Stakeholder views regarding ethical issues in the design and conduct of pragmatic trials : study protocol

This work is supported by the Canadian Institutes of Health Research through the Project Grant competition (competitive, peer reviewed), award number PJT-153045. Jeremy Grimshaw holds a Canada Research Chair in Health Knowledge Transfer and Uptake and a CIHR Foundation Grant (FDN-143269). Charles Weijer holds a Canada Research Chair in Bioethics. Joanne McKenzie is supported by an Australian National Health and Medical Research Council Career Development Fellowship (1143429). Vipul Jairath hold a personal Endowed Chair at Western University (John and Susan McDonald Endowed Chair). Marion Campbell is based with the Health Services Research Unit which is core-funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. Ian Graham is a CIHR Foundation Grant recipient (FDN# 143237).Peer reviewedPublisher PD

Continuous Multi-Parameter Heart Rate Variability Analysis Heralds Onset of Sepsis in Adults

BACKGROUND: Early diagnosis of sepsis enables timely resuscitation and antibiotics and prevents subsequent morbidity and mortality. Clinical approaches relying on point-in-time analysis of vital signs or lab values are often insensitive, non-specific and late diagnostic markers of sepsis. Exploring otherwise hidden information within intervals-in-time, heart rate variability (HRV) has been documented to be both altered in the presence of sepsis, and correlated with its severity. We hypothesized that by continuously tracking individual patient HRV over time in patients as they develop sepsis, we would demonstrate reduced HRV in association with the onset of sepsis. METHODOLOGY/PRINCIPAL FINDINGS: We monitored heart rate continuously in adult bone marrow transplant (BMT) patients (n = 21) beginning a day before their BMT and continuing until recovery or withdrawal (12+/-4 days). We characterized HRV continuously over time with a panel of time, frequency, complexity, and scale-invariant domain techniques. We defined baseline HRV as mean variability for the first 24 h of monitoring and studied individual and population average percentage change (from baseline) over time in diverse HRV metrics, in comparison with the time of clinical diagnosis and treatment of sepsis (defined as systemic inflammatory response syndrome along with clinically suspected infection requiring treatment). Of the 21 patients enrolled, 4 patients withdrew, leaving 17 patients who completed the study. Fourteen patients developed sepsis requiring antibiotic therapy, whereas 3 did not. On average, for 12 out of 14 infected patients, a significant (25%) reduction prior to the clinical diagnosis and treatment of sepsis was observed in standard deviation, root mean square successive difference, sample and multiscale entropy, fast Fourier transform, detrended fluctuation analysis, and wavelet variability metrics. For infected patients (n = 14), wavelet HRV demonstrated a 25% drop from baseline 35 h prior to sepsis on average. For 3 out of 3 non-infected patients, all measures, except root mean square successive difference and entropy, showed no significant reduction. Significant correlation was present amongst these HRV metrics for the entire population. CONCLUSIONS/SIGNIFICANCE: Continuous HRV monitoring is feasible in ambulatory patients, demonstrates significant HRV alteration in individual patients in association with, and prior to clinical diagnosis and treatment of sepsis, and merits further investigation as a means of providing early warning of sepsis

Age of Transfused Blood in Critically Ill Adults

International audienceBetween March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses.CONCLUSIONS:Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults

The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Intolerance to enteral nutrition is common in critically ill adults, and may result in significant morbidity including ileus, abdominal distension, vomiting and potential aspiration events. Prokinetic agents are prescribed to improve gastric emptying. However, the efficacy and safety of these agents in critically ill patients is not well-defined. Therefore, we conducted a systematic review and meta-analysis to determine the efficacy and safety of prokinetic agents in critically ill patients. METHODS: We searched MEDLINE, EMBASE, and Cochrane Library from inception up to January 2016. Eligible studies included randomized controlled trials (RCTs) of critically ill adults assigned to receive a prokinetic agent or placebo, and that reported relevant clinical outcomes. Two independent reviewers screened potentially eligible articles, selected eligible studies, and abstracted pertinent data. We calculated pooled relative risk (RR) for dichotomous outcomes and mean difference for continuous outcomes, with the corresponding 95 % confidence interval (CI). We assessed risk of bias using Cochrane risk of bias tool, and the quality of evidence using grading of recommendations assessment, development, and evaluation (GRADE) methodology. RESULTS: Thirteen RCTs (enrolling 1341 patients) met our inclusion criteria. Prokinetic agents significantly reduced feeding intolerance (RR 0.73, 95 % CI 0.55, 0.97; P = 0.03; moderate certainty), which translated to 17.3 % (95 % CI 5, 26.8 %) absolute reduction in feeding intolerance. Prokinetics also reduced the risk of developing high gastric residual volumes (RR 0.69; 95 % CI 0.52, 0.91; P = 0.009; moderate quality) and increased the success of post-pyloric feeding tube placement (RR 1.60, 95 % CI 1.17, 2.21; P = 0.004; moderate quality). There was no significant improvement in the risk of vomiting, diarrhea, intensive care unit (ICU) length of stay or mortality. Prokinetic agents also did not significantly increase the rate of diarrhea. CONCLUSION: There is moderate-quality evidence that prokinetic agents reduce feeding intolerance in critically ill patients compared to placebo or no intervention. However, the impact on other clinical outcomes such as pneumonia, mortality, and ICU length of stay is unclear

Prediction Scores Do Not Correlate with Clinically Adjudicated Categories of Pulmonary Embolism in Critically Ill Patients

Copyright © 2014 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BACKGROUND: Prediction scores for pretest probability of pulmonary embolism (PE) validated in outpatient settings are occasionally used in the intensive care unit (ICU).OBJECTIVE: To evaluate the correlation of Geneva and Wells scores with adjudicated categories of PE in ICU patients.METHODS: In a randomized trial of thromboprophylaxis, patients with suspected PE were adjudicated as possible, probable or definite PE. Data were then retrospectively abstracted for the Geneva Diagnostic PE score, Wells, Modified Wells and Simplified Wells Diagnostic scores. The chance-corrected agreement between adjudicated categories and each score was calculated. ANOVA was used to compare values across the three adjudicated PE categories.RESULTS: Among 70 patients with suspected PE, agreement was poor between adjudicated categories and Geneva pretest probabilities (kappa 0.01 [95% CI −0.0643 to 0.0941]) or Wells pretest probabilities (kappa −0.03 [95% CI −0.1462 to 0.0914]). Among four possible, 16 probable and 50 definite PEs, there were no significant differences in Geneva scores (possible = 4.0, probable = 4.7, definite = 4.5; P=0.90), Wells scores (possible = 2.8, probable = 4.9, definite = 4.1; P=0.37), Modified Wells (possible = 2.0, probable = 3.4, definite = 2.9; P=0.34) or Simplified Wells (possible = 1.8, probable = 2.8, definite = 2.4; P=0.30).CONCLUSIONS: Pretest probability scores developed outside the ICU do not correlate with adjudicated PE categories in critically ill patients. Research is needed to develop prediction scores for this population

Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review

<div><p>The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I² 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.</p></div

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570