Frequency of Screening and Spontaneous Breathing Trial Techniques: A Randomized Clinical Trial.

Importance: The optimal screening frequency and spontaneous breathing trial (SBT) technique to liberate adults from ventilators are unknown. Objective: To compare the effects of screening frequency (once-daily screening vs more frequent screening) and SBT technique (pressure-supported SBT with a pressure support level that was >0-≤8 cm H2O and a positive end-expiratory pressure [PEEP] level that was >0-≤5 cm H2O vs T-piece SBT) on the time to successful extubation. Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design including critically ill adults who were receiving invasive mechanical ventilation for at least 24 hours, who were capable of initiating spontaneous breaths or triggering ventilators, and who were receiving a fractional concentration of inspired oxygen that was 70% or less and a PEEP level of 12 cm H2O or less. Recruitment was between January 2018 and February 2022 at 23 intensive care units in North America; last follow-up occurred October 18, 2022. Interventions: Participants were enrolled early to enable protocolized screening (more frequent vs once daily) to identify the earliest that patients met criteria to undergo pressure-supported or T-piece SBT lasting 30 to 120 minutes. Main Outcome and Measures: Time to successful extubation (time when unsupported, spontaneous breathing began and was sustained for ≥48 hours after extubation). Results: Of 797 patients (198 in the once-daily screening and pressure-supported SBT group, 204 in once-daily screening and T-piece SBT, 195 in more frequent screening and pressure-supported SBT, and 200 in more frequent screening and T-piece SBT), the mean age was 62.4 (SD, 18.4) years and 472 (59.2%) were men. There were no statistically significant differences by screening frequency (hazard ratio [HR], 0.88 [95% CI, 0.76-1.03]; P = .12) or by SBT technique (HR, 1.06 [95% CI, 0.91-1.23]; P = .45). The median time to successful extubation was 2.0 days (95% CI, 1.7-2.7) for once-daily screening and pressure-supported SBT, 3.1 days (95% CI, 2.7-4.8) for once-daily screening and T-piece SBT, 3.9 days (95% CI, 2.9-4.7) for more frequent screening and pressure-supported SBT, and 2.9 days (95% CI, 2.0-3.1) for more frequent screening and T-piece SBT. An unexpected interaction between screening frequency and SBT technique required pairwise contrasts that revealed more frequent screening (vs once-daily screening) and pressure-supported SBT increased the time to successful extubation (HR, 0.70 [95% CI, 0.50-0.96]; P = .02). Once-daily screening and pressure-supported SBT (vs T-piece SBT) did not reduce the time to successful extubation (HR, 1.30 [95% CI, 0.98-1.70]; P = .08). Conclusions and Relevance: Among critically ill adults who received invasive mechanical ventilation for more than 24 hours, screening frequency (once-daily vs more frequent screening) and SBT technique (pressure-supported vs T-piece SBT) did not change the time to successful extubation. However, an unexpected and statistically significant interaction was identified; protocolized more frequent screening combined with pressure-supported SBTs increased the time to first successful extubation. Trial Registration: ClinicalTrials.gov Identifiers: NCT02399267 and NCT02969226.

Variability in deceased donor care in Canada: a report of the Canada-DONATE cohort study.

