Title: Evaluating the clinical and cost effectiveness of using a more conservative mean arterial pressure target range to guide careful titration of vasopressors to minimise dose and duration in older critically ill patients with vasodilatory hypotension: the 65 trial.
Funder: Department of Health and Social Care

Abstract: Design: Pragmatic, multi-centre, randomised clinical trial. Setting: 65 NHS adult, general, critical care units. Target population: Adult critical care admissions, 65+ years, with vasodilatory hypotension and have recently started to receive vasopressors. Inclusion criteria: age 65 years or older; vasodilatory hypotension as assessed by treating clinician; started a vasopressor infusion (for at least one hour) within prior 6 hours following/during adequate fluid resuscitation; vasopressors expected to continue for 6 hours or more as assessed by treating clinician. If the vasopressor the patient is receiving is noradrenaline, then they must be receiving a dose of at least 0.1 µg kg-1 min-1. Exclusion criteria: vasopressors being used solely as therapy for bleeding, acute ventricular failure (left or right) or post-cardiopulmonary bypass vasoplegia, ongoing treatment for brain injury or spinal cord injury, death perceived as imminent, previous enrolment to the 65 Trial. Health technologies: Intervention - a permissive hypotension strategy (mean arterial pressure target range of 60 - 65 mmHg whilst receiving vasopressors). Control - usual care. [If vasopressors re-started for vasodilatory hypotension (during same critical care unit stay), then managed according to original, randomly assigned allocation.] Measurement of costs and outcomes: Integrated economic evaluation. [With no additional primary data collection - using 65 trial and Case Mix Programme (CMP) data from sites both within/outside trial - CMP has 100% coverage and high data accuracy.] Primary outcome: 90-day mortality. Secondary outcomes: mortality at discharge from the critical care unit and acute hospital, duration of survival to longest available follow-up, duration of advanced respiratory and renal support (defined according to the Critical Care Minimum Dataset) during the critical care unit stay, days alive and free of advanced respiratory support and renal support, duration of critical care unit and acute hospital stay, cognitive function, assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (short form) at 90 days and one year, health-related quality of life, assessed using the EuroQol EQ-5D-5L questionnaire, at 90 days and one year, resource use and costs at 90 days and one year, estimated lifetime incremental cost-effectiveness. Throughout the critical care admission, there will be continuous adverse event monitoring and reporting. [Note: one year outcomes will only be measured for those patients recruited in the first nine months of the recruitment period]. Sample size: Assuming 90-day mortality of 35% (CMP data), 2,600 patients (allowing for 2.5% withdrawal/loss to follow-up) provides 90% power to detect a 6% absolute risk reduction (corresponding to a 17% relative risk reduction) - to 29% in the intervention group (P<0.05). Difference between current and planned care pathways: Current care pathway for the control group is informed by recent research evidence indicating that critical care unit policy, rather than patient characteristics, drives vasopressor use and by data from the CALORIES trial (HTA 07/52/03) indicating that vasopressor use continues for days in a substantial percentage of patients with MAP values above 80 mmHg. Planned care pathway for the intervention group is informed by the current evidence base indicating that a strategy of permissive hypotension (mean arterial pressure target range of 60 - 65 mmHg whilst receiving vasopressors) may improve survival in older critically ill patients. Project timetables: Total duration 32 months (set-up 1-6, recruitment 7-24, follow-up 10-30, analysis/dissemination 28-32). Expertise in team: critical care - patients (DHe, CW), trialists (PM, KR, FL, AG, DY including the trialist that led the pilot RCT FL - who will be based in the ICNARC CTU), statistician (DHa), health economists (RG, ZS) and clinicians (FL, AG, DY, JC).

Lay abstract: Shock is a state in which not enough blood and oxygen can reach the body’s organs. One of the signs of shock is having a low blood pressure, also known as hypotension. Hypotension is common in critically ill patients. If left untreated, hypotension can lead to death. Current guidelines recommend maintaining mean arterial pressure (MAP – a person’s average blood pressure) above 65 mmHg. These guidelines are based on low quality evidence and no guidance is given for an upper MAP limit. There is some evidence that overuse of interventions, such as vasopressors, to continue increasing an already high MAP, may be harmful. A recently completed meta-analysis of data from two trials suggests that targeting higher MAP values of between 75 and 85 mmHg, achieved through increased use of intensive interventions, may be associated with an increased risk of death in older patients. Previous research studies suggest that using a lower average blood pressure target range may improve survival among older patients. However, very few studies have looked at this and they often involved a small number of patients. Our aim is to compare using a strategy of permissive hypotension (mean arterial pressure target range of 60 - 65 mmHg whilst receiving vasopressors) with the approach that is currently being used in the NHS, in older adults admitted to a critical care unit. It is not yet known whether the strategy of permissive hypotension will improve survival, and that is why this clinical trial is needed. The results of this study will have a large and immediate impact on clinical practice and on patient outcomes for older, critically ill patients in the NHS. We will also explore the relative costs. A patient can participate in the study if they: • are admitted to one of 65 NHS adult, general, critical care units; • are 65 years old and over; • have a diagnosis of vasodilatory hypotension; and • require vasopressors. We plan to include 2,600 patients, with half receiving vasopressor treatment guided by the lower average blood pressure target range of 60 - 65 mmHg and the other half receiving the care they usually would have received. Participants will be randomly assigned to one of these groups. This type of study is known as a randomised clinical trial. It ensures that the two groups of participants are as similar as possible, except for the use of the lower target range. It therefore allows us to see whether the lower target range is any more or less beneficial than the usual care. All other medical care will be left up to the treating clinician. We have patient representatives as co-investigators on this study. They are involved in developing how the study will be done. They will also be involved in overseeing the conduct and management of this study. Once the study is complete, the results will be published in a widely read and well regarded medical journal. The results will also be presented at various national and international conferences for intensive care doctors, nurses, other health professionals, managers and policy makers. We will also make the results available to the public and patients through the ICNARC website.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR