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1. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Author

Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., Lawler, P.R., Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., and Lawler, P.R.

Abstract

Item does not contain fulltext, IMPORTANCE: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. OBJECTIVE: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. INTERVENTIONS: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). MAIN OUTCOMES AND MEASURES: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. RESULTS: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06

Published
2023

2. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Author

Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., Webb, S.A., Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., and Webb, S.A.

Abstract

Item does not contain fulltext, 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 surv

Published
2023

3. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Author

Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., Gordon A.C., Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., and Gordon A.C.

Abstract

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective(s): To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): 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). Intervention(s): 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. Result(s): 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 prespe

Published
2022

4. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., Gordon, A.C., Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., and Gordon, A.C.

Abstract

Item does not contain fulltext, 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 c

Published
2022

5. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Author

Gordon, A.C., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Nichol, A.D., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buzgau, A., Cheng, A.C., Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Lamontagne, F., Lawler, P.R., Leavis, H.L., Linstrum, K.M., Litton, E., Lorenzi, E., Marshall, J.C., Mayr, F.B., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Murthy, S., Orr, K., Parke, R.L., Parker, J.C., Patanwala, A.E., Pettilä, V., Rademaker, E., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Sligl, W.I., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Schouten, J.A., Pickkers, P., Webb, S.A., Derde, L.P.G., Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), REMAP-CAP Investigators, Pour la France: Bruno Megarbane, Inserm U1144, European Project: 602386,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,CREDITS4HEALTH(2013), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Gordon, Anthony C [0000-0002-0419-547X], Mouncey, Paul R [0000-0002-8510-8517], Beane, Abi [0000-0001-7046-1580], Bradbury, Charlotte A [0000-0001-5248-8165], Detry, Michelle A [0000-0002-2794-1439], Duffy, Eamon J [0000-0002-4515-5116], Estcourt, Lise J [0000-0003-4309-9162], Haniffa, Rashan [0000-0002-8288-449X], Higgins, Alisa M [0000-0001-8295-7559], Hills, Thomas E [0000-0003-0322-5822], Horvat, Christopher M [0000-0002-1593-2252], Lawler, Patrick R [0000-0001-5155-5071], Litton, Edward [0000-0002-5125-6829], Mayr, Florian B [0000-0002-2298-9011], McVerry, Bryan J [0000-0002-1175-4874], Patanwala, Asad E [0000-0003-3999-4703], Saunders, Christina T [0000-0003-4325-9568], Shankar-Hari, Manu [0000-0002-5338-2538], Angus, Derek C [0000-0002-7026-5181], Derde, Lennie PG [0000-0002-3577-5629], Apollo - University of Cambridge Repository, Investigators, REMAP-CAP, HAL UVSQ, Équipe, Credits-based, people-centric approach for the adoption of healthy life-styles and balanced Mediterranean diet in the frame of social participation and innovation for health promotion. - CREDITS4HEALTH - - EC:FP7:HEALTH2013-09-01 - 2016-08-31 - 602386 - VALID, and Platform foR European Preparedness Against (Re-)emerging Epidemics - PREPARE - - EC:FP7:HEALTH2014-02-01 - 2019-01-31 - 602525 - VALID

Subjects
Male, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, middle aged, Credible interval, Odds Ratio, odds ratio, 030212 general & internal medicine, Hospital Mortality, humans, 11 Medical and Health Sciences, adult, Hazard ratio, Covid19, General Medicine, Middle Aged, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], aged, Intensive Care Units, Antibodies, Monoclonal, Humanized/adverse effects, COVID-19/complications, Original Article, Female, Adult, medicine.medical_specialty, Critical Care, Critical Illness, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Tocilizumab, male, Internal medicine, General & Internal Medicine, medicine, Humans, Aged, hospital mortality, business.industry, SARS-CoV-2, COVID-19, Odds ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment, Coronavirus, Sarilumab, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Receptors, Interleukin-6/antagonists & inhibitors, REMAP-CAP Investigators, interleukin-6 receptor antagonists, coronavirus disease, business
Abstract

BACKGROUNDThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.METHODSWe 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.RESULTSBoth 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.CONCLUSIONSIn 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. opens in new tab.)

