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Rachel L Bussard,1 Laurence W Busse2,3 1Critical Care Pharmacy Specialist, Department of Pharmacy, Emory St Joseph’s Hospital, Atlanta, GA, USA; 2Department of Critical Care, Emory St Joseph’s Hospital, Atlanta, GA, USA; 3Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA Abstract: Angiotensin II (Ang II), part of the renin–angiotensin–aldosterone system (RAS), is a potent vasoconstrictor and has been recently approved for use by the US Food and Drug Administration in high-output shock. Though not a new drug, the recently published Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial, as well as a number of retrospective analyses have sparked renewed interest in the use of Ang II, which may have a role in treating refractory shock. We describe refractory shock, the unique mechanism of action of Ang II, RAS dysregulation in shock, and the evidence supporting the use of Ang II to restore blood pressure. Evidence suggests that Ang II may preferentially be of benefit in acute kidney injury and acute respiratory distress syndrome, where the RAS is known to be disrupted. Additionally, there may be a role for Ang II in cardiogenic shock, angiotensin converting enzyme inhibitor overdose, cardiac arrest, liver failure, and in settings of extracorporeal circulation. Keywords: catecholamine resistance, refractory shock

Background: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock., Methods: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h., Results: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], p interaction  = 0.38), but a greater reduction in norepinephrine equivalent dose (p interaction  = 0.0031) and study-drug dose (p interaction  < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], p interaction  = 0.0299), norepinephrine equivalent dose (p interaction  < 0.0001), and study-drug dose (p interaction  = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients., Conclusions: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015)., (© 2024. The Author(s).)

Background: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock., Methods: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events., Discussion: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial., Trial Registration: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023., (© 2024. The Author(s).)

Objective: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients., Design: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial., Setting: Forty-three hospitals across the United States., Patients: Biorepository samples of 103 patients., Interventions: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use., Measurements and Main Results: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HR Q2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HR Q4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention., Conclusions: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death., Competing Interests: Dr. Schaich received funding from the National Institute on Aging (K01AG073581) and an internal institutional pilot grant. Dr. Chappell’s institution received funding from the National Heart, Lung, and Blood Institute (R01HL146818); he received support for article research from the National Institutes of Health (NIH). Dr. McCurdy’s institution received funding from the Maryland Innovation Initiative; he disclosed he is chief medical officer for BOA Biomedical. Drs. Sevransky, Rothman, and Wright’s institutions received funding from the Marcus Foundation. Dr. Sevransky’s institution received funding from the Centers for Disease Control and Prevention and the Department of Health and Human Services; He disclosed he is an associate editor for Critical Care Medicine. Dr. Rothman disclosed use of Vit C, thiamine and steroid for treatment of sepsis. Dr. Wright’s institution received funding from the NIH; he received funding from the Neurotrauma Sciences Advisory Board and Astrocyte Pharma; he disclosed he was an expert witness for multiple different legal firms; he received support for article research from the Marcus Foundation. Dr. Khanna received grant funding from Hypertension and Vascular Research Center at the Wake Forest University School of Medicine (AG073581) to study mechanisms of renin dysregulation in shock. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Steven Y. Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals, and participation on the data safety monitoring board for an unrelated, local study at Ronald Reagan UCLA Medical Center, outside the submitted work. Manjusha Gaglani reports serving as the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics co-chair of the ID and Immunization Committee, outside the submitted work. Adit A. Ginde reports support from Biomeme and Seastar, outside the submitted work. Carlos G. Grijalva reports other funding from Merck, contracts from Syneos Health and the Food and Drug Administration, and grants from National Institutes of Health (NIH) and Agency for Health Care Research and Quality, outside the submitted work. Akram Khan reports grant funding from 4DMedical, Dompe Pharmaceuticals, Ely Lilly, and Roche Pharmaceuticals, outside the submitted work. Adam S. Lauring reports research support from the National Institute of Allergy and Infectious Diseases, Michigan Department of Health and Human Services, Burroughs Wellcome Fund, Flu Lab, and consulting fees from Roche, outside the submitted work. Christopher Mallow reports medical legal consulting, outside the submitted work. Emily T. Martin reports research funding from Merck, outside the submitted work. Ithan D. Peltan reports grant support from NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals, and funding to his institution from Bluejay Diagnostics and Regeneron, outside the submitted work. Karthik Natarajan reports institutional support from NIH, Office of the Director, the National Center for Advancing Translational Sciences, and the National Heart, Lung, and Blood Institute. Brian E. Dixon reports Institutional support from NIH, National Library of Medicine in the form of a T15 training grant in biomedical informatics, salary support from the U.S. Department of Veterans Affairs, royalties from Elsevier, Inc. for a book on health information technology and from Springer Nature for a book on health information technology. Nicola P. Klein reports support from GSK, Merck, Pfizer, Sanofi Pasteur, and Seqirus for work unrelated to this report. No other potential conflicts of interest were disclosed.

Background: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS., Methods: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO 2 /FiO 2 -ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality., Results: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH 2 O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH 2 O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH 2 O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group., Conclusions: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock., Trial Registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015)., (© 2023. The Author(s).)

