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Bradbury, Charlotte A. M. D. PhD, Lawler, Patrick R. M. D. M. P. H.; Stanworth, Simon J. M. D.; McVerry, Bryan J. M. D.; McQuilten, Zoe PhD, Higgins, Alisa M. PhD, Mouncey, Paul R. MSc, Al-Beidh, Farah PhD, Rowan, Kathryn M. PhD, Berry, Lindsay R. PhD, Lorenzi, Elizabeth PhD, Zarychanski, Ryan M. D. MSc, Arabi, Yaseen M. M. D.; Annane, Djillali M. D. PhD, Beane, Abi PhD, van Bentum-Puijk, Wilma MSc, Bhimani, Zahra M. P. H.; Bihari, Shailesh PhD, M Bonten, Marc J. M. D. PhD, Brunkhorst, Frank M. M. D. PhD, Buzgau, Adrian MSc, Buxton, Meredith PhD, Carrier, Marc M. D. MSc, Cheng, Allen C. Mbbs PhD, Cove, Matthew Mbbs, Detry, Michelle A. PhD, Estcourt, Lise J. MBBCh PhD, Fitzgerald, Mark PhD, Girard, Timothy D. M. D. Msci, Goligher, Ewan C. M. D. PhD, Goossens, Herman PhD, Haniffa, Rashan PhD, Hills, Thomas Mbbs PhD, Huang, David T. M. D. M. P. H.; Horvat, Christopher M. M. D.; Hunt, Beverley J. M. D. PhD, Ichihara, Nao M. D. M. P. H. PhD, Lamontagne, Francois M. D.; Leavis, Helen L. M. D. PhD, Linstrum, Kelsey M. M. S.; Litton, Edward M. D. PhD, Marshall, John C. M. D.; McAuley, Daniel F. M. D.; McGlothlin, Anna PhD, McGuinness, Shay P. M. D.; Middeldorp, Saskia M. D. PhD, Montgomery, Stephanie K. MSc, Morpeth, Susan C. M. D. PhD, Murthy, Srinivas M. D.; Neal, Matthew D. M. D.; Nichol, Alistair D. M. D. PhD, Parke, Rachael L. PhD, Parker, Jane C. B. N.; Reyes, Luis F. M. D. PhD, Saito, Hiroki M. D. M. P. H.; Santos, Marlene S. M. D. Mshs, Saunders, Christina T. PhD, Serpa-Neto, Ary PhD MSc M. D.; Seymour, Christopher W. M. D. MSc, Shankar-Hari, Manu M. D. PhD, Singh, Vanessa, Tolppa, Timo Mbbs, Turgeon, Alexis F. M. D. MSc, Turner, Anne M. M. P. H.; van de Veerdonk, Frank L. M. D. PhD, Green, Cameron MSc, Lewis, Roger J. M. D. PhD, Angus, Derek C. M. D. M. P. H.; McArthur, Colin J. M. D.; Berry, Scott PhD, G Derde, Lennie P. M. D. PhD, Webb, Steve A. M. D. PhD, Gordon, Anthony C. Mbbs M. D..
JAMA ; 327(13):1247, 2022.
Article in English | ProQuest Central | ID: covidwho-1801957

ABSTRACT

Importance The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control;n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of intensive care unit–based respiratory or cardiovascular organ support) within 21 days, ranging from −1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support–free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years;521 [33.6%] female). The median for organ support–free days was 7 (IQR, −1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23];95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62];adjusted absolute difference, 5% [95% CrI, −0.2% to 9.5%];97% posterior probability of efficacy). Among survivors, the median for organ support–free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28];adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%];99.4% probability of harm). Conclusions and Relevance Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support–free days within 21 days.

2.
JAMA ; 327(13): 1247-1259, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1750260

ABSTRACT

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.


Subject(s)
COVID-19 , Venous Thromboembolism , Adult , Anticoagulants/therapeutic use , Aspirin/adverse effects , Bayes Theorem , Critical Illness/therapy , Female , Hemorrhage/chemically induced , Humans , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Respiration, Artificial , Venous Thromboembolism/drug therapy
4.
Intensive Care Med ; 47(8): 867-886, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1305144

ABSTRACT

PURPOSE: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. RESULTS: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). CONCLUSION: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.