Published
2021
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6. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., Shankar-Hari, M., Estcourt, L.J., Turgeon, A.F., McQuilten, Z.K., McVerry, B.J., Al-Beidh, F., Annane, D., Arabi, Y.M., Arnold, D.M., Beane, A., Bégin, P., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Birchall, J.E., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Callum, J.L., Chassé, M., Cheng, A.C., Cove, M.E., Daly, J., Derde, L., Detry, M.A., Jong, Menno de, Evans, A., Fergusson, D.A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A.C., Gosbell, I.B., Green, C., Haniffa, R., Harvala, H., Higgins, A.M., Hills, T.E., Hoad, V.C., Horvat, C., Huang, D.T., Hudson, C.L., Ichihara, N., Laing, E., Lamikanra, A.A., Lamontagne, F., Lawler, P.R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D.F., McDyer, J.F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P.R., Murthy, S., Nichol, A., Parke, R., Parker, J.C., Priddee, N., Purcell, D.F.J., Reyes, L.F., Richardson, P., Robitaille, N., Rowan, K.M., Rynne, J., Saito, H., Santos, M., Saunders, C.T., Neto, A. Serpa, Seymour, C.W., Silversides, J.A., Tinmouth, A.A., Triulzi, D.J., Turner, A.M., Veerdonk, F.L. van de, Walsh, T.S., Wood, E.M., Berry, S., Lewis, R.J., Menon, D.K., McArthur, C., Zarychanski, R., Angus, D.C., Webb, S.A., Roberts, D.J., and Shankar-Hari, M.

Abstract

Item does not contain fulltext, IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromb

Published
2021

7. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., Webb, S.A., Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., and Webb, S.A.

Abstract

Item does not contain fulltext, 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.

Published
2021

8. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients with COVID-19: A Randomized Clinical Trial.

Author

Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., Shankar-Hari M., Estcourt L.J., Turgeon A.F., McQuilten Z.K., McVerry B.J., Al-Beidh F., Annane D., Arabi Y.M., Arnold D.M., Beane A., Begin P., Van Bentum-Puijk W., Berry L.R., Bhimani Z., Birchall J.E., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Callum J.L., Chasse M., Cheng A.C., Cove M.E., Daly J., Derde L., Detry M.A., De Jong M., Evans A., Fergusson D.A., Fish M., Fitzgerald M., Foley C., Goossens H., Gordon A.C., Gosbell I.B., Green C., Haniffa R., Harvala H., Higgins A.M., Hills T.E., Hoad V.C., Horvat C., Huang D.T., Hudson C.L., Ichihara N., Laing E., Lamikanra A.A., Lamontagne F., Lawler P.R., Linstrum K., Litton E., Lorenzi E., Maclennan S., Marshall J., McAuley D.F., McDyer J.F., McGlothlin A., McGuinness S., Miflin G., Montgomery S., Mouncey P.R., Murthy S., Nichol A., Parke R., Parker J.C., Priddee N., Purcell D.F.J., Reyes L.F., Richardson P., Robitaille N., Rowan K.M., Rynne J., Saito H., Santos M., Saunders C.T., Serpa Neto A., Seymour C.W., Silversides J.A., Tinmouth A.A., Triulzi D.J., Turner A.M., Van De Veerdonk F., Walsh T.S., Wood E.M., Berry S., Lewis R.J., Menon D.K., McArthur C., Zarychanski R., Angus D.C., Webb S.A., Roberts D.J., and Shankar-Hari M.

Abstract

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. Objective(s): To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. Intervention(s): The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL +/- 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; veno

Published
2021

10. Vascular segmental permeabilities at high peak inflation pressure in isolated rat lungs

Author

Parker, J.C. and Yoshikawa, S.

