Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT.

BACKGROUND: Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med 2018;44:12-21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. OBJECTIVE: To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60-65 mmHg) in older critically ill patients. DESIGN: A pragmatic, randomised clinical trial with integrated economic evaluation. SETTING: Sixty-five NHS adult general critical care units. PARTICIPANTS: Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. INTERVENTIONS: Intervention - permissive hypotension (i.e. a mean arterial pressure target of 60-65 mmHg). Control (usual care) - a mean arterial pressure target at the treating clinician's discretion. MAIN OUTCOME MEASURES: The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. RESULTS: Of 2600 patients randomised, 2463 (permissive hypotension, n = 1221; usual care, n = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference -9.9 hours (95% confidence interval -14.3 to -5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference -12.8 mg (95% CI -18.0 mg to -17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference -2.85%, 95% confidence interval -6.75% to 1.05%; p = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval -£1347 to £2103). LIMITATIONS: The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. CONCLUSIONS: In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. FUTURE WORK: Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10580502. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 14. See the NIHR Journals Library website for further project information

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Corticosteroid therapy for sepsis: a clinical practice guideline

Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients’ values and preferences may guide this decision-making process. This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: • ADRENAL (3658 patients who had septic shock) found no statistically significant difference in 90 day mortality between the hydrocortisone and placebo groups.1 • APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality.2 The trials are incorporated into a linked systematic review comparing corticosteroids with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. C urrently most guidelines advise against WHAT YOU NEED TO KNOW • Sepsis is a syndrome of life threatening infection with organ dysfunction, and most guidelines do not advise use of corticosteroids to treat it in the absence of refractory shock • Two new trials of corticosteroid treatment for sepsis came to differing conclusions • Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular weakness by a small amount, but the evidence is not definitive • This guideline makes a weak recommendation for corticosteroids in patients with sepsis; both steroids and no steroids are reasonable management options • Fully informed patients who value avoiding death over quality of life and function would likely choose corticosteroids No commercial reuse: See rights and reprints http://www.bmj.com/permissions giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction. The box below shows publications linked in this Rapid Recommendation package. The main infographic provides an overview of the absolute benefits and harms. The table at the end of the article shows any evidence that has emerged since the publication of this guideline.This guideline was not funded

Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline

What is the role of gastrointestinal bleeding prophylaxis (stress ulcer prophylaxis) in critically ill patients? This guideline was prompted by the publication of a new large randomised controlled trial

Corticosteroid therapy for sepsis: A clinical practice guideline

Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients’ values and preferences may guide this decision-making process. This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: • ADRENAL (3658 patients who had septic shock) found no statistically significant difference in 90 day mortality between the hydrocortisone and placebo groups.1 • APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality.2 The trials are incorporated into a linked systematic review comparing corticosteroids with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. C urrently most guidelines advise against WHAT YOU NEED TO KNOW • Sepsis is a syndrome of life threatening infection with organ dysfunction, and most guidelines do not advise use of corticosteroids to treat it in the absence of refractory shock • Two new trials of corticosteroid treatment for sepsis came to differing conclusions • Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular weakness by a small amount, but the evidence is not definitive • This guideline makes a weak recommendation for corticosteroids in patients with sepsis; both steroids and no steroids are reasonable management options • Fully informed patients who value avoiding death over quality of life and function would likely choose corticosteroids No commercial reuse: See rights and reprints http://www.bmj.com/permissions giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction. The box below shows publications linked in this Rapid Recommendation package. The main infographic provides an overview of the absolute benefits and harms. The table at the end of the article shows any evidence that has emerged since the publication of this guideline