PURPOSE: Canadian donor management practices have not been reported. Our aim was to inform clinicians and other stakeholders about the range of current practices. METHODS: This prospective observational cohort study enrolled consecutive, newly consented organ donors from August 1 2015 to July 31 2018 at 27 academic and five community adult intensive care units in British Columbia, Alberta, Ontario, and Quebec. Research staff prospectively recorded donor management data. Provincial organ donation organizations verified the organs donated. We formally compared practices across provinces. RESULTS: Over a median collection period of eight months, 622 potential donors were classified at baseline as having neurologic determination of death (NDD donors; n = 403) or circulatory death (DCD donors; n = 219). Among NDD donors, 85.6% underwent apnea testing (rarely with carbon dioxide insufflation), 33.2% underwent ancillary testing, and subsequent therapeutic hypothermia (34-35°C) was rare. Neurologic determination of death donors were more hemodynamically unstable with most having received vasopressin and norepinephrine infusions, with a large majority having received high-dose corticosteroids and intravenous thyroxine. Among DCD donors, 61.6% received corticosteroids, and 8.9% received thyroxine. Most donors did not receive lung-protective ventilation strategies. Invasive procedures after donation consent included bronchoscopy (71.7%), cardiac catheterization (NDD donors only; 21.3%), and blood transfusions (19.3%). Physicians ordered intravenous antemortem heparin for 94.8% of DCD donors. The cohort donated 1,629 organs resulting in 1,532 transplants. Case selection, death determinations, and hormone, nutrition and heparin practices all varied across provinces. CONCLUSION: These study findings highlight areas for knowledge translation and further clinical research. Interprovincial discrepancies will likely pose unique challenges to national randomized trials. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03114436); registered 10 April, 2017.

RéSUMé: OBJECTIF: Les pratiques canadiennes de prise en charge des donneurs n'ont pas été rapportées. Notre objectif était d'informer les cliniciens et autres parties intéressées quant à l'éventail des pratiques actuelles. MéTHODE: Cette étude de cohorte observationnelle et prospective a recruté des donneurs d'organes consécutifs ayant récemment consenti au don entre le 1er août 2015 et le 31 juillet 2018 dans 27 unités de soins intensifs universitaires et cinq unités de soins intensifs pour adultes en milieu communautaire en Colombie-Britannique, en Alberta, en Ontario et au Québec. Le personnel de recherche a enregistré de manière prospective les données de prise en charge des donneurs. Les organismes de dons d'organes provinciaux ont vérifié les organes donnés. Nous avons formellement comparé les pratiques d'une province à l'autre. RéSULTATS: Sur une période médiane de collecte de huit mois, 622 donneurs potentiels ont été catégorisés au départ comme ayant un diagnostic de décès neurologique (donneurs DDN; n = 403) ou un décès cardiocirculatoire (donneurs DDC; n = 219). Parmi les donneurs DDN, 85,6 % ont subi un test d'apnée (rarement avec insufflation de dioxyde de carbone), 33,2 % ont subi des tests complémentaires, et une hypothermie thérapeutique subséquente (34-35°C) était rare. Les donneurs par diagnostic de décès neurologique étaient plus instables hémodynamiquement, la plupart ayant reçu des perfusions de vasopressine et de norépinéphrine, et une vaste majorité de ces donneurs ont reçu des corticostéroïdes à forte dose ainsi que de la thyroxine intraveineuse. Parmi les donneurs par DDC, 61,6 % avaient reçu des corticostéroïdes, et 8,9 % de la thyroxine. La plupart des donneurs n'avaient pas bénéficié de stratégies de ventilation protectrice des poumons. Les interventions invasives réalisées après le consentement au don comprenaient la bronchoscopie (71,7 %), le cathétérisme cardiaque (donneurs DDN seulement; 21,3 %) et les transfusions sanguines (19,3 %). Les médecins ont prescrit de l'héparine intraveineuse ante mortem chez 94,8 % des donneurs DDC. La cohorte a donné 1629 organes, résultant en 1532 greffes. La sélection de cas, la détermination de décès et les pratiques hormonales, nutritionnelles et hépariniques variaient toutes d'une province à l'autre. CONCLUSION: Ces résultats soulignent des domaines propices à la transmission de connaissances et aux recherches cliniques plus poussées. Les différences interprovinciales poseront probablement des défis uniques pour les études randomisées nationales. Enregistrement de l'étude : www.clinicaltrials.gov (NCT03114436); enregistrée le 10 avril 2017.

A randomized trial of supplemental parenteral nutrition in underweight and overweight critically ill patients: the TOP-UP pilot trial.

