; for the 65 trial investigators IMPORTANCE Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients. OBJECTIVE To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension. DESIGN, SETTING, AND PARTICIPANTS A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019. INTERVENTIONS Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307). MAIN OUTCOME AND MEASURES The primary clinical outcome was all-cause mortality at 90 days. RESULTS Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians,-5.0; 95% CI,-7.8 to-2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians,-8.7 mg; 95% CI,-12.8 to −4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, −2.85%; 95% CI, −6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]). CONCLUSIONS AND RELEVANCE Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.

The dose requirements and duration of effect of transdermal nitroglycerin in patients with heart failure are not clearly established. In a first series of eight patients with chronic heart failure we gave transdermal nitroglycerin in incremental doses until pulmonary capillary wedge pressure fell at least 30% within 4 hr in three consecutive patients. Thus we found that a single dose of 60 mg/24 hr (120 cm2) was the minimal effective dose. Transdermal nitroglycerin or placebo was then given as a single application of 60 mg/24 hr in random double-blind fashion to 15 additional patients with heart failure (eight received transdermal nitroglycerin and seven received placebo), and hemodynamics were monitored for up to 24 hr. After administration of transdermal nitroglycerin, the control pulmonary capillary wedge pressure of 22 + 7 mm Hg fell by 6 + 6 mm Hg at 2 hr (p < .05) and reached maximal reduction of 8 + 6 mm Hg (p < .01) at 4 hr. The reduction in wedge pressure remained significant through 12 hr but was no longer statistically significant by 18 hr after administration of the drug. Transdermal nitroglycerin also significantly reduced pulmonary arterial and right atrial pressures as well as pulmonary vascular resistance from 4 through 12 hr but did not affect systemic hemodynamics. No significant hemodynamic changes occurred after administration of placebo. Thus transdermal nitroglycerin is an effective vasodilator in patients with heart failure, but a dose of at least 60 mg/24 hr is needed. Even with this dose, hemodynamic effects do not last beyond 18 hr, suggesting altered absorption or development of tolerance. Circulation 71, No. 5, 980-986, 1985. VASODILATORS are commonly used for the treatment of acute and chronic congestive heart failure. Among the presently available vasodilator agents, only nitrates and angiotensin-converting enzyme inhibitors have produced sustained hemodynamic improvement along with increased exercise tolerance in placebo-controlled trials in patients with chronic heart failure.1-6 Both captopril and nitrates require frequent dosing, so that practical problems related to drug delivery and patient compliance still exist. The duration of action of sublingually administered nitroglycerin is far

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.

Vasodilatory shock is common in critically ill patients and vasopressors are a mainstay of therapy. A meta-analysis suggested that use of a higher, as opposed to a lower, mean arterial pressure target to guide titration of vasopressor therapy, could be associated with a higher risk of death in older critically ill patients. The 65 trial is a pragmatic, multi-centre, parallel-group, open-label, randomised clinical trial of permissive hypotension (a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial is conducted in 2600 patients from 65 United Kingdom adult, general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. The 65 trial received favourable ethical opinion from the South Central – Oxford C Research Ethics Committee and approval from the Health Research Authority. The results will be presented at national and international conferences and published in peer-reviewed medical journals. Trial registration: ISRCTN10580502

Vasodilatory shock is common in critically ill patients and vasopressors are a mainstay of therapy. A meta-analysis suggested that use of a higher, as opposed to a lower, mean arterial pressure target to guide titration of vasopressor therapy, could be associated with a higher risk of death in older critically ill patients. The 65 trial is a pragmatic, multi-centre, parallel-group, open-label, randomised clinical trial of permissive hypotension (a mean arterial pressure target of 60 -65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial is conducted in 2600 patients from 65 United Kingdom adult, general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. The 65 trial received favourable ethical opinion from the South Central - Oxford C Research Ethics Committee and approval from the Health Research Authority. The results will be presented at national and international conferences and published in peer-reviewed medical journals. Trial registration: ISRCTN10580502