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N Engl J Med ; 387(21): 1947-1956, 2022 11 24.
Article in English | MEDLINE | ID: covidwho-2254781


BACKGROUND: Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation. METHODS: We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge. RESULTS: A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively). CONCLUSIONS: Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF number, NCT04080986.).

Electric Countershock , Out-of-Hospital Cardiac Arrest , Ventricular Fibrillation , Adult , Humans , Canada , Defibrillators , Electric Countershock/adverse effects , Electric Countershock/instrumentation , Electric Countershock/methods , Out-of-Hospital Cardiac Arrest/mortality , Out-of-Hospital Cardiac Arrest/therapy , Ventricular Fibrillation/mortality , Ventricular Fibrillation/therapy , Cross-Over Studies , Cluster Analysis
Can J Anaesth ; 67(10): 1405-1416, 2020 10.
Article in English | MEDLINE | ID: covidwho-1777848


During the coronavirus disease (COVID-19) global pandemic, urgent strategies to alleviate shortages are required. Evaluation of the feasibility, practicality, and value of drug conservation strategies and therapeutic alternatives requires a collaborative approach at the provincial level. The Ontario COVID-19 ICU Drug Task Force was directed to create recommendations suggesting drug conservation strategies and therapeutic alternatives for essential drugs at risk of shortage in the intensive care unit during the COVID-19 pandemic. Recommendations were rapidly developed using a modified Delphi method and evaluated on their ease of implementation, feasibility, and supportive evidence. This article describes the recommendations for drug conservation strategies and therapeutic alternatives for drugs at risk of shortage that are commonly used in the care of critically ill patients. Recommendations are identified as preferred and secondary ones that might be less desirable. Although the impetus for generating this document was the COVID-19 pandemic, recommendations should also be applicable for mitigating drug shortages outside of a pandemic. Proposed provincial strategies for drug conservation and therapeutic alternatives may not all be appropriate for every institution. Local implementation will require consultation from end-users and hospital administrators. Competing equipment shortages and available resources should be considered when evaluating the appropriateness of each strategy.

RéSUMé: Pendant la pandémie mondiale du coronavirus (COVID-19), des stratégies urgentes pour réduire les pénuries sont nécessaires. L'évaluation de la faisabilité, de l'aspect pratique et du mérite des stratégies de préservation des médicaments et des alternatives thérapeutiques nécessite une approche collaborative au niveau provincial. Le Groupe de travail ontarien sur les médicaments à l'USI pendant la COVID-19 a reçu comme mandat d'élaborer des recommandations proposant des stratégies de préservation des médicaments et des alternatives thérapeutiques pour les médicaments essentiels utilisés dans les unités de soins intensifs courant un risque de pénurie pendant la pandémie de COVID-19. Des recommandations ont été rapidement élaborées en utilisant une méthode Delphi modifiée, puis évaluées selon leur facilité de mise en œuvre, leur faisabilité et les données probantes les préconisant. Cet article décrit les recommandations quant aux stratégies de préservation des médicaments et aux alternatives thérapeutiques aux médicaments possiblement à risque de pénurie fréquemment utilisés pour les soins des patients en état critique. Les recommandations sont identifiées comme 'à privilégier' ou 'secondaires' si moins souhaitables. Bien que la pandémie de la COVID-19 ait été l'impulsion incitant la création de ce document, ces recommandations devraient également être applicables pour réduire les pénuries de médicaments en contexte normal. Les stratégies provinciales proposées pour la préservation des médicaments et les alternatives thérapeutiques pourraient ne pas être adaptées pour toutes les institutions. La mise en œuvre locale nécessitera la consultation des utilisateurs et des administrateurs hospitaliers. Il faudrait tenir compte des pénuries de matériel concurrentes et des ressources disponibles lors de l'évaluation de la faisabilité de chaque stratégie.

Coronavirus Infections/drug therapy , Intensive Care Units , Pharmaceutical Preparations/supply & distribution , Pneumonia, Viral/drug therapy , Advisory Committees , COVID-19 , Critical Illness , Humans , Ontario , Pandemics , COVID-19 Drug Treatment
Nat Med ; 27(11): 2012-2024, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526091


The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

COVID-19/therapy , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , COVID-19/epidemiology , Canada/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Immunization, Passive , Intention to Treat Analysis , Male , Middle Aged , SARS-CoV-2/immunology , Treatment Outcome , United States/epidemiology , COVID-19 Serotherapy
Chest ; 161(2): 418-428, 2022 02.
Article in English | MEDLINE | ID: covidwho-1363121