Objectives: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022., Data Sources: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update., Study Selection: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article., Data Extraction: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature., Data Synthesis: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia., Conclusions: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Understanding the changing epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) informs research priorities and public health policies., Methods: Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed., Results: Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47-72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar-Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun-Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9-122.0) to 11.5 mg/L (2.7-42.8) and 3.1 mcg/mL (0.8-640.0) to 1.0 mcg/mL (0.5-2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period., Conclusions: Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death., Competing Interests: Potential conflicts of interest. J. C. reports grants from the National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. C. reports receiving grants from the NIH, DoD, outside the submitted work. A. D, reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) platform and Prevention and Early Treatment of Acute Lung Injury (PETAL) network respectively, as well as consulting fees for Alung Technologies, outside the submitted work. S. C. reports receiving consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a Data and Safety Monitoring Board (DSMB) member for a neuromodulation study at University of California, Los Angeles, outside the submitted work. M. E. reports grants from NIH and Regeneron, personal funds for speaking at the ASPEN conference for Abbott Labs, and payment for testimony from Medical Legal Expert Witness, outside the submitted work. M. G. reports receiving grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD, outside the submitted work. A. G. reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. D. H. reports receiving grants from NHLBI, outside the submitted work. A. K. reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. J. K. reports a grant from NIH, outside the submitted work A. L. reports receiving grants from CDC, National Institute of Allergy and Infectious Diseases (NIAID), and Burroughs Wellcome Fund, Michigan Department of Health and Human Services, Flu Lab, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. N. reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D, P. reports grants from NIH/NHLBI, Janssen Pharmaceuticals and institutional support from Regeneron, outside the submitted work. J. S. reports a grant from NHLBI, outside the submitted work. W. B. S, reports grants from NIH/NHLBI, outside the submitted work. J. W. reports a grant from NIH/NHLBI, payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic and subgenomic RNA levels are frequently used as a correlate of infectiousness. The impact of host factors and SARS-CoV-2 lineage on RNA viral load is unclear., Methods: Total nucleocapsid (N) and subgenomic N (sgN) RNA levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in specimens from 3204 individuals hospitalized with coronavirus disease 2019 (COVID-19) at 21 hospitals. RT-qPCR cycle threshold (Ct) values were used to estimate RNA viral load. The impact of time of sampling, SARS-CoV-2 variant, age, comorbidities, vaccination, and immune status on N and sgN Ct values were evaluated using multiple linear regression., Results: Mean Ct values at presentation for N were 24.14 (SD 4.53) for non-variants of concern, 25.15 (SD 4.33) for Alpha, 25.31 (SD 4.50) for Delta, and 26.26 (SD 4.42) for Omicron. N and sgN RNA levels varied with time since symptom onset and infecting variant but not with age, comorbidity, immune status, or vaccination. When normalized to total N RNA, sgN levels were similar across all variants., Conclusions: RNA viral loads were similar among hospitalized adults, irrespective of infecting variant and known risk factors for severe COVID-19. Total N and subgenomic RNA N viral loads were highly correlated, suggesting that subgenomic RNA measurements add little information for the purposes of estimating infectivity., Competing Interests: Potential conflicts of interest. J. Ca. reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. Ch. reports grants from the NIH, DoD, and Dolly Parton COVID-19 Research Fund, outside the submitted work. D. D. reports a grant from NIH, outside the submitted work. A. D. reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV platform and PETAL network, respectively; and consulting fees for Alung Technologies, outside the submitted work. M. E. reports grants from NIH and Regeneron; personal funds for speaking at the ASPEN conference for Abbott Labs; and payment for testimony from Medical Legal Expert Witness, outside the submitted work. A. F. reports grants from NIH, outside the submitted work. M. G. reports grants from CDC, CDC-Abt Associates, and CDC-Westat; and served as cochair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD; and support for MHSRS 2022 travel from the DoD, outside the submitted work. A. G. reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, and Agency for Healthcare Research and Quality; speaking at medicine grand rounds at New York Medical College; travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly; data and safety monitoring board (DSMB) membership fees from Regeneron; and participating on the scientific advisory panel for Endpoint, outside the submitted work. C. G. reports grants from NIH, CDC, AHRQ, FDA, and Campbell Alliance/Syneos Health; and consulting fees from and participating on a DSMB for Merck, outside the submitted work. D. H. reports grants from NHLBI, outside the submitted work. N. H. reports grants from Sandofi and Quidel; and a Genentech educational grant to give a lecture, outside the submitted work. A. K. reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. A. L. reports grants from CDC, National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund; and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir, respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. M. reports a grant from CDC; a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure; and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D. P. reports grants from NIH and Janssen Pharmaceuticals; and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. W. B. S. reports grants and support for meetings/travel from the NIH/NHLBI, outside the submitted work. J. W. reports payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined., Methods: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined., Results: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%)., Conclusion: Vaccination data from EMR only may substantially underestimate COVID-19 VE., Competing Interests: Declaration of Competing Interest All authors have completed and submitted the International Committee of Medical Journal Editors (ICJME) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Samuel Brown reports institutional funds from Janssen for influenza research. Jonathan Casey reports a travel grant from Fischer and Paykel, outside the submitted work. Steven Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a DSMB member for a study at UCLA, outside the submitted work. Manjusha Gaglani reports grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. Kevin Gibbs reports grants from NIH and DoD, as well as support for MHSRS 2022 travel from the DoD, outside the submitted work. Adit Ginde reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI, CDC, AHRQ, speaking at medicine grand rounds at New York Medical College, travel support for the ATS executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos Grijalva reports grants from NIH, CDC, AHRQ, FDA, Campbell Alliance/Syneos Health; receiving consulting fees from and participating on a DSMB for Merck, outside the submitted work. David Hager reports receiving grants from NIH, outside the submitted work. Akram Khan reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. Adam Lauring reports receiving grants from CDC, FluLab, NIAID, and Burroughs Wellcome Fund, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. Emily Martin reports grants from Merck and NIH, outside the submitted work. Tresa McNeal reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Jennifer Wilson reports grants from NHLBI, outside the submitted work. No other potential conflicts of interest were disclosed., (Published by Elsevier Ltd.)

Background: High dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II)., Methods: Exploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55-70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation., Results: Of 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274-0.945, p = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644-1.350, p = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups., Conclusions: This exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial., Trial Registration: The ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015., (© 2023. The Author(s).)

