Research on vasopressors offers few definitive answers, Ashish Khanna, MD, warned attendees at the annual meeting of the Society of Critical Care Medicine, held in Orlando in February.
Dr. Khanna, a critical care specialist and associate professor of anesthesiology at Wake Forest School of Medicine in Winston-Salem, N.C., reviewed comparisons of mean arterial pressure (MAP) targets and vasopressors in critically ill patients.
The evidence is particularly inconclusive on the former. “The best level of evidence is the classic work done by Asfar and colleagues,” he said. That septic shock trial found no difference in outcomes between patients randomized to a MAP target of 80 to 85 mm Hg or one of 65 to 70 mm Hg, according to results published in the New England Journal of Medicine (NEJM) in 2014.
“All the way from then to two weeks ago, when the 65 trial came out, there wasn't really a large randomized trial of MAP thresholds,” said Dr. Khanna. The 65 trial randomized 2,600 older ICU patients to a MAP target of 60 to 65 mm Hg or to usual care (i.e., vasopressors at the discretion of treating clinicians) and was published by JAMA on Feb. 12. “They found no difference in mortality whatsoever.”
Yet some research based on large datasets and conducted in the time between these trials has favored higher targets, including a study by Dr. Khanna and his colleagues that found mortality and myocardial injury risks increased at MAPs below 85 mm Hg. That study included more than 8,000 ICU patients with sepsis and was published by Intensive Care Medicine in 2018. This was similar to a study of a surgical ICU cohort, published by Critical Care Medicine last year, which found those adverse outcomes in patients with hypotension compared to the median MAP of 87 mm Hg.
But then another study he coauthored, published in the March 2020 Anesthesia & Analgesia, found that delirium increased in postoperative patients around a MAP of 75 mm Hg.
“I know I've confused you guys, again, with what an appropriate MAP threshold is. The debate is still not closed and probably still very much wide open,” Dr. Khanna said. “The answer is probably that a MAP of 65 mm Hg is not the one answer for everyone, and that precision medicine would demand more individualized MAP targets in future.”
There is slightly less debate about which vasopressor to use. “Norepinephrine does remain our drug of choice for septic shock, and for good reason,” he said. In the last decade, the drug won out in comparisons against epinephrine and dopamine, Dr. Khanna reported. “Epinephrine is still a very valid agent in case of a failing right ventricle or poor cardiac output situations, understanding that we're looking at lactic acidosis and increased tachycardia,” he noted.
More recent research has compared norepinephrine with vasopressin and found some benefits to the latter. The VANISH trial, published by JAMA in 2016, found no difference in survival among septic shock patients randomized to early vasopressin versus norepinephrine, but there was less renal replacement therapy with vasopressin. “Certainly something to think about, as a clinically useful outcome,” said Dr. Khanna.
Then there was the VANCS trial of postcardiac surgery patients with vasoplegic shock, published in Anesthesiology in 2017, which found less renal failure and atrial fibrillation with vasopressin than norepinephrine. “We know catecholamines tend to trigger more arrhythmias,” he said. “More evidence to suggest vasopressin is probably a slightly safer agent in some subsets of ICU populations.”
Dr. Khanna and other researchers are also looking at the potential of an alternative agent: angiotensin II. “The renin-angiotensin system is certainly that unexplored frontier of management of hypotension in the ICU,” he said.
Their double-blind, randomized, placebo-controlled trial, published in 2017 by NEJM, found that 70% of high-output shock patients treated with angiotensin II got to their MAP targets, although there was no difference in mortality. Post hoc analyses have shown faster liberation from renal replacement therapy, and improved survival in patients on renal replacement due to acute kidney injury, among other benefits, he noted.
“Most interestingly, we saw that patients who have low endogenous angiotensin II, that was an independent predictor of mortality. And when these patients were given exogenous angiotensin II, they tended to do better,” said Dr. Khanna. That's a positive finding, and a potential biological rationale to use the agent, but this therapy is in its early days, he noted. “Still a lot needs to be done, and further investigation will provide better answers.”
It's not surprising that recent trials of vasopressors have not shown improvements in mortality, because they never do, said Dr. Khanna. “Vasopressors have not directly influenced mortality in the ICU. They are instrumental in helping us to get hemodynamic stability, and buy time to fix the underlying etiology of shock, but not necessarily drive mortality,” he said. “Vasopressors in and of themselves may not be the reason for improved or poor survival in the ICU.”
That's one reason thought leaders are suggesting clinicians might want to ease up on their monotherapy and consider lower doses of individual agents as combination therapy. Dr. Khanna noted that he was a coauthor on an article titled, “Less Is More: Catecholamine-Sparing Strategies in Septic Shock,” published by Intensive Care Medicine last year. He and his coauthors suggested using adjuncts such as steroids, and newer vasopressors such as angiotensin II, in order to lessen patients' exposure to high-dose catecholamines.
“This might be the way forward as we look at evolution of the therapy in sepsis and septic shock,” he said. But then, illustrating how complicated the issue is, he also reminded the audience to give their patients multiple vasopressors for the best results. “Probably early multimodal therapy is going to be most beneficial and will achieve best results with minimal side effects.”