Subjects
Rats as laboratory animals -- Research, Lungs -- Research, Biological sciences
Abstract

The response of segmental filtration coefficients ([K.sub.f]) to high peak inflation pressure (PIP) injury was determined in isolated perfused rat lungs. Total ([K.sub.f,t]), arterial ([K.sub.f,a]), and venous ([K.sub.f,v]) filtration coefficients were measured under baseline conditions and after ventilation with 40-45 cm[H.sub.2]O PIP. [K.sub.f,a] and [K.sub.f,v] were measured under zone I conditions by increasing airway pressure to 25-27 cm[H.sub.2]O. The microvascular segment [K.sub.f] ([K.sub.f,mv]) was then calculated by: [K.sub.f,mv] = [K.sub.f,t] - [K.sub.f,a] - [K.sub.f,v]. The baseline [K.sub.f,t] was 0.090 [+ or -] 0.022 ml*[min.sup.-1]*cm[H.sub.2][O.sup.-1]*100 [g.sup.-1] and segmentally distributed 18% arterial, 41% venous, and 41% microvascular. After high PIP injury, [K.sub.f,t] increased by 680%, whereas [K.sub.f,a], [K.sub.f,v], and [K.sub.f,mv] increased by 398, 589, and 975%, respectively. Pretreatment with 50 [micro]M gadolinium chloride prevented the high PIP-induced increase in [K.sub.f] in all vascular segments. These data imply a lower hydraulic conductance for microvascular endothelium due to its large surface area and a gadolinium-sensitive high-PIP injury, produced in both alveolar and extra-alveolar vessel segments. barotrauma; mechanical ventilation; capillary permeability; gadolinium; filtration coefficient

Published
2002

12. Reactive nanophase oxide additions to melt-processed high-Tc superconductors

Author

Goretta, K.C., Brandel, B.P., Lanagan, M.T., Hu, J.G., Miller, D.J., Sengupta, S., Parker, J.C., Ali, M.N., and Nan Chen

Subjects
High temperature superconductors -- Research, Oxides -- Research, Business, Electronics, Electronics and electrical industries
Abstract

The use of oxide additions to improve the flux pinning characteristics of high-temperature superconductors was investigated. Specifically, nanophase TiO2 and Al2O3 powders prepared by a vapor-phase process were incorporated into melt-processed YBa2Cu3Ox and TlBa2Ca2Cu3Ox pellets in 20 mole% concentrations. The results showed that pellets which were quickly heated and slowly cooled contained superconducting grains and enhanced flux pinning behavior at temperatures above 50 K.

Published
1995

13. Modeling free product migration and recovery at hydrocarbon spill sites

Author

Parker, J.C., Zhu, J.L., Johnson, T.G., Kremesec, V.J., and Hockman, E.L.

Subjects
Hydrocarbon research -- Observations, Aquifers -- Testing, Earth sciences
Abstract

Areal flow of water and free phase hydrocarbon in both natural gradients and in situations which include hydrocarbon skimming, is simulated by the numerical model ARMOS. The influence of hydrocarbon discharge on the environment and the comparison of other restorative steps can be assessed using this model. Quantity and exact phase of product recovery wells can be maximized, and system performances and input supply for regulatory decisions can be controlled.

Published
1994

15. Reply to 'comments on 'boundary conditions for displacement experiments through short laboratory soil columns.' (response to article by B.S. Shukla in this issue, p.991)

Author

Genuchten, M.Th. van and Parker, J.C.

Subjects
Soil science -- Research, Earth sciences
Abstract

First-type and third-type boundary conditions used in column displacement experiments help obtain accurate solute mass balance equations. Both the conditions are inlet boundary conditions and involve solute flux continuity and concentration continuity assumptions. A general equation representing a zero mass-balance error is presented.

Published
1994

21. Corrigendum to “Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors” [Bioorg. Med. Chem. Lett. 17 (2007) 6707–6713]

Author

Corbett, J.W., primary, Dirico, K., additional, Song, W., additional, Boscoe, B.P., additional, Doran, S.D., additional, Boyer, D., additional, Qiu, X., additional, Ammirati, M., additional, VanVolkenburg, M.A., additional, McPherson, R.K., additional, Parker, J.C., additional, and Cox, E.D., additional

Published
2008
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