Background: Patients supported on mechanical circulatory support devices experience vasodilatory hypotension due to high surface area exposure to nonbiological and non-endothelialized surfaces. Angiotensin II has been studied in general settings of vasodilatory shock, however concerns exist regarding the use of this vasopressor in patients with pre-existing cardiac failure. The objective of this study was to assess the systemic and central hemodynamic effects of angiotensin II in patients with primary cardiac or respiratory failure requiring treatment with mechanical circulatory support devices. Methods: Multicenter retrospective observational study of adults supported on a mechanical circulatory support device who received angiotensin II for vasodilatory shock. The primary outcome was the intraindividual change from baseline in mean arterial pressure (MAP) and vasopressor dosage after angiotensin II. Results: Fifty patients were included with mechanical circulatory devices that were primarily used for cardiac failure (n = 41) or respiratory failure (n = 9). At angiotensin II initiation, the norepinephrine equivalent vasopressor dosage was 0.44 (0.34, 0.64) and 0.47 (0.33, 0.73) mcg/kg/min in the cardiac and respiratory groups, respectively. In the cardiac group, MAP increased from 60 to 70 mmHg (intraindividual P  < .001) in the 1 h after angiotensin II initiation and the vasopressor dosage declined by 0.04 mcg/kg/min (intraindividual P  < .001). By 12 h, the vasopressor dosage declined by 0.16 mcg/kg/min ( P  = .001). There were no significant changes in cardiac index or mean pulmonary artery pressure throughout the 12 h following angiotensin II. In the respiratory group, similar but nonsignificant effects at 1 h on MAP (61-81 mmHg, P  = .26) and vasopressor dosage (decline by 0.13 mcg/kg/min, P  = .06) were observed. Conclusions: In patients requiring mechanical circulatory support for cardiac failure, angiotensin II produced beneficial systemic hemodynamic effects without negatively impacting cardiac function or pulmonary pressures. The systemic hemodynamic effects in those with respiratory failure were nonsignificant due to limited sample size.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology., Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II., Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022., Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo., Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension., Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo., Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Background: Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were authorized in the United States in December 2020. Although vaccine effectiveness (VE) against mild infection declines markedly after several months, limited understanding exists on the long-term durability of protection against COVID-19-associated hospitalization., Methods: Case-control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states 11 March-15 December 2021, including COVID-19 case patients and reverse transcriptase-polymerase chain reaction-negative controls. We included adults who were unvaccinated or vaccinated with 2 doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. Models included dichotomous time (<180 vs ≥180 days since dose 2) and continuous time modeled using restricted cubic splines., Results: A total of 10 078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (interquartile range, 46-70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE <180 days was 90% (95% confidence interval [CI], 88-91) versus 82% (95% CI, 79-85) at ≥180 days (P < .001). VE declined for Pfizer-BioNTech (88% to 79%, P < .001) and Moderna (93% to 87%, P < .001) products, for younger adults (18-64 years) (91% to 87%, P = .005), and for adults ≥65 years of age (87% to 78%, P < .001). In models using restricted cubic splines, similar changes were observed., Conclusions: In a period largely predating Omicron variant circulation, effectiveness of 2 mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months., Competing Interests: Potential conflicts of interest. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. W. H. S. reports grant funding from the Centers for Disease Control and Prevention (CDC) for this work, grants and consultant fees from Merck (for research on the surveillance of pneumococcal infections) and Gilead Sciences (for research on the surveillance of hepatitis C virus infections) outside this work. M. G. reports grant support from CDC (Ambulatory US Flu/COVID VE Network and Adult Inpatient Flu/COVID VE Network, HAIVEN), CDC-Abt Associates (Flu Vax Immunogenitiy RCT and RECVOERPROTECT COVID/Flu VE studies), CDC-Westat (VISION COVID Study), and Janssen (Johnson & Johnson) (RSV Severity App Birth Cohort Study). A. A. G. reports grant support from CDC, National Institute of Health (NIH), Department of Defense (DoD), AbbVie, and Faron Pharmaceuticals. J. D. C. reports grants from the CDC, NIH (K23HL153584), and Department of Defense. N. M. reports grants from the CDC (funded two other multicenter COVID-related projects separate from this work through payments to my institution). T. M. reports a grant from CDC and fees from the Society of Hospital Medicine for a talk about managing patients with congestive heart failure. K. G. reports grants from the CDC and the received grant funding for participation in executive committee of COVID-19 therapeutics from the NIH (ACTIV-4HT NECTAR Trial). D. C. F. reports grant support from CDC, consultant fees from Cytovale, and membership on a Medpace Data Safety Monitoring Board (DSMB). D. N. H. reports contracts from CDC, National Heart, Lung, and Blood Institute (NHLBI; funding for participation in the ACTIV4d - Host Tissue Trial), and Incyte Corporation (funding to enroll in RUCOVID-DEVENT) and membership on the SAFE EVICT Trial of VIT C in COVID-19 as DSMB chair. M. C. E. reports talks on nutrition in COVID pneumonia at the American Society of Parenteral and Enteral Nutrition (ASPEN) conference sponsored by Abbott Labs. M. N. G. reports grant support from CDC, NHLBI, NIH, and Agency for Healthcare Research and Quality (AHRQ), travel support for American Thoracic Society board meeting, and membership on the Regeneron DSMB for monoclonal antibodies in COVID-19. N. J. reports grants from CDC, NIH/NHLBI/NINDS, and University of Washington Royalty Research Fund, and payment for expert testimony from the Washington Department of Health. I. D. P. reports grants from CDC, NIH, Intermountain Research & Medical Foundation, and Janssen Pharmaceuticals, and institutional fees from Asahi Kasei Pharma and from Regeneron Pharmaceuticals. S. M. B. reports grants from CDC, NIH (for trials and other research activities related to COVID), and DoD (to study COVID); fees from Hamilton ventilators for chairing a DSMB; and personal fees from New York University for service on a DSMB. E. T. M. reports a grant from Merck outside the submitted work. A. M. reports grant support from CDC, NIH, NIAID, and membership on a DSMB for the Food and Drug Administration (FDA). A. K. reports grants from CDC, Gilead Sciences, Ely Lily, United Therapeutics, BOA-Medical, and 4D Medical and membership on the Guidelines Committee for Chest. C. L. H. reports grants from CDC, NIH, and the American Lung Association. A. D. reports a grant from the CDC and consulting fees from ALung Technologies (Steering Committee). J. W. reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. S. Y. C. reports grants from CDC and Regeneron (for 6R88-COV-2040 trial) and consulting fees from PureTech Health (for COVID study) and Kiniska (for possible ARDS study). J. H. K. reports grant support from CDC and NIH (1K23 AI137321-01A1). A. S. L. reports grants from the CDC, NIH, and Burroughs Wellcome Fund, consultant fees for antiviral drugs from Sanofi and fees from Roche for membership on a baloxavir trial steering committee. N. H. reports grants from CDC, NIH, Sanofi, and Quidel and honoraria for speaking at a continuing medical education event at American Academy of Pediatrics. C. G. G. reports consultant fees from Pfizer, Merck, and Sanofi and grants from Syneos Health, CDC, NIH, FDA, AHRQ, and Sanofi. T. R. reports grants from CDC and Abbvie Inc, consultant fees from Cytovale, Inc. and Cumberland Pharmaceuticals Inc., membership on a Sanofi, Inc. DSMB, a voluntary role as the Immediate Past President of ASPEN and stock in Cumberland Pharmaceuticals, Inc. I. J. reports grants/contracts from the CDC, NIH, Quidel, and Sanofi. C. J. L. reports grants/contracts from CDC, NIH, DoD, bioMerieux, Endpoint Health, Entegrion, Inc., and AbbVie; a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock, membership on a Study Principal Investigators DSMB for clinical trials unrelated to the current work, Executive Committee; Immediate Past President, Member, Board of Directors, Association for Clinical and Translational Science, and stock options in Bioscape Digita unrelated to the current work. W. B. S. reports a grant from the CDC and NIH (5K12HL133117-05). