Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial

Abstract

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Results: Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men).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.

Trial registration: isrctn.org Identifier: ISRCTN10580502.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lamontagne reported receiving grants from National Institute for Health Research (NIHR) and grants from Fonds de recherche du Québec-Santé. Mr Richards-Belle reported receiving grants from The NIHR Technology Assessment Programme. Ms Thomas reported receiving grants from the NIHR Health Technology Assessment Programme. Dr Harrison reported receiving grants from the NIHR Technology Assessment Programme. Dr Grieve reported receiving grants from the NIHR Technology Assessment Programme. Mrs Camsooksai reported receiving grants from the NIHR Health Technology Assessment Programme. Mr Darnell reported receiving grants from the NIHR Technology Assessment Programme. Dr Gordon reported receiving grants from the NIHR Technology Assessment Programme and other support from Bristol-Myers Squibb and GlaxoSmithKline. Ms Saull reported receiving grants from the NIHR Technology Assessment Programme. Dr Rowan reported receiving grants from the NIHR Health Technology Assessment Programme. Mr Mouncey reported receiving grants from the NIHR Technology Assessment Programme. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-Up of Patients in the 65 Trial

aAs assessed by the treating clinician. bSome patients met more than 1 criterion.

Figure 2.. Kaplan-Meier Survival Curves

All randomized patients are included when calculating survival, excluding 8 patients in the permissive hypotension group and 7 in the usual care group who did not consent to the trial and refused permission for data use. Other surviving patients were censored at the last known date alive or at date of withdrawal or refusal of consent (from whom trial consent was not obtained). The median follow-up time (using the reverse Kaplan-Meier method) was 14.3 months (interquartile range [IQR], 8.8-19.3) for the permissive hypotension group and 14.2 months (IQR, 8.5-19.4) for the usual care group. HR indicates hazard ratio.

Figure 3.. Subgroup Analyses of the Primary Outcome

aAdjusted for age, sex, comorbidities, prior dependency, vasopressor infusions received at randomization, duration of vasopressor infusion prior to randomization, location prior to admission to intensive care unit (ICU) or urgency of surgery, Intensive Care National Audit & Research Centre physiology score, Sepsis-3, and random effect of site. bP value for test of interactions of risk ratio in adjusted generalized estimating equation (GEE) Poisson regression model. cP value for test of interactions in the odds ratio (OR) in adjusted multilevel logistic regression model. dThree patients in the usual care group were identified after randomization to be younger than 65 years and are included in this subgroup. eTest of continuous linear interaction with age: adjusted OR, 0.82 (95% CI, 0.69-0.99) at age 75 years (mean value), interaction OR, 0.90 (95% CI, 0.78-1.02) per 5-year increase in age. fTest of continuous linear interaction with predicted log odds of acute hospital mortality: adjusted OR, 0.82 (95% CI, 0.68 to 0.99) at predicted log odds of –0.64 (mean value) (predicted risk of 35%), interaction OR, 0.97 (95% CI, 0.84-1.12) per increase of 1 in predicted log odds. gNorepinephrine equivalent doses were calculated according to the method described in Khanna et al, using the following conversion factors: epinephrine μg/kg/min (× 1), dopamine μg/kg/min (/150), phenylephrine μg/kg/min (× 0.1), and vasopressin U min –1 ( × 2.5).