Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Monitoring and auditing protocol adherence, data integrity and ethical conduct of a randomized clinical trial: A case study.

PURPOSE: To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients. MATERIALS & METHODS: In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety. RESULTS: Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety. CONCLUSIONS: Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety. TRIAL REGISTRATION: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

BACKGROUND: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. METHODS: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. RESULTS: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). CONCLUSIONS: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Consent models in Canadian critical care randomized controlled trials: a scoping review.

PURPOSE: Our primary objective was to describe consent models used in Canadian-led adult and pediatric intensive care unit (ICU/PICU) randomized controlled trials (RCTs). Our secondary objectives were to determine the consent rate of ICU/PICU RCTs that did and did not use an alternate consent model to describe consent procedures. SOURCE: Using scoping review methodology, we searched MEDLINE, Embase, and CENTRAL databases (from 1998 to June 2019) for trials published in English or French. We included Canadian-led RCTs that reported on the effects of an intervention on ICU/PICU patients or their families. Two independent reviewers assessed eligibility, abstracted data, and achieved consensus. PRINCIPAL FINDINGS: We identified 48 RCTs of 17,558 patients. Included RCTs had ethics approval to use prior informed consent (43/48; 90%), deferred consent (13/48; 27%), waived consent (5/48; 10%), and verbal consent (1/48; 2%) models. Fifteen RCTs (15/48; 31%) had ethics approval to use more than one consent model. Twice as many trials used alternate consent between 2010 and 2019 (13/19) than between 2000 and 2009 (6/19). The consent rate for RCTs using only prior informed consent ranged from 54 to 91% (ICU) and 43 to 94% (PICU) and from 78 to 100% (ICU) and 74 to 87% (PICU) in trials using an alternate/hybrid consent model. CONCLUSION: Alternate consent models were used in the minority of Canadian-led ICU/PICU RCTs but have been used more frequently over the last decade. This suggests that Canadian ethics boards and research communities are becoming more accepting of alternate consent models in ICU/PICU trials.

RéSUMé: OBJECTIF: Notre objectif principal était de décrire les modèles de consentement utilisés dans les études randomisées contrôlées (ERC) menées par des chercheurs canadiens dans les unités de soins intensifs adultes et pédiatriques (USI/USIP). Nos objectifs secondaires étaient de déterminer le taux de consentement aux ERC à l'USI et l'USIP qui utilisaient et n'utilisaient pas un autre modèle de consentement pour décrire les processus de consentement. SOURCES: À l'aide d'une méthodologie d'étude de portée, nous avons effectué des recherches dans les bases de données MEDLINE, Embase et CENTRAL (de 1998 à juin 2019) pour en tirer les études publiées en anglais ou en français. Nous avons inclus des ERC dirigées par des chercheurs canadiens qui rapportaient les effets d'une intervention sur les patients à l'USI/USIP ou leurs familles. Deux examinateurs indépendants ont évalué l'admissibilité, résumé les données et atteint un consensus. RéSULTATS PRINCIPAUX: Nous avons identifié 48 ERC portant sur 17 558 patients. Les ERC incluses avaient obtenu l'approbation du comité d'éthique pour l'utilisation de modèles de consentement éclairé préalable (43/48; 90 %), de consentement différé (13/48; 27 %), de renoncement au consentement (5/48; 10 %) et de consentement verbal (1/48; 2 %). Quinze ERC (15/48; 31 %) avaient reçu l'approbation du comité d'éthique pour utiliser plus d'un modèle de consentement. Deux fois plus d'études ont utilisé un autre type de consentement entre 2010 et 2019 (13/19) qu'entre 2000 et 2009 (6/19). Le taux de consentement pour les ERC utilisant uniquement un consentement éclairé préalable variait de 54 à 91 % (USI) et de 43 à 94 % (USIP), contre 78 à 100 % (USI) et 74 à 87 % (USIP) pour les études utilisant un modèle de consentement alternatif/hybride. CONCLUSION: Des modèles de consentement alternatif ont été utilisés dans une minorité des ERC en USI/USIP dirigées par des chercheurs canadiens, mais ils ont été utilisés plus fréquemment au cours de la dernière décennie. Cela donne à penser que les comités d'éthique et les communautés de recherche canadiens acceptent de plus en plus les modèles de consentement alternatifs dans les études réalisées en USI et en USIP.

Feasibility of implementing Extubation Advisor, a clinical decision support tool to improve extubation decision-making in the ICU: a mixed-methods observational study.