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines., Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE., Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary., Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Test-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls., Methods: Adults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group., Results: 5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64 years, VE was 93 % (95 % CI: 90-94) using syndrome-negative controls and 91 % (95 % CI: 88-93) using test-negative controls., Conclusions: Despite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors (ICMJE) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. Samuel Brown reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), participation as the DSMB chair for Hamilton Ventilators, and participation as a member of the DSMB for New York University COVID clinical trials. Jonathan Casey reports funding from NIH and DoD. Steven Chang reports consulting fees from La Jolla Pharmaceuticals, PureTech Health, and Kiniska Pharmaceuticals, payment/honoraria from La Jolla Pharmaceuticals, and participation on a DSMB for an investigator-initiated study conducted at UCLA. James Chappell reports grants and other support from NIH. Abhijit Duggal reports consulting fees from ALung technologies. Matthew Exline reports payment/honorariua from Abbott Lab for sponsored talks. D. Clark Files reports consulting fees from Cytovale and participation on a DSMB for Medpace. Anne Frosch reports grants from NIH. Manjusha Gaglani reports grants from Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership role as co-chair of the Infectious Disease and Immunization Committee of the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. Kevin Gibbs reports funding from NIH/ National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV-4HT NECTAR trial. Nicholas Mohr reports grants from the CDC (funded 2 other multicenter COVID-related projects separate from this work through payments to author’s institution). Adit Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle Gong reports grants from NIH/NHLBI and Agency for Healthcare Research and Quality (AHRQ), consulting fees from Endpoint, a leadership role on the American Thoracic Society (ATS) executive committee and board as well as support from ATS for meeting travel expenses, and participation on a DSMB for Regeneron. Carlos Grijalva reports grants from NIH, CDC, Food and Drug Administration (FDA), AHRQ, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. David Hager reports grants from NIH/NHLBI for the ACTIV-4HT NECTAR trial and Incyte Corporation and participation as a DSMB chair for the SAFE EVICT Trial of vitamin C in COVID-19. Jennifer Wilson reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. Natasha Halasa reports grants from NIH, Quidel, and Sanofi and honoraria for speaking at the American Academy of Pediatrics (AAP) conference. Nicholas Johnson reports grants from NIH/NHLBI/NINDS and the University of Washington Royalty Research Fund and payment for expert testimony for the Washington Department of Health. Akram Khan reports grants from United Therapeutics, Gilead Sciences, and 4D Medical and a leadership role on the guidelines committee for Chest. Jennie Kwon reports grants from NIH/NIAID. Adam Lauring reports grants from CDC, NIH/NIAID, and Burroughs Wellcome Fund and consulting fees from Sanofi and Roche. Christopher Lindsell reports grants from NIH, DoD, CDC, bioMerieux, Entegrion Inc., Endpoint Health, and AbbVie, patents for risk stratification in sepsis and septic shock, participation on DSMBs for clinical trials unrelated to the current work, a leadership role on the executive committee for the Board of Directors of the Association for Clinical and Translational Science, and stock options in Bioscape Digita. Emily Martin reports grants from Merck, CDC, and NIH and payment/honoraria from the Michigan Infectious Disease Society. Tresa McNeal reports payment/honoraria from the Society of Hospital Medicine. Ithan Peltan reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. Todd Rice reports grants from AbbVie Inc., consulting fees from Cumberland Pharmaceuticals, Inc. and Cytovale, Inc., membership on a DSMB for Sanofi, Inc., a leadership role as immediate past president of the American Society of Parenteral and Enteral Nutrition, and stock options in Cumberland Pharmaceuticals, Inc. Wesley Self reports receiving the primary funding for this project from the United States Centers for Disease Control and Prevention, and research funding from Merck and Gilead Sciences. William Stubblefield reports grants from the NIH/NHLBI., (Published by Elsevier Ltd.)

Background: During the COVID-19 pandemic, self-reported COVID-19 vaccination might facilitate rapid evaluations of vaccine effectiveness (VE) when source documentation (e.g., immunization information systems [IIS]) is not readily available. We evaluated the concordance of COVID-19 vaccination status ascertained by self-report versus source documentation and its impact on VE estimates., Methods: Hospitalized adults (≥18 years) admitted to 18 U.S. medical centers March-June 2021 were enrolled, including COVID-19 cases and SARS-CoV-2 negative controls. Patients were interviewed about COVID-19 vaccination. Abstractors simultaneously searched IIS, medical records, and other sources for vaccination information. To compare vaccination status by self-report and documentation, we estimated percent agreement and unweighted kappa with 95% confidence intervals (CIs). We then calculated VE in preventing COVID-19 hospitalization of full vaccination (2 doses of mRNA product ≥14 days prior to illness onset) independently using data from self-report or source documentation., Results: Of 2520 patients, 594 (24%) did not have self-reported vaccination information to assign vaccination group; these patients tended to be more severely ill. Among 1924 patients with both self-report and source documentation information, 95.0% (95% CI: 93.9-95.9%) agreement was observed, with a kappa of 0.9127 (95% CI: 0.9109-0.9145). VE was 86% (95% CI: 81-90%) by self-report data only and 85% (95% CI: 81-89%) by source documentation data only., Conclusions: Approximately one-quarter of hospitalized patients could not provide self-report COVID-19 vaccination status. Among patients with self-report information, there was high concordance with source documented status. Self-report may be a reasonable source of COVID-19 vaccination information for timely VE assessment for public health action., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63-75%) overall, including 55% (29-72%) among immunocompromised patients, and 72% (64-77%) among immunocompetent patients, for whom VEs was similar at 14-90 days (73% [59-82%]), 91-180 days (71% [60-80%]), and 181-274 days (70% [54-81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18-65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients., Competing Interests: Potential conflicts of interest. M. G.: CDC: Baylor Scott & White Health (BSWH) US Flu/COVID VE Network, HAIVEN, Synergy studies; CDC-Abt: BSWH FluVax Trial and RECOVER-PROTECT Cohort Studies; CDC-Westat: BSWH VISION COVID-Flu VE Study; Janssen: BSWH Respiratory Syncytial Virus (RSV) Severity App Birth Cohort Study; Co-Chair of Infectious Diseases and Immunization Committee—Texas Pediatric Society—Texas Chapter of American Academy of Pediatrics. A. G.: National Institutes of Health (NIH), Department of Defense; Faron Pharmaceuticals; AbbVie; D Douin: NIH/National