Subject(s)
COVID-19 , Ritonavir , Adult , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/drug therapy , Critical Illness , Drug Combinations , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2
5.
Am J Emerg Med ; 49: 142-147, 2021 11.
Article in English | MEDLINE | ID: covidwho-1240141

ABSTRACT

OBJECTIVE: To identify trends in pediatric emergency department (ED) utilization following the COVID-19 pandemic. METHODS: We performed a cross-sectional study from 37 geographically diverse US children's hospitals. We included ED encounters between January 1, 2010 and December 31, 2020, transformed into time-series data. We constructed ensemble forecasting models of the most common presenting diagnoses and the most common diagnoses leading to admission, using data from 2010 through 2019. We then compared the most common presenting diagnoses and the most common diagnoses leading to admission in 2020 to the forecasts. RESULTS: 29,787,815 encounters were included, of which 1,913,085 (6.4%) occurred during 2020. ED encounters during 2020 were lower compared to prior years, with a 65.1% decrease in April relative to 2010-2019. In forecasting models, encounters for depression and diabetic ketoacidosis remained within the 95% confidence interval [CI]; fever, bronchiolitis, hyperbilirubinemia, skin/subcutaneous infections and seizures occurred within the 80-95% CI during the portions of 2020, and all other diagnoses (abdominal pain, otitis media, asthma, pneumonia, trauma, upper respiratory tract infections, and urinary tract infections) occurred below the predicted 95% CI. CONCLUSION: Pediatric ED utilization has remained low following the COVID-19 pandemic, and below forecasted utilization for most diagnoses. Nearly all conditions demonstrated substantial declines below forecasted rates from the prior decade and which persisted through the end of the year. Some declines in non-communicable diseases may represent unmet healthcare needs among children. Further study is warranted to understand the impact of policies aimed at curbing pandemic disease on children.


Subject(s)
COVID-19 , Delivery of Health Care/organization & administration , Emergency Service, Hospital/statistics & numerical data , Facilities and Services Utilization/statistics & numerical data , Pediatrics , Child , Child, Preschool , Cross-Sectional Studies , Female , Forecasting , Hospitalization/statistics & numerical data , Humans , Infant , Male , Models, Organizational , United States
6.
N Engl J Med ; 384(16): 1491-1502, 2021 04 22.
Article in English | MEDLINE | ID: covidwho-1101727

ABSTRACT

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Critical Illness , Female , Hospital Mortality , Humans , Intensive Care Units , Male , Middle Aged , Odds Ratio , Respiration, Artificial
7.
JAMA Netw Open ; 4(2): e2037227, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1083348

ABSTRACT

Importance: In early 2020, the United States declared a public health emergency in response to coronavirus disease 2019 (COVID-19) and implemented a variety of social distancing measures. The association between the COVID-19 pandemic and the number of pediatric admissions is unclear. Objective: To determine the changes in patterns of pediatric admissions in 2020 compared with the prior decade. Design, Setting, and Participants: This cross-sectional study included 49 US hospitals contributing to the Pediatric Health Information Systems database. Inpatient admissions were transformed into time-series data, and ensemble forecasting models were generated to analyze admissions across a range of diagnoses in 2020 compared with previous years. The setting was inpatient admissions. All patients discharged between January 1, 2010, and June 30, 2020, from an inpatient hospital encounter were included. Main Outcomes and Measures: Number of hospital admissions by primary diagnosis for each encounter. Results: Of 5 424 688 inpatient encounters among 3 372 839 patients (median [interquartile range] age, 5.1 [0.7-13.3] years; 2 823 748 [52.1%] boys; 3 171 224 [58.5%] White individuals) at 49 hospitals, 213 571 (3.9%) were between January 1, 2020, and June 30, 2020. There was a decrease in the number of admissions beginning in March 2020 compared with the period from 2010 to 2019. At the nadir, admissions in April 2020 were reduced 45.4% compared with prior years (23 798 in April 2020 compared with a median [interquartile range] of 43 550 [42 110-43 946] in April 2010-2019). Inflation-adjusted hospital charges decreased 27.7% in the second quarter of 2020 compared with prior years ($4 327 580 511 in 2020 compared with a median [interquartile range] of $5 983 142 102 [$5 762 690 022-$6 324 978 456] in 2010-2019). Seasonal patterns were evident between 2010 and 2019 for a variety of common pediatric conditions, including asthma, atrial septal defects, bronchiolitis, diabetic ketoacidosis, Kawasaki syndrome, mental health admissions, and trauma. Ensemble models were able to discern seasonal patterns in admission diagnoses and accurately predicted admission rates from July 2019 until December 2019 but not from January 2020 to June 2020. All diagnoses except for birth decreased below the model 95% CIs between January 2020 and June 2020. Conclusions and Relevance: In this cross-sectional study, pediatric admissions to US hospitals decreased in 2020 across an array of pediatric conditions. Although some conditions may have decreased in incidence, others may represent unmet needs in pediatric care during the COVID-19 pandemic.


Subject(s)
COVID-19 , Hospitalization , Hospitals, Pediatric , Pandemics , Seasons , Adolescent , Child , Cross-Sectional Studies , Diabetic Ketoacidosis/epidemiology , Female , Heart Septal Defects, Atrial/epidemiology , Hospitalization/statistics & numerical data , Hospitalization/trends , Humans , Male , Mental Disorders/epidemiology , Mucocutaneous Lymph Node Syndrome/epidemiology , Patient Admission , Respiratory Tract Diseases/epidemiology , Retrospective Studies , United States/epidemiology , Wounds and Injuries/epidemiology
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