BACKGROUND: Nutrition guidelines recommendations differ on the use of parenteral nutrition (PN), and existing clinical trial data are inconclusive. Our recent observational data show that amounts of energy/protein received early in the intensive care unit (ICU) affect patient mortality, particularly for inadequate nutrition intake in patients with body mass indices (BMIs) of <25 or >35. Thus, we hypothesized increased nutrition delivery via supplemental PN (SPN) + enteral nutrition (EN) to underweight and obese ICU patients would improve 60-day survival and quality of life (QoL) versus usual care (EN alone). METHODS: In this multicenter, randomized, controlled pilot trial completed in 11 centers across four countries, adult ICU patients with acute respiratory failure expected to require mechanical ventilation for >72 hours and with a BMI of <25 or ≥35 were randomized to receive EN alone or SPN + EN to reach 100% of their prescribed nutrition goal for 7 days after randomization. The primary aim of this pilot trial was to achieve a 30% improvement in nutrition delivery. RESULTS: In total, 125 patients were enrolled. Over the first 7 post-randomization ICU days, patients in the SPN + EN arm had a 26% increase in delivered calories and protein, whereas patients in the EN-alone arm had a 22% increase (both p < 0.001). Surgical ICU patients received poorer EN nutrition delivery and had a significantly greater increase in calorie and protein delivery when receiving SPN versus medical ICU patients. SPN proved feasible to deliver with our prescribed protocol. In this pilot trial, no significant outcome differences were observed between groups, including no difference in infection risk. Potential, although statistically insignificant, trends of reduced hospital mortality and improved discharge functional outcomes and QoL outcomes in the SPN + EN group versus the EN-alone group were observed. CONCLUSIONS: Provision of SPN + EN significantly increased calorie/protein delivery over the first week of ICU residence versus EN alone. This was achieved with no increased infection risk. Given feasibility and consistent encouraging trends in hospital mortality, QoL, and functional endpoints, a full-scale trial of SPN powered to assess these clinical outcome endpoints in high-nutritional-risk ICU patients is indicated-potentially focusing on the more poorly EN-fed surgical ICU setting. TRIAL REGISTRATION: NCT01206166.

Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83-0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Mechanical Ventilation after Traumatic Spinal Cord Injury-A Multicentric Cohort Study-based Prediction Model for Weaning Success: The BICYCLE Score.

Rationale: Limited information exists about the epidemiology, outcomes, and predictors of weaning from mechanical ventilation in patients with spinal cord injury. Objectives: Our aim was to investigate predictors of weaning outcomes for patients with traumatic spinal cord injury (tSCI) and develop and validate a prognostic model and score for weaning success. Methods: This was a registry-based, multicentric cohort study including all adult patients with tSCI requiring mechanical ventilation (MV) and admitted to one of the intensive care units (ICUs) of the Trauma Registry at St. Michael's Hospital (Toronto, ON, Canada) and the Canadian Rick Hansen Spinal Cord Injury Registry between 2005 and 2019. The primary outcome was weaning success from MV at ICU discharge. Secondary outcomes included weaning success at Days 14 and 28, time to liberation from MV accounting for competing risk of death, and ventilator-free days at 28 and 60 days. Associations between baseline characteristics and weaning success or time to liberation from MV were measured using multivariable logistic and competing risk regressions. A parsimonious model to predict weaning success and ICU discharge was developed and validated via bootstrap. A prediction score for weaning success at ICU discharge was derived, and its discriminative ability was assessed using receiver operating characteristic curve analysis and compared with the Injury Severity Score (ISS). Results: Of 459 patients analyzed, 246 (53.6%), 302 (65.8%), and 331 (72.1%) were alive and free of MV at Day 14, Day 28, and ICU discharge, respectively; 54 (11.8%) died in the ICU. Median time to liberation from MV was 12 days. Factors associated with weaning success were Blunt injury (odds ratio [OR], 2.96; P = 0.010), ISS (OR, 0.98; P = 0.025), Complete syndrome (OR, 0.53; P = 0.009), age in Years (OR, 0.98; P = 0.003), and Cervical LEsion (OR, 0.60; P = 0.045). The BICYCLE score showed a greater area under the curve than the ISS (0.689 [95% confidence interval (CI), 0.631-0.743] vs. 0.537 [95% CI, 0.479-0.595]; P < 0.0001). Factors predicting weaning success also predicted time to liberation. Conclusions: In a large multicentric cohort, 72% of patients with tSCI were weaned and discharged alive from the ICU. Readily available admission characteristics can reasonably predict weaning success and help prognostication.