Institute of General Medical Sciences (NIGMS) Institutional Training Grant. J. C.: NIH and Department of Defense grants unrelated to this work. T. A. M.: Panelist for Society of Hospital Medicine Updates in Heart Failure; Board member for Scott & White Clinic Physicians Board of Directors. K. G.: NECTAR Executive Committee member ACTIV4-HT; D. C. F.: Cytovale consulting fees; Medpace Data Safety Monitoring Board. D. N. H.: National Heart, Lung, and Blood Institute (NIHLBI) participant in the ACTIV4d-Host Tissue Trial; Chair DSMD—SAFE EVICT Trial of VIT C in COVID-19. M. N. G.: Grants from NHLBI and Agency for Healthcare Research and Quality (AHRQ); Consulting fees for Endpoint for scientific advisory panel; Honoraria—Medicine Grand Rounds from Westchester Medical Center; Support for attending ATS Board of Directors meeting; Data and Safety Monitoring Board (DSMB) for Regeneron study and REPLENISH trial. N. J. J.: IH grants paid to University of Washington Royalty Research Fund; Department of Defense grants; Medic One Foundation grants; WA Department of Health expert testimony payment; DSMB for Opticyte, Inc.; Chair, ACEP Critical Care Section. I. P.: NIH grants; Regeneron Pharmaceuticals grant; Intermountain Research & Medical Foundation grant; Asahi Kasei Pharma grant; Janssen Pharmaceuticals grant. S. B.: NIH grants and Department of Defense grants; DSMB for Hamilton ventilators and NYU. E. T. M.: Merck grant. A. S. M.: NIH grant. A. K.: NIH grants; United Therapeutics grants; Eli Lily grants; Johnson & Johnson—BOA Medical—4DMedical research grants; rA. D.: Center PI for PETAL network through NHLBI grant; on steering committee for A Lung technologies. J. G. W.: NIH/NHLBI funding for ACTIV-3 and ACTIV-4 trials; American Board of Internal Medicine—member of Critical Care Exam Committee. S. Y. C.: Consulting fees for PureTech Health and Kiniska Pharmaceuticals; Honoraria for La Jolla. H. M. B.: CDC grant for HCP COVID vaccine effectiveness. J. H. K.: NIAID grant. M. C. E.: Abbott Labs honoraria for speaking on ASPEN on nutrition in critical illness from COVID. A. L.: grants from CDC, NIH, and Burroughs Wellcome Fund; consulting fees from Sanofi on antiviral drugs and for Roche on baloxavir trial steering committee. N. H.: grants from NIH, Quidel, and Sanofi; Honoraria for speaking at CME event at AAP. C. G. G.: grants from Campbell Alliance/Syneos Health, Sanofi, CDC, AHRQ, NIH, and FDA; consulting fees from Merck, Pfizer, and Sanofi-Pasteur. T. W. R.: grants from NIH, Department of Defense and AbbVie; consulting fees for Cumberland Pharmaceuticals, Inc. and Cytovale, Inc.; DSMB for Sanofi, Inc.; Immediate Past President—ASPEN; Stock in Cumberland Pharmaceuticals, Inc. for consulting work. W. B. S.: NIH training grants. C. J. L.: grants from NIH, Department of Defense; CDC; bioMerieux; Entegrion, Inc.; Endpoint Health; AbbVie; Patents for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center; DSMBs for clinical trials for Study Principal Investigators; Association for Clinical and Translational Science (Executive Committee, Immediate Past President, and Board of Directors); stock options in Bioscape Digita. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

Background: The study objective was to evaluate 2- and 3-dose coronavirus disease 2019 (COVID-19) mRNA vaccine effectiveness (VE) in preventing COVID-19 hospitalization among adult solid organ transplant (SOT) recipients., Methods: We conducted a 21-site case-control analysis of 10 425 adults hospitalized in March to December 2021. Cases were hospitalized with COVID-19; controls were hospitalized for an alternative diagnosis (severe acute respiratory syndrome coronavirus 2-negative). Participants were classified as follows: SOT recipient (n = 440), other immunocompromising condition (n = 1684), or immunocompetent (n = 8301). The VE against COVID-19-associated hospitalization was calculated as 1-adjusted odds ratio of prior vaccination among cases compared with controls., Results: Among SOT recipients, VE was 29% (95% confidence interval [CI], -19% to 58%) for 2 doses and 77% (95% CI, 48% to 90%) for 3 doses. Among patients with other immunocompromising conditions, VE was 72% (95% CI, 64% to 79%) for 2 doses and 92% (95% CI, 85% to 95%) for 3 doses. Among immunocompetent patients, VE was 88% (95% CI, 87% to 90%) for 2 doses and 96% (95% CI, 83% to 99%) for 3 doses., Conclusions: Effectiveness of COVID-19 mRNA vaccines was lower for SOT recipients than immunocompetent adults and those with other immunocompromising conditions. Among SOT recipients, vaccination with 3 doses of an mRNA vaccine led to substantially greater protection than 2 doses., Competing Interests: Potential conflicts of interest. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. J. H. K. reports grant support from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (1K23 AI137321-01A1). M. G. reports grant support from CDC, CDC-Abt, CDC-Westat, and Janssen and a role as the Co-Chair of the Infectious Diseases and Immunization Committee, Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics (AAP). H. K. T. reports a grant from CDC. A. A. G. reports grant support from CDC, NIH, US Department of Defense (DOD), AbbVie, and Faron Pharmaceuticals. T. M. reports payments as a panelist for the Society of Hospital Medicine Updates in Heart Failure (August 25, 2021) and as a board member of the Scott & White Clinic Physicians Board of Directors. D. J. D. reports grant support from NIH/National Institute of General Medical Sciences (T32GM135169). J. D. C. reports grants from the NIH and DOD. K. W. G. reports grant support as a NECTAR Executive Committee member ACTIV-4HT. D. C. F. reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). D. N. H. reports a contract from CDC and grant support from National Heart, Lung, and Blood Institute (NHLBI) for participation in the ACTIV4d-Host Tissue Trial. M. C. E. reports talks on nutrition in COVID pneumonia at ASPEN conference sponsored by Abbott Laboratories. M. N. G. reports grant support from the CDC, funding from NHLBI and Agency for Healthcare Research and Quality (AHRQ), and fees from Endpoint for participating on a scientific advisory panel, payment for Medicine Grand Rounds at Westchester Medical Center, travel support for attending the ATS Board of Directors meeting, and participation on a DSMB for Regeneron and REPLINISH trial. N. J. J. reports grants from the NIH, DOD, and Medic One Foundation, payment for expert testimony from the Washington Department of Health, participation on DSMBs for Opticyte Inc., Multi-Center, Randomized Control Trial to Study the Effectiveness of Hyperbaric Oxygen for COVID-19 patients with Moderate to Severe Hypoxemia (NCT04619719), and Remote Ischemic Conditioning to Enhance Resuscitation (RICE) Pilot (NCT04265807), and participation as Chair of the ACEP Critical Care Section. I. D. P. reports grants from the CDC, NIH, Janssen Pharmaceuticals, and Intermountain Research & Medical Foundation, institutional fees from Asahi Kasei Pharma and from Regeneron Pharmaceuticals. S. M. B. reports grants from the CDC, NIH, and DOD, fees from Hamilton ventilators for chairing a DSMB, and personal fees from New York University for service on a DSMB. E. T. M. reports a grant from Merck outside the submitted work. A. K. reports grants from the NIH, Ely Lily, United Therapeutics, Johnson & Johnson, BOA Medical, and 4D Medical. A. D. reports funding as the Center PI for PETAL network through NHLBI grant and for participation on a steering committee for ALung technologies. J. G. W. reports grant support from NIH/NHLBI for ACTIV-3 and ACTIV-4 trials and membership on the American Board of Internal Medicine Critical Care Exam Committee. S. Y. C. reports payment as a speaker for La Jolla Pharmaceuticals and consultant fees for PureTech Health and Kiniska Pharmaceuticals. H. M. B. reports grants from the CDC. A. S. L. reports grants from the CDC, NIH, and Burroughs Wellcome Fund, consultant fees from Sanofi, and fees from Roche for membership on a trial steering committee. N. H. reports grants from the CDC, NIH, Sanofi, and Quidel and honoraria for speaking at Continuing Medical Education event at AAP. J. D. C. reports grant support from the CDC. C. G. G. reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, CDC, NIH, US Food and Drug Administration, AHRQ, and Sanofi. T. W. R. reports grants from the NIH, DOD, and AbbVie, personal fees from Cumberland Pharmaceuticals as the Director of Medical Affairs, consultant fees from Cytovale, Inc., personal fees from Sanofi, Inc. for serving as a DSMB board member, a role as the Immediate Past President of the American Society of Parenteral and Enteral Nutrition (ASPEN), and stock from Cumberland Pharmaceuticals for consulting work. C J. L. reports grants/contracts from the CDC, NIH, DOD, bioMerieux, Endpoint LLC, Entegrion, Inc., and AbbVie, a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock, participation on DSMBS for Study Principal Investigators, roles on the Executive Committee, Immediate Past President, Member, Board of Directors for the Association of Clinical and Translational Science, and stock options in Bioscape Digita. W. H. S. reports grant funding from the CDC for this work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Catecholamines and vasopressin are commonly used in patients with post cardiovascular surgery vasoplegia (PCSV). Multimodal therapy, including methylene blue (MB), hydroxocobalamin, and angiotensin II (Ang II), may improve outcomes in patients who remain hypotensive despite catecholamine and vasopressin therapy. However, a standardized approach has not been established. We created a protocol at Emory Healthcare (Emory Protocol), which provides guidance on norepinephrine equivalent dose (NED) and the use of noncatecholamines in the setting of PCSV and sought to determine the clinical significance of adherence to the protocol., Design: Retrospective study., Setting: Multisite study at Emory University Hospital., Patients: Patients receiving Ang II for PCSV in any cardiovascular ICU from 2018 to 2020., Interventions: Patient encounters were scored on Emory Protocol compliance based on NED (1-5), use of vasopressin (1-2), use of MB (1-2), and documentation of high-output shock (1-4). A compliant score was less than 7, moderately compliant 7 to 8, and poorly compliant greater than 8. Demographics, clinical data, and outcomes were abstracted from the medical records., Measurements and Main Results: Of the 78 consecutive patients receiving Ang II for PCSV, overall ICU mortality was 26.9%, with an average compliance score of 6.2. ICU mortality was 21.1% for compliant cases ( n = 38), 29.7% for moderately compliant cases ( n = 24), and 37.5% for poorly compliant cases ( n = 16). In regression analysis, the cumulative compliance score to the Emory Protocol was predictive of ICU mortality ( p = 0.027)., Conclusions: Compliance with the Emory Protocol, emphasizing early initiation of the noncatecholamines vasopressin, MB, hydroxocobalamin, and Ang II at lower catecholamine doses in high-output shock, is associated with improved ICU mortality., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes., Methods: In a multicenter case-control analysis of US adults hospitalized March 11-May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2., Results: Among 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval [CI], 80.7-91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.4%; 95% CI, 79.3-9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8-82.6) than without immunosuppression (91.3%; 95% CI, 85.6-94.8)., Conclusion: During March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) are effective at preventing COVID-19-associated hospitalization (1-3). However, how well mRNA vaccines protect against the most severe outcomes of these hospitalizations, including invasive mechanical ventilation (IMV) or death is uncertain. Using a case-control design, mRNA vaccine effectiveness (VE) against COVID-19-associated IMV and in-hospital death was evaluated among adults aged ≥18 years hospitalized at 21 U.S. medical centers during March 11, 2021-January 24, 2022. During this period, the most commonly circulating variants of SARS-CoV-2, the virus that causes COVID-19, were B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Previous vaccination (2 or 3 versus 0 vaccine doses before illness onset) in prospectively enrolled COVID-19 case-patients who received IMV or died within 28 days of hospitalization was compared with that among hospitalized control patients without COVID-19. Among 1,440 COVID-19 case-patients who received IMV or died, 307 (21%) had received 2 or 3 vaccine doses before illness onset. Among 6,104 control-patients, 4,020 (66%) had received 2 or 3 vaccine doses. Among the 1,440 case-patients who received IMV or died, those who were vaccinated were older (median age = 69 years), more likely to be immunocompromised* (40%), and had more chronic medical conditions compared with unvaccinated case-patients (median age = 55 years; immunocompromised = 10%; p<0.001 for both). VE against IMV or in-hospital death was 90% (95% CI = 88%-91%) overall, including 88% (95% CI = 86%-90%) for 2 doses and 94% (95% CI = 91%-96%) for 3 doses, and 94% (95% CI = 88%-97%) for 3 doses during the Omicron-predominant period. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated death and respiratory failure treated with IMV. CDC recommends that all persons eligible for vaccination get vaccinated and stay up to date with COVID-19 vaccination (4)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton ventilators, and grants from the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD). Jonathan D. Casey reports grants from the NIH and DoD. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018, consulted for PureTech Health in 2020, and consulted for Kiniska Pharmaceuticals in December 2021. David J. Douin reports a grant from NIH/National Institute of General Medical Sciences. Abhijit Duggal reports grants from NIH and participation on a Steering Committee for ALung Technologies. Matthew C. Exline reports support from Abbott Labs for sponsored talks. D. Clark Files reports personal consultant fees from Cytovale and membership on a data and safety monitoring board (DSMB) from Medpace. Anne E. Frosch reports grants from NIH/National Institute of Allergy and Infectious Diseases (NIAID), NIH/National Heart, Lung, and Blood Institute (NHLBI), and NIH/INSIGHT/ICC. Manjusha Gaglani reports grants from Abt Associates, Westat, and Janssen. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), and DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. David N. Hager reports grants from NIH/NHLBI. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel and NIH. Nicholas J. Johnson reports grants from NIH, DoD, and Medic One Foundation. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, and Eli Lilly. Jennie H. Kwon reports grants from NIH/NIAID. Adam S. Lauring reports personal fees from Sanofi and Roche, and grants from NIH and Burroughs Wellcome Fund. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint Health, Entegrion Inc, and AbbVie; and a patent for risk stratification in sepsis and septic shock. Emily T. Martin reports grants from Merck. Arnold S. Monto reports a grant from NIH. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals, and Intermountain Research and Medical Foundation, and institutional support from Asahi Kasei Pharma and Regeneron. Todd W. Rice reports grants from NIH, DoD, and AbbVie and personal fees from Cumberland Pharmaceuticals, Inc., and Cytovale, Inc. No other potential conflicts of interest were disclosed.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Abhijit Duggal reports grants from NIH and participation on a steering committee for ALung Technologies, Inc., outside the submitted work. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Manjusha Gaglani reports grants from CDC-Vanderbilt University Medical Center for the submitted work, CDC-Abt Associates, CDC-Westat, Janssen and Pfizer, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation and EMPACT Precision Medicine via Vanderbilt University Medical Center and grants from NHLBI, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, and GlaxoSmithKline, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work; in addition, Dr. Lindsell has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc., and Sanofi, Inc., outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck, outside the submitted work. No other potential conflicts of interest were disclosed.