BACKGROUND: Critically ill adults are at increased risk of VTE, including DVT, and pulmonary embolism. Various agents exist for venous thromboprophylaxis in this population. RESEARCH QUESTION: What is the comparative efficacy and safety of prophylaxis agents for prevention of VTE in critically ill adults? STUDY DESIGN AND METHODS: Systematic review and network meta-analysis of randomized clinical trials (RCTs) evaluating efficacy of thromboprophylaxis agents among critically ill patients. We searched six databases (including PubMed, EMBASE, and Medline) from inception through January 2021 for RCTs of patients in the ICU receiving pharmacologic, mechanical, or combination therapy (pharmacologic agents and mechanical devices) for thromboprophylaxis. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. RESULTS: We included 13 RCTs (9,619 patients). Compared with control treatment (a composite of no prophylaxis, placebo, or compression stockings only), low-molecular-weight heparin (LMWH) reduced the incidence of DVT (OR, 0.59 [95% credible interval [CrI], 0.33-0.90]; high certainty) and unfractionated heparin (UFH) may reduce the incidence of DVT (OR, 0.82 [95% CrI, 0.47-1.37]; low certainty). LMWH probably reduces DVT compared with UFH (OR, 0.72 [95% CrI, 0.46-0.98]; moderate certainty). Compressive devices may reduce risk of DVT compared with control treatments; however, this is based on low-certainty evidence (OR, 0.85 [95% CrI, 0.50-1.50]). Combination therapy showed unclear effect on DVT compared with either therapy alone (very low certainty). INTERPRETATION: Among critically ill adults, compared with control treatment, LMWH reduces incidence of DVT, whereas UFH and mechanical compressive devices may reduce the risk of DVT. LMWH is probably more effective than UFH in reducing incidence of DVT and should be considered the primary pharmacologic agent for thromboprophylaxis. The efficacy and safety of combination pharmacologic therapy and mechanical compressive devices were unclear. TRIAL REGISTRY: Open Science Framework; URL:

Anticoagulants/therapeutic use , Critical Illness , Intermittent Pneumatic Compression Devices , Venous Thromboembolism/prevention & control , Adult , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Pulmonary Embolism/prevention & control , Randomized Controlled Trials as Topic
Trials ; 22(1): 323, 2021 May 04.
Article in English | MEDLINE | ID: covidwho-1273249


BACKGROUND: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. METHODS: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600). DISCUSSION: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. TRIAL REGISTRATION: NCT04348656 . Registered on 16 April 2020.

COVID-19 , Coronavirus Infections , Adult , Bisoprolol , COVID-19/therapy , Humans , Immunization, Passive , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , COVID-19 Serotherapy
JAMA Netw Open ; 3(12): e2029250, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-973282


Importance: In the current setting of the coronavirus disease 2019 pandemic, there is concern for the possible need for triage criteria for ventilator allocation; to our knowledge, the implications of using specific criteria have never been assessed. Objective: To determine which and how many admissions to intensive care units are identified as having the lowest priority for ventilator allocation using 2 distinct sets of proposed triage criteria. Design, Setting, and Participants: This retrospective cohort study conducted in spring 2020 used data collected from US hospitals and reported in the Philips eICU Collaborative Research Database. Adult admissions (N = 40 439) to 291 intensive care units from 2014 to 2015 who received mechanical ventilation and were not elective surgery patients were included. Exposures: New York State triage criteria and original triage criteria proposed by White and Lo. Main Outcomes and Measures: Sequential Organ Failure Assessment (SOFA) scores were calculated for admissions. The proportion of patients who met initial criteria for the lowest level of priority for mechanical ventilation using each set of criteria and their characteristics and outcomes were assessed. Agreement was compared between the 2 sets of triage criteria, recognizing differences in stated criteria aims. Results: Among 40 439 intensive care unit admissions of patients who received mechanical ventilation, the mean (SD) age was 62.6 (16.6) years, 54.9% were male, and the mean (SD) SOFA score was 4.5 (3.7). Using the New York State triage criteria, 8.9% (95% CI, 8.7%-9.2%) were in the lowest priority category; these lowest priority admissions had a mean (SD) age of 62.9 (16.6) years, used a median (interquartile range) of 57.3 (20.1-133.5) ventilator hours each, and had a hospital survival rate of 38.6% (95% CI, 37.0%-40.2%). Using the White and Lo triage criteria, 4.3% (95% CI, 4.1%-4.5%) were in the lowest priority category; these admissions had a mean (SD) age of 68.6 (13.2) years, used a median (interquartile range) of 61.7 (24.3-142.8) ventilator hours each, and had a hospital survival rate of 56.2% (95% CI, 53.8%-58.7%). Only 655 admissions (1.6%) were in the lowest priority category for both guidelines, with the κ statistic for agreement equal to 0.20 (95% CI, 0.18-0.21). Conclusions and Relevance: Use of 2 initially proposed ventilator triage guidelines identified approximately 1 in every 10 to 25 admissions as having the lowest priority for ventilator allocation, with little agreement. Clinical assessment of different potential criteria for triage decisions in critically ill populations is important to ensure valid and equitable allocation of resources.

COVID-19 , Health Care Rationing/methods , Triage/methods , Ventilators, Mechanical , Aged , COVID-19/classification , COVID-19/epidemiology , COVID-19/therapy , Critical Illness , Female , Health Care Rationing/standards , Humans , Intensive Care Units , Male , Middle Aged , New York , Organ Dysfunction Scores , Retrospective Studies , SARS-CoV-2 , Triage/standards
Am J Respir Crit Care Med ; 203(1): 3-4, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-934187