OBJECTIVES: Although spontaneous breathing trials (SBTs) are standard of care to extubation readiness, no tool exists that optimises prediction and standardises assessment. In this study, we evaluated the feasibility and clinical impressions of Extubation Advisor (EA), a comprehensive clinical extubation decision support (CDS) tool. DESIGN: Phase I mixed-methods observational study. SETTING: Two Canadian intensive care units (ICUs). PARTICIPANTS: We included patients on mechanical ventilation for ≥24 hours and clinicians (respiratory therapists and intensivists) responsible for extubation decisions. INTERVENTIONS: Components included a predictive model assessment, feasibility evaluation, questionnaires and interviews with clinicians. RESULTS: We enrolled 117 patients, totalling 151 SBTs and 80 extubations. The incidence of extubation failure was 11% in low-risk patients and 21% in high-risk patients stratified by the predictive model; 38% failed extubation when both the model and clinical impression were at high risk. The tool was well rated: 94% and 75% rated the data entry and EA report as average or better, respectively. Interviews (n=15) revealed favourable impressions regarding its user interface and functionality, but unexpectedly, also concerns regarding EA's potential impact on respiratory therapists' job security. CONCLUSIONS: EA implementation was feasible, and users perceived it to have potential to support extubation decision-making. This study helps to understand bedside implementation of CDS tools in a multidisciplinary ICU. TRIAL REGISTRATION NUMBER: NCT02988167.

Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial.

INTRODUCTION: Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60-65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years. METHODS AND ANALYSIS: OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation. ETHICS AND DISSEMINATION: This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums. TRIAL REGISTRATION NUMBER: NCT03431181.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

BACKGROUND: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. METHODS: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis.

BACKGROUND: Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. OBJECTIVE: The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. METHODS: Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. RESULTS: From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46) L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration-time curve from time zero to 24 h [AUC24]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC24 ≥ 700), a loading dose of 2400 mg followed by daily doses of 1600 mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. CONCLUSIONS: In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels.

Correction to: Project management lessons learned from the multicentre CYCLE pilot randomized controlled trial.

Following publication of the original article [1], we have been notified that one of the authors' names is spelled incorrectly. In this Correction the incorrect and correct author name are shown.

Project management lessons learned from the multicentre CYCLE pilot randomized controlled trial.

BACKGROUND: Clinical trials management can be studied using project management theory. The CYCLE pilot randomized controlled trial (RCT) was conducted to determine the feasibility of a future rehabilitation trial of early in-bed cycling in the intensive care unit (ICU). In-bed cycling is a novel intervention, not typically available in ICUs. Implementation of this intervention requires personnel with specialized clinical expertise caring for critically ill patients and use of the in-bed cycle. Our objective was to describe the implementation and conduct of our pilot RCT using a project management approach. METHODS: We retrospectively reviewed activities, timelines, and personnel involved in the trial. We organized activities into four project management phases: initiation, planning, execution, and monitoring and controlling. Data sources included Methods Centre documents used for trial coordination and conduct, and the trial data set. We report descriptive statistics as counts and proportions and also medians and quartiles, and we summarize the lessons learned. RESULTS: Seven ICUs in Canada participated in the trial. Time from research ethics board and contracts submission to first enrolment was a median (first quartile, third quartile) of 185 (146, 209) and 162 (114, 181) days, respectively. We trained 128 personnel on the CYCLE pilot RCT protocol, and 80 (63%) completed trial-related activities. Four sites required additional training after start-up due to staff turnover and leaves of absence. Over 15 months, we screened 864 patients: 256 were eligible and 66 were enrolled. Despite an 85% consent rate, 74% (190/256) of eligible patients were not randomized, largely (80% [152/190]) due to physiotherapist availability. Thirteen percent of recruitment weeks were lost due to physiotherapist staffing shortages. We highlight five key lessons learned: (1) prepare and anticipate site needs; (2) communicate regularly; (3) proactively analyse and act on process measure data; (4) develop contingency plans; (5) express appreciation to participating sites. CONCLUSIONS: Our analysis highlights the scope of relevant activities, rigorous training and monitoring, number and types of required personnel, and time required to conduct a multicentre ICU rehabilitation intervention trial. Our lessons learned can help others interested in implementing complex intervention trials, such as rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02377830 . Registered prospectively on 4 March 2015.

Saline versus albumin fluid for extracorporeal removal with slow low-efficiency dialysis (SAFER-SLED): study protocol for a pilot trial.

BACKGROUND: Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality.Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive.As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED. METHODS: This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure. DISCUSSION: The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018.

Piperacillin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis.

BACKGROUND: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. OBJECTIVE: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. METHODS: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. RESULTS: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L. CONCLUSIONS AND RELEVANCE: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.