Importance: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people., Objective: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease., Design, Setting, and Participants: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021., Exposures: COVID-19 vaccination., Main Outcomes and Measures: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression., Results: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58)., Conclusions and Relevance: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Wesley H. Self reports grants and consultant fees from Merck and consultant fees from Aerpio Pharmaceuticals. Adit A. Ginde reports grant support from AbbVie and Faron Pharmaceuticals. Jonathan D. Casey reports a grant (N23HL153584) from the National Institutes of Health (NIH). D. Clark Files reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). David N. Hager reports salary support from Incyte Corporation, EMPACT Precision Medicine, and the Marcus Foundation. Michelle N. Gong reports grant support from NIH and the Agency for Healthcare Research and Quality (AHRQ) and fees for participating on a DSMB for Regeneron and for participating on a scientific advisory panel for Philips Healthcare. Daniel J. Henning reports consulting fees from Cytovale and Opticyte. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals, institutional fees from Asahi Kasei Pharma and from Regeneron. Samuel M. Brown reports fees from Hamilton for chairing a DSMB, and institutional fees from Faron, Sedana, and Janssen; grants from Sedana, Janssen, NIH, and the Department of Defense (DoD); book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. Emily T. Martin reports personal fees from Pfizer for unrelated work and a grant from Merck for unrelated work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals and a Consultant for PureTech Health. Jennie H. Kwon reports grant support from NIH. Matthew C. Exline reports talks on nutrition in COVID pneumonia at APEN conference sponsored by Abbott Labs. Natasha Halasa reports grants from Sanofi and Quidel. James D. Chappell reports a grant from the National Center for Advancing Translational Sciences, NIH. Adam S. Lauring reports consultant fees from Sanofi and fees from Roche for membership on a trial steering committee. Carlos G. Grijalva reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc., as the Director of Medical Affairs, consultant fees from Avisa Pharma, LLC; and DSMB membership fees from Sanofi. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint LLC, and Entegrion, Inc.; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. No other potential conflicts of interest were disclosed.

Real-world evaluations have demonstrated high effectiveness of vaccines against COVID-19-associated hospitalizations (1-4) measured shortly after vaccination; longer follow-up is needed to assess durability of protection. In an evaluation at 21 hospitals in 18 states, the duration of mRNA vaccine (Pfizer-BioNTech or Moderna) effectiveness (VE) against COVID-19-associated hospitalizations was assessed among adults aged ≥18 years. Among 3,089 hospitalized adults (including 1,194 COVID-19 case-patients and 1,895 non-COVID-19 control-patients), the median age was 59 years, 48.7% were female, and 21.1% had an immunocompromising condition. Overall, 141 (11.8%) case-patients and 988 (52.1%) controls were fully vaccinated (defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines ≥14 days before illness onset), with a median interval of 65 days (range = 14-166 days) after receipt of second dose. VE against COVID-19-associated hospitalization during the full surveillance period was 86% (95% confidence interval [CI] = 82%-88%) overall and 90% (95% CI = 87%-92%) among adults without immunocompromising conditions. VE against COVID-19- associated hospitalization was 86% (95% CI = 82%-90%) 2-12 weeks and 84% (95% CI = 77%-90%) 13-24 weeks from receipt of the second vaccine dose, with no significant change between these periods (p = 0.854). Whole genome sequencing of 454 case-patient specimens found that 242 (53.3%) belonged to the B.1.1.7 (Alpha) lineage and 74 (16.3%) to the B.1.617.2 (Delta) lineage. Effectiveness of mRNA vaccines against COVID-19-associated hospitalization was sustained over a 24-week period, including among groups at higher risk for severe COVID-19; ongoing monitoring is needed as new SARS-CoV-2 variants emerge. To reduce their risk for hospitalization, all eligible persons should be offered COVID-19 vaccination., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), and the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Jonathan D. Casey reports grants from NIH, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, and personal fees from Philips Healthcare, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHQR, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation, the Marcus Foundation, and EMPACT Precision Medicine via Vanderbilt University Medical Center, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and Quidel outside the submitted work. Daniel J. Henning reports personal consultant fees from Cytovale and Opticyte. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work and has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus outside the submitted work. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc. and personal fees from Avisa Pharma, LLC and Sanofi, outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck outside the submitted work. No other potential conflicts of interest were disclosed.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis., Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis., Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020., Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone., Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality., Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group., Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Purpose of Review: This review discusses the macrocirculatory and microcirculatory aspects of renal perfusion, as well as novel methods by which to measure renal blood flow. Finally, therapeutic options are briefly discussed, including renal-specific microcirculatory effects., Recent Findings: The optimal mean arterial pressure (MAP) needed for preservation of renal function has been debated but is most likely a MAP of 60-80 mmHg. In addition, attention should be paid to renal outflow pressure, typically central venous pressure. Heterogeneity in microcirculation can exist and may be mitigated through appropriate use of vasopressors with unique microcirculatory effects. Excessive catecholamines have been shown to be harmful and should be avoided. Both angiotensin II and vasopressin may improve glomerular flow through a number of mechanisms. Macrocirculatory and microcirculatory blood flow can be measured through a number of bedside ultrasound modalities, sublingual microscopy and urinary oxygen measurement, SUMMARY: Acute kidney injury (AKI) is a common manifestation of organ failure in shock, and avoidance of hemodynamic instability can mitigate this risk. Measurement of renal haemodynamics is not routinely performed but may help to guide therapeutic goals. A thorough understanding of pathophysiology, measurement techniques and therapeutic options may allow for a personalized approach to blood pressure management in patients with septic shock and may ultimately mitigate AKI.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios ( r  = 0.39; P  < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo ( P  < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P  = 0.012) ( P  = 0.048 for the interaction). Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Background: Patients with distributive shock who are unresponsive to traditional vasopressors are commonly considered to have severe distributive shock and are at high mortality risk. Here, we assess the cost-effectiveness of adding angiotensin II to the standard of care (SOC) for severe distributive shock in the US critical care setting from a US payer perspective., Methods: Short-term mortality outcomes were based on 28-day survival rates from the ATHOS-3 study. Long-term outcomes were extrapolated to lifetime survival using individually estimated life expectancies for survivors. Resource use and adverse event costs were drawn from the published literature. Health outcomes evaluated were lives saved, life-years gained, and quality-adjusted life-years (QALYs) gained using utility estimates for the US adult population weighted for sepsis mortality. Deterministic and probabilistic sensitivity analyses assessed uncertainty around results. We analyzed patients with severe distributive shock from the ATHOS-3 clinical trial., Results: The addition of angiotensin II to the SOC saved .08 lives at Day 28 compared to SOC alone. The cost per life saved was estimated to be $108,884. The addition of angiotensin II to the SOC was projected to result in a gain of .96 life-years and .66 QALYs. This resulted in an incremental cost-effectiveness ratio of $12,843 per QALY. The probability of angiotensin II being cost-effective at a threshold of $50,000 per QALY was 86 percent., Conclusions: For treatment of severe distributive shock, angiotensin II is cost-effective at acceptable thresholds.