Nimodipine systemic exposure and outcomes following aneurysmal subarachnoid hemorrhage: a pilot prospective observational study (ASH-1 study).

Background: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Guidelines recommend that all patients should receive a fixed-dose nimodipine for 21 days. However, studies reported variability of nimodipine concentrations in aSAH. It is not clear if reduced systemic exposure contributes to worsening outcomes. The aim of this study was to compare nimodipine systemic exposure in those who experienced poor outcomes to those who experienced favorable outcomes. Methods: This was a pilot prospective observational study in 30 adult patients admitted to the University of Alberta Hospital with aSAH. Data were collected from the electronic health records following enrollment. Blood samples were collected around one nimodipine 60 mg dose at a steady state, and nimodipine [total, (+)-R and (-)-S enantiomers] plasma concentrations were determined. The poor outcome was defined as a modified Rankin Scale (mRS) score at 90 days of 3-6, while the favorable outcome was an mRS score of 0-2. The correlation between nimodipine concentrations and percent changes in mean arterial pressure (MAP) before and after nimodipine administration was also determined. Furthermore, covariates potentially associated with nimodipine exposure were explored. Results: In total, 20 (69%) participants had favorable outcomes and 9 (31%) had poor outcomes. Following the exclusion of those with delayed presentation (>96 h from aSAH onset), among those presented with the World Federation of Neurological Surgeons (WFNS) grade 3-5, nimodipine median (interquartile range) area under the concentration time curve (AUC0-3h) in those with favorable outcomes were 4-fold higher than in those with poor outcomes [136 (52-192) vs. 33 (23-39) ng.h/mL, respectively, value of p = 0.2]. On the other hand, among those presented with WFNS grade 1-2, nimodipine AUC0-3h in those with favorable outcomes were significantly lower than in those with poor outcomes [30 (28-36) vs. 172 (117-308) ng.h/mL, respectively, value of p = 0.03)]. (+)-R-nimodipine AUC0-3h in those who did not develop vasospasm were 4-fold significantly higher than those who had vasospasm (value of p = 0.047). (-)-S-nimodipine was significantly correlated with percentage MAP reduction. Similar results were obtained when the whole cohort was analyzed. Conclusion: The study was the first to investigate the potential association between nimodipine exposure following oral dosing and outcomes. In addition, it suggests differential effects of nimodipine enantiomers, shedding light on the potential utility of nimodipine enantiomers. Larger studies are needed.

Timing of tracheostomy in acute traumatic spinal cord injury: A systematic review and meta-analysis.

