Optimal VAsopressor TitraTION in Patients 65 Years and Older (OVATION-65)

Background:

When it is severe, hypotension compromises tissue perfusion and organ function, leading to multiple organ failure and death. Commonly in intensive care units (ICUs), excessive vasodilation causes hypotension. In response, clinicians administer vasopressors to induce vasoconstriction and thereby raise blood pressure. However, these medications may reduce blood flow to vital organs, including the heart, and therefore damage them. Titrating vasopressors therefore requires balancing the risks of organ dysfunction arising from vasopressors or hypotension. Current guidelines recommend titrating vasopressors to a mean arterial pressure (MAP) of 65 mmHg. By not specifying an upper limit, guidelines and clinicians put more emphasis on preventing hypotension than on minimizing vasopressor exposure. Permissive hypotension, defined as a MAP target below traditional levels, may reduce vasopressor-induced harm while avoiding organ dysfunction induced by severe hypotension.

Observational data show that the average MAP in Canadian patients on vasopressors is 75 mmHg, 10 mmHg above current guideline recommendations and self-reported practices.The recent CIHR-funded OVATION pilot RCT (n=118) of permissive hypotension met feasibility objectives of demonstrating a separation in mean MAP between arms (9 mmHg, p<0.0001) and enrolling patients efficiently (2.3 patients/site/month). Investigators have also completed an individual patient data meta-analysis with the French SEPSISPAM trial and found that a lower MAP target may be beneficial in patients 65 years old.

Objective:

The overarching goal of this randomized controlled trial (RCT) of permissive hypotension vs. usual blood pressure targets in hypotensive patients ≥65 years old is to determine whether permissive hypotension reduces the risk of harm associated with usual vasopressor therapy. The proposed RCT has specific objectives to ascertain the effect of permissive hypotension vs. usual care on: 1) markers of organ injury (primarily in the heart at day 3, secondarily (on day 3 and day 7) in the brain, liver, intestine, and skeletal muscle); 2) global tissue dysoxia (assessed by plasma lactate); 3) organ function (assessed by Sequential Organ Failure Assessment [SOFA] Score ); 4) resource utilization, 5) pre-specified adverse events, 6) mortality at 90 days and 6 months; 7) cognitive impairment in survivors at 6 months.