Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial

Abstract

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

Introduction

To guide treatment with vasopressors, doctors typically prescribe a mean arterial pressure (MAP) target and bedside nurses continuously adjust the rate of vasopressor infusions to achieve the target MAP. Previous guidelines recommended maintaining MAP above 65 mmHg, but these were based on low quality evidence and did not provide guidance for an upper MAP limit. ¹ A pooled analysis of two randomised clinical trials (RCTs)^2,3 suggested that, with increasing age, higher MAP targets may be associated with a greater risk of death.^4,5 An alternative strategy (termed “permissive hypotension”) is to target blood pressure values below traditional levels to reduce the exposure to vasopressors and minimise their side effects.

Study type

The 65 trial is a pragmatic, multi-centre, open-label, RCT of permissive hypotension versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. Favourable ethical opinion was given by South Central – Oxford C Research Ethics Committee and the trial is approved by the Health Research Authority.

Intervention(s)

Intervention group: a permissive hypotension strategy – a MAP target range of 60–65 mmHg during vasopressor therapy.

Control group: Usual care (as per local practices).

Inclusion and exclusion criteria

Inclusion: Age 65 years or older; vasodilatory hypotension; started infusion (for at least one hour) of vasopressors within prior six hours (if noradrenaline, then a minimum dose of 0.1 µg kg−1 min−1); adequate fluid resuscitation is completed or ongoing; and vasopressors expected to continue for six hours or more

Exclusion: Vasopressors being used solely as therapy for bleeding, acute ventricular failure (left or right) or post-cardiopulmonary bypass vasoplegia; ongoing treatment for brain or spinal cord injury; death perceived as imminent; and previous enrolment to the 65 Trial.

Randomisation is concealed and performed as soon as possible after confirming eligibility. Given the emergency nature of the treatment, the trial uses research without prior consent, with consent sought after randomisation.

Outcomes

Primary outcome: All-cause mortality at 90 days.

Secondary outcomes: Receipt and duration of respiratory and renal support; critical care unit and acute hospital length of stay; and cognitive decline and health-related quality of life at 90 days and one year. Economic outcomes include incremental net monetary benefit (primary), resource use and costs at 90 days and one year (secondary).

Target study size

Two thousand six hundred patients from 65 adult, general critical care units across England, Wales and Northern Ireland.

Status

Patient recruitment is planned to be complete in the first quarter of 2019. Results will be disseminated in early 2020.