BACKGROUND: Patients with acute traumatic cervical or high thoracic level spinal cord injury (SCI) typically require mechanical ventilation (MV) during their acute admission. Placement of a tracheostomy is preferred when prolonged weaning from MV is anticipated. However, the optimal timing of tracheostomy placement in patients with acute traumatic SCI remains uncertain. We systematically reviewed the literature to determine the effects of early versus late tracheostomy or prolonged intubation in patients with acute traumatic SCI on important clinical outcomes. METHODS: Six databases were searched from their inception to January 2020. Conference abstracts from relevant proceedings and the gray literature were searched to identify additional studies. Data were obtained by two independent reviewers to ensure accuracy and completeness. The quality of observational studies was evaluated using the Newcastle Ottawa Scale. RESULTS: Seventeen studies (2,804 patients) met selection criteria, 14 of which were published after 2009. Meta-analysis showed that early tracheostomy was not associated with decreased short-term mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.39-1.79; p = 0.65; n = 2,072), but was associated with a reduction in MV duration (mean difference [MD], 13.1 days; 95% CI, -6.70 to -21.11; p = 0.0002; n = 855), intensive care unit length of stay (MD, -10.20 days; 95% CI, -4.66 to -15.74; p = 0.0003; n = 855), and hospital length of stay (MD, -7.39 days; 95% CI, -3.74 to -11.03; p < 0.0001; n = 423). Early tracheostomy was also associated with a decreased incidence of ventilator-associated pneumonia and tracheostomy-related complications (RR, 0.86; 95% CI, 0.75-0.98; p = 0.02; n = 2,043 and RR, 0.64; 95% CI, 0.48-0.84; p = 0.001; n = 812 respectively). The majority of studies ranked as good methodologic quality on the Newcastle Ottawa Scale. CONCLUSION: Early tracheostomy in patients with acute traumatic SCI may reduce duration of mechanical entilation, length of intensive care unit stay, and length of hospital stay. Current studies highlight the lack of high-level evidence to guide the optimal timing of tracheostomy in acute traumatic SCI. Future research should seek to understand whether early tracheostomy improves patient comfort, decreases duration of sedation, and improves long-term outcomes. LEVEL OF EVIDENCE: Systematic Review, level III.

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.

Characteristics and outcomes of patients with COVID-19 admitted to hospital and intensive care in the first phase of the pandemic in Canada: a national cohort study.

BACKGROUND: Clinical data on patients admitted to hospital with coronavirus disease 2019 (COVID-19) provide clinicians and public health officials with information to guide practice and policy. The aims of this study were to describe patients with COVID-19 admitted to hospital and intensive care, and to investigate predictors of outcome to characterize severe acute respiratory infection. METHODS: This observational cohort study used Canadian data from 32 selected hospitals included in a global multisite cohort between Jan. 24 and July 7, 2020. Adult and pediatric patients with a confirmed diagnosis of COVID-19 who received care in an intensive care unit (ICU) and a sampling of up to the first 60 patients receiving care on hospital wards were included. We performed descriptive analyses of characteristics, interventions and outcomes. The primary analyses examined in-hospital mortality, with secondary analyses of the length of hospital and ICU stay. RESULTS: Between January and July 2020, among 811 patients admitted to hospital with a diagnosis of COVID-19, the median age was 64 (interquartile range [IQR] 53-75) years, 495 (61.0%) were men, 46 (5.7%) were health care workers, 9 (1.1%) were pregnant, 26 (3.2%) were younger than 18 years and 9 (1.1%) were younger than 5 years. The median time from symptom onset to hospital admission was 7 (IQR 3-10) days. The most common symptoms on admission were fever, shortness of breath, cough and malaise. Diabetes, hypertension and cardiac, kidney and respiratory disease were the most common comorbidities. Among all patients, 328 received care in an ICU, admitted a median of 0 (IQR 0-1) days after hospital admission. Critically ill patients received treatment with invasive mechanical ventilation (88.8%), renal replacement therapy (14.9%) and extracorporeal membrane oxygenation (4.0%); 26.2% died. Among those receiving mechanical ventilation, 31.2% died. Age was an influential predictor of mortality (odds ratio per additional year of life 1.06, 95% confidence interval 1.03-1.09). INTERPRETATION: Patients admitted to hospital with COVID-19 commonly had fever, respiratory symptoms and comorbid conditions. Increasing age was associated with the development of critical illness and death; however, most critically ill patients in Canada, including those requiring mechanical ventilation, survived and were discharged from hospital.