Background
Postoperative hypotension is common, life threatening and poorly understood, and is associated with higher risk of myocardial injury, acute kidney injury and death. Vasopressors are often used to support blood pressure in postoperative and most existing research has used intravenous vasopressors that require intensive care unit admission. Oral vasopressor treatment has been proposed to deal with this problem. The most frequently advocated option is midodrine, which is currently being used in perioperative practice despite limited evidence. Recently atomoxetine has been used off-label to treat orthostatic hypotension but has not been previously assessed to treat postoperative hypotension. There is an urgent need for comparative trials of medications to reduce the incidence of postoperative hypotension.
Aims, objectives, hypotheses and outcomes
The study aimed to test the feasibility and processes of a large phase three randomised controlled trial (RCT) of candidate oral vasopressors to prevent postoperative hypotension. Outcomes include:
1. the desired recruitment rate of at least four patients per week can be achieved (Primary Outcome)
2. the proportion of patients who received the allocated intervention in its entirety
3. the blinding strategy is successful (assessed using perceived allocation questionnaire)
4. the intervention is acceptable to anaesthetists, patients and research staff using the Acceptability of Interventions Measure
5. the rate at which participants decline to provide confirmation of consent when approached
6. the rate of case report form completion and estimate the time required to complete all trial procedures and establish the views of trial coordinators on recruitment, data collection and follow-up.
Clinical outcomes to inform the larger trial include:
- an estimate of the incidence and variance of postoperative hypotension and secondary outcomes within each of the treatment arms to facilitate a sample size calculation for a definitive trial.
- the prevalence of secondary clinical outcomes
- an estimate of health economic effects, including changes to need for MET calls, ICU admission, and mortality in each group to test procedures for the larger definitive trial.
Methods
The research team propose a single-centre, three-arm, placebo-controlled randomised pilot study for a large definitive randomised controlled trial (RCT) comparing midodrine and atomoxetine to placebo. It will include adult patients who have had major non-cardiac, non-obstetric surgery under general anaesthesia, who are hypotensive (systolic blood pressure <90 mmHg) for at least 10 minutes in the PACU.
Participants will receive an initial dose of study medication in PACU, and then receive two more doses at eight and sixteen hours after enrolment. The study will have three treatment groups, being midodrine 10mg thrice daily, atomoxetine 18microg once daily and placebo. The trial is expected to be feasible to conduct at RMH. Outcomes will be obtained by reviewing electronic medical record data, as well as interviews with staff and participants.
Significance
The outcomes of the research will help develop a large definitive RCT of treatments for postoperative hypotension. The trial will be novel in selecting a group at very high risk of postoperative hypotension, who would benefit from interventions to protect their blood pressure. Previous work on oral vasopressors has been limited by using relatively sensitive but not specific tools to identify patients, rather than individual’s physiological responses to surgery, and may have been underpowered to detect true differences in risk with oral vasopressor treatment. The research will contribute to advancing perioperative medicine to a field with treatment options that can improve outcomes, reduce morbidity and mortality after surgery and improve the patient experience of surgical care.
Royal Melbourne Hospital and Department of Critical Care, University of Melbourne
Dr Ned Douglas, Associate Professor Jeff Presneil, Associate Professor Adam Deane, Professor Kate Leslie and Associate Professor Jai Darvall.
The project was awarded A$65,311 funding through the ANZCA research grants program for 2024.
Low blood pressure after surgery is an important problem because it can cause damage to organs such as the heart, kidneys and brain. There are a wide variety of ways to treat low blood pressure, but which one will work is determined by what the cause of the low blood pressure might be.
The aim of the project was to determine if giving patients who had low blood pressure in the post anaesthetic care unit, either of two drugs used to treat low blood pressure caused by other problems, was effective in preventing them developing more low blood pressure later on the ward. While some anaesthetists use these medications, there is no data to tell us if they are effective or not, and hence the need to conduct a large scale trial to evaluate their effectiveness. The logistics of running such a trial are uncertain, particularly because of the different methods needed to be used and recruiting patients to the trial compared to our usual studies. It was necessary to conduct this study to understand if it was feasible to conduct a large trial.
Few patients were recruited than expected, but found that overall the trial was feasible to run. Surprising results were also identified with regard to how the medications worked, and plan to investigate these more definitively with a larger study.
The research team now have the information necessary to run a large trial to definitively evaluate if these medications can be useful in managing low blood pressure after surgery. Given over 300 million patients have surgery every year across the world, and up to one in every 10 patients develops low blood pressure, the potential impact of these findings is enormous.
The study is currently being prepared for publication.
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