Background: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study., Methods: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes., Results: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses., Conclusions: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction., Trial Registration: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence. Research into treatment of this syndrome is limited and extrapolated primarily from that pertaining to septic shock, but is evolving with the expanded use of catecholamine-sparing agents. Recent reports demonstrate potential benefit in novel treatment options, but large clinical trials are needed to confirm.

Background: Despite multiple treatment options, antihypertensive overdose remains a cause of significant morbidity and mortality. Intravenous angiotensin II (AG II) is approved for use in vasodilatory shock. We describe 2 cases of refractory shock from antihypertensive overdose that were successfully treated using AG II., Case Reports: A 24-year-old female presented after an overdose of multiple antihypertensive medications, including an angiotensin converting enzyme inhibitor (ACEI). She developed hypotension that was refractory to norepinephrine, epinephrine, and vasopressin, with a mean arterial pressure (MAP) of 57 mm Hg 9 h after emergency department arrival. Fifteen minutes after starting AG II at 10 ng/kg/min, her heart rate and MAP rose by 7 beats/min and 12 mm Hg, respectively. Her hemodynamic parameters continued to improve thereafter. She developed acute kidney injury, which resolved prior to discharge. The second patient, a 65-year-old male, presented after an overdose of multiple antihypertensive medications, including an ACEI. Despite norepinephrine, epinephrine, and hyperinsulinemia-euglycemia, he remained bradycardic and hypotensive, with a heart rate of 47 beats/min and MAP of 59 mm Hg. Thirty minutes after starting AG II at 10 ng/kg/min, his heart rate was 61 beats/min and MAP was 66 mm Hg. He recovered without apparent sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Antihypertensive overdose can lead to shock refractory to catecholamine and vasopressin therapy. Our experience suggests that AG II is efficacious in antihypertensive overdose and may be particularly efficacious in instances of ACEI overdose. However, further study is required to confirm the appropriate indication(s)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is common in the setting of shock. Hemodynamic instability is a risk factor for the development of AKI, and pathophysiological mechanisms include loss of renal perfusion pressure and impaired microcirculation. Although restoration of mean arterial pressure (MAP) may mitigate the risk of AKI to some extent, evidence on this is conflicting. Also debatable is the optimal blood pressure needed to minimize the risk of kidney injury. A MAP of 65 mm Hg traditionally has been considered adequate to maintain renal perfusion pressure, and studies have failed to consistently show improved outcomes at higher levels of MAP. Therapeutic options to support renal perfusion consist of catecholamines, vasopressin, and angiotensin II. Although catecholamines are the most studied, they are associated with adverse events at higher doses, including AKI. Vasopressin and angiotensin II are noncatecholamine options to support blood pressure and may improve microcirculatory hemodynamics through unique mechanisms, including differential vasoconstriction of efferent and afferent arterioles within the nephron. Future areas of study include methods by which clinicians can measure renal blood flow in a macrocirculatory and microcirculatory way, a personalized approach to blood pressure management in septic shock using patient-specific measures of perfusion adequacy, and novel agents that may improve the microcirculation within the kidneys without causing adverse microcirculatory effects in other organs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg -1  min -1 angiotensin II at 30 min (≤ 5 ng kg -1  min -1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg -1  min -1 angiotensin II at 30 min (> 5 ng kg -1  min -1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used., Results: The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg -1  min -1 at treatment initiation to ≤ 5 ng kg -1  min -1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg -1  min -1 subgroup (84/163). Patients in the ≤ 5 ng kg -1  min -1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg -1  min -1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63-19.7], P < 0.001). Day 28 survival was also higher in the ≤ 5 ng kg -1  min -1 subgroup versus the > 5 ng kg -1  min -1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28-0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg -1  min -1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg -1  min -1 subgroup., Conclusions: This prespecified analysis showed that down-titration to ≤ 5 ng kg -1  min -1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency.

Background: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed., Methods: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed., Discussion: VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Introduction: Despite international guidelines, regional differences in treatment of vasodilatory shock remain. We characterized these differences using data from Angiotensin II in High Output Shock (ATHOS-3) trial., Methods: The 321 patients treated in the ATHOS-3 trial were included. Baseline and hour-48 data were analyzed for differences in demographics, clinical characteristics, and treatment patterns, and grouped into four geographical areas: United States, Canada, Europe, and Australasia. Differences were analyzed by Kruskal-Wallis tests for continuous, and chi-square tests for categorical data. Temporal analysis compared changes in the treatment of shock during the treatment period., Results: Differences in baseline characteristics across geographic areas were noted in BMI, albumin, CVP, MELD score, APACHE II score, and total SOFA score. Baseline norepinephrine and norepinephrine equivalent doses (NED) were higher (p < .0001 and p = .0494, respectively), and vasopressin use was lower (p < .0001) in Europe. Baseline steroids were utilized more in the US and Canada (p = .0011)., Conclusions: Management of vasodilatory shock differs globally with respect to utilization of steroids and vasopressors. This practice heterogeneity may influence shock trials interpretation and patient outcomes, though more definitive evidence would require larger prospective intervention data., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) trial demonstrated the vasopressor effects and catecholamine-sparing properties of angiotensin II. As a result, the Food and Drug Administration has approved angiotensin II for the treatment of vasodilatory shock. This review details the goals of treatment of vasodilatory shock in addition to the history, current use, and recent research regarding the use of angiotensin II. An illustrative case of the use of angiotensin II is also incorporated for understanding the clinical utility of the drug., (Copyright © 2018 Elsevier Inc. All rights reserved.)