in 11 European countries participated in this stepped-wedge cluster randomised controlled multicentre intervention study. After a 6 month baseline, three hospitals were randomised to one of three interventions every quarter: (1) CVC insertion strategy (CVCi); (2) HH promotion strategy (HHi); and (3) both interventions combined (COMBi). Primary outcome was prospective CRBSI incidence density. Secondary outcomes were a CVC insertion score and HH compliance.

Results

Overall 25,348 patients with 35,831 CVCs were included. CRBSI incidence density decreased from 2.4/1000 CVC-days at baseline to 0.9/1000 (p < 0.0001). When adjusted for patient and CVC characteristics all three interventions significantly reduced CRBSI incidence density. When additionally adjusted for the baseline decreasing trend, the HHi and COMBi arms were still effective. CVC insertion scores and HH compliance increased significantly with all three interventions.

Conclusions

This study demonstrates that multimodal prevention strategies aiming at improving CVC insertion practice and HH reduce CRBSI in diverse European ICUs. Compliance explained CRBSI reduction and future quality improvement studies should encourage measuring process indicators.

     

Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial

Purpose

The EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA?≥?0.60. No difference was found in 28-day all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA?≥?0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6–0.89.

Methods

Post-hoc analysis of the EUPHRATES trial for the 194 patients with EAA?≥?0.6–0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline.

Results

At 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group [risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99), P?=?0.047]. When unadjusted for baseline variables, P?=?0.11. The 28-day survival time in the PMX group was longer than for the sham group [HR 0.56 (95% CI 0.33, 0.95) P?=?0.03]. PMX treatment compared with sham showed greater change in MAP [median (IQR) 8 mmHg (??0.5, 19.5) vs. 4 mmHg (??4.0, 11) P?=?0.04] and VFD [median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20), P?=?0.004]. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture [PMX, 6/30 (20%) vs. sham, 13/31 (41.9%), P?=?0.005]. The median EAA change in the population was ??12.9% (range: increase 49.2%–reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%), P?=?0.08.

Conclusions

These hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA?≥?0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality.

Trial registration

Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.

     

Prolonging Time to Flare in Pediatric Atopic Dermatitis: A Randomized,Investigator-Blinded,Controlled, Multicenter Clinical Study of a Ceramide-Containing Moisturizer

Introduction

Delaying or preventing flares is important in atopic dermatitis (AD) management. The objective of the study was to evaluate whether using a ceramide-containing moisturizer in addition to a body wash during latent AD can delay flares.

Methods

This was a randomized, investigator-blinded, parallel-group, controlled study among Chinese children with a history of mild to moderate AD, within 1 week of successful treatment with a topical corticosteroid. Subjects were randomized to receive moisturizer twice daily and body wash once daily, or body wash alone once daily for 12 weeks. The primary efficacy endpoint was time to flare [necessitating medical therapy and/or Investigator Global Assessment (IGA) > 1 (at least mild AD)]. Other efficacy endpoints were AD characteristics and emollient effects. The patient-reported outcome comprised satisfaction at week 12. The safety endpoint was incidence of undesirable events.

Results

A total of 64 subjects aged 2–12 years were randomized. Median time to flare was delayed by nearly 2 months for moisturizer/body wash compared to body wash alone (89 vs. 27 days, respectively). A significantly earlier onset of action in terms of fewer flares favoring moisturizer was found at week 4 (31 vs. 59%, respectively, p = 0.022), and after 12 weeks, fewer flares occurred (50 vs. 72%). At week 12 for flare-free subjects, nearly half in both groups had clear IGA, and an emollient effect in terms of less dryness or burning was more marked for moisturizer/body wash. Both products led to high patient satisfaction and were well tolerated.

Conclusion

A regimen incorporating a moisturizer plus body wash delayed AD flares by nearly 2 months compared to body wash alone, and yielded high patient satisfaction.

Funding

Galderma R&D.

Trial Registration

ClinicalTrials.gov identifier, NCT02589392.