The 65 Trial: Less is More?

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Determining what MAP should be targeted.

An 85-year-old from a nursing home arrives with a blood pressure of 85/40 and a possible urinary tract infection. After a dose of antibiotics and 30 mL/kg of fluid she remains hypotensive so you start an infusion of norepinephrine. As you get up to see the next patient, the nurse asks “What mean arterial pressure (MAP) do you want me to target?”


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Why do we target a MAP of 65?

In 2012, the Surviving Sepsis guidelines recommended a target MAP of >65mmHg. These were given a strong consensus recommendation and widely adopted although they were based on a low grade of evidence.[[1]] This recommendation comes largely from expert opinion and appears to be heavily influenced from previous study protocols. In a review of 13 studies, Sevransky found that ~46% of protocols targeted a MAP between 65-70mmHg.[[2]]

Too much or not enough?


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Despite this robust recommendation, the available literature does not clearly show that targeting a MAP of 65mmHg results in any improved patient-oriented outcomes. In a retrospective analysis of 111 patients, Varpula et al. found that time spent below a MAP of 65mmHg during the first 48 hours in the ICU was the best predictor of 30-day mortality.

Unfortunately the authors did not control for overall severity of illness, which makes these findings difficult to interpret.[[3]] Looking beyond a specific targeted BP, there is little support for the theory that higher MAP targets result in improved outcomes with large prospective studies (SEPSISPAM and OVATION) failing to show any association between mortality and specific MAP targets. [[4],[5]]

Beyond the low level of evidence surrounding using a MAP of 65 as a target, some previous studies have found that targeting a higher MAP may be harmful in some cases.

In a retrospective analysis, Dünser et al. looked at patients with septic shock who had mean arterial pressures above 70mmHg. In a group of 290 patients there was no association between MAP >70 and 28-day mortality while there was a positive association between mean vasopressor load and rates of mortality and adverse events.[[6]] In a patient level meta-analysis of SEPSISPAM and OVATIAN, Lamontagne et al. did not find any increase in mortality or adverse events when lower MAP (60-70mmHG) were targeted. There was an increased risk of death when a higher MAP (75-85mmHG) was targeted in patients who had been on vasopressors for > 6 hours.[[7]]


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The 65 Trial

Published in February, the 65 trial examined whether allowing patients ≥65 years of age with vasodilatory hypotension to have permissive hypotension (MAP target 60-65mmHg) in an effort to limit vasopressor use would help reduce 90-day mortality.[[8]]

Across 65 ICUs in the UK, the authors randomized 2,600 patients into one of two groups. In the “permissive hypotension” group the MAP target was 60-65mmHg while patients in the “usual care” group were not given a MAP target and were treated “at the discretion of the treating clinician.”

Overall, the enrollment criteria and study protocols were simple. To be enrolled, patients had to be ≥65 years of age with vasodilatory hypotension, a diagnosis made by the treating clinician. Patients had to have adequate or ongoing fluid resuscitation — at the discretion of the clinician — with the expectation being that they would need vasopressors for ≥ six hours. Physicians were free to choose their own vasopressor and perform any other needed interventions.

The primary outcome was all-cause mortality at 90 days with a range of secondary outcomes looking at various endpoints including length of stay, adverse events and need for advanced respiratory and renal support.

Is 60 the New 65?

Overall, there was not a statistically significant difference between the usual care and permissive hypotension groups. At 90 days, the mortality for the permissive hypotension group was 41% compared to 43.8% in the patient who received usual care resulting in an absolute Risk Difference of -2.85%; 95% CI -6.75 to 1.05; P = 0.15.

From a treatment standpoint, fluid use was similar in both groups while patients in the permissive hypotension group received ~five fewer hours of vasopressors compared to those in the standard care groups (33 hours vs. 38 hours).

In terms of secondary outcomes, there were no differences in ICU length of stay, need for dialysis or advanced respiratory support. Across various subgroups of patients there were no notable differences except in patients who had a history of chronic hypertension. When treated with permissive hypotension, patients with chronic hypertension had a 90-day mortality of 38.2% compared to 44.3% in the usual care group resulting in an adjusted OR 0.67; 95% CI 0.51 to 0.88; p = 0.047.

From a basic pathophysiologic standpoint, patients with chronically elevated baseline blood pressures would seem to be most at risk from permissive hypotension yet in this study they appeared to benefit from this reduction in their MAP.  Although reaching statistical significance, it isn’t clear if these findings reflect a true benefit or if  they are a statistical fluke.

Out of the ICU and into the ED

Strictly speaking, this ICU-based study does not directly apply to our practice in the ED, but it does provide us with some important teaching points:

  1. Prolonged vasopressor use had no effect on adverse events

The results of the 65 trial call into question some of the findings from previous studies relating to potential risks associated with use of vasopressors or various blood pressure targets. Patients in both groups were exposed to higher than targeted MAPs with peaks ranging from 83mmHg – 92mmHg between the two groups. In contrast to previous studies prolonged exposure to vasopressors and elevated MAPs was not associated with an increase in adverse events. Similarly patient outcomes did not seem to change when vasopressor use was limited and lower MAPs were targeted.

 

  1. A MAP lower than current established guidelines wasn’t shown to be harmful and was even beneficial in certain patient subgroups

This study also gives some insight into the challenge of using resources appropriately while caring for critically ill patients. Targeting a specific MAP can be labor intensive and at best is an inexact science. Despite being part of a formal study group, patients in the permissive hypotension group had a MAP of 66.7mmHg that technically was outside their study parameters. In a busy ED the notion that we can precisely target a particular MAP is likely unrealistic.

 

Conclusion

Ultimately while failing to identify an ideal MAP target for patients with vasodilatory shock, the 65 Trial lends support to the principle of “less is more.” In a busy ICU or emergency department having a more relaxed approach to targeted MAPs would likely free up valuable resources. Rather than putting a patient through a potentially invasive procedure and increasing doses of vasopressors for a MAP < 65mmHG, the 65 trial tells us that allowing for some blood pressure variability is a safe and effective strategy.

 

Ideally future studies will help us identify more precise targets or clarify parameters for implementing permissive hypotension. For now, the 65 Trial tells us that it is time to give ourselves and our patients some room for variability when it comes to vasodilatory shock.

 

REFERENCES:

[1] Dellinger  RP, Levy  MM, Rhodes  A,  et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup.  Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.  Crit Care Med. 2013;41(2):580-637. doi:10.1097/CCM.0b013e31827e83af

[2] Sevransky JE, Nour S, Susla GM, Needham DM, Hollenberg S, Pronovost P. Hemodynamic goals in randomized clinical trials in patients with sepsis: a systematic review of the literature. Crit Care. 2007;11(3):R67. doi:10.1186/cc5948

[3] Varpula M, Tallgren M, Saukkonen K, et al: Hemodynamic variables related to outcome in septic shock. Intensive Care Med 2005; 31:1066–1071

[4] Asfar P, Meziani F, Hamel J, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173

[5] Lamontagne F, Meade M, Hébert P, et al. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42(4):542-550. doi:10.1007/s00134-016-4237-3

[6] Dünser MW, Ruokonen E, Pettilä V, et al. Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Crit Care. 2009;13(6):R181. doi:10.1186/cc8167

[7] Lamontagne F, Day A, Meade M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med. 2018;44(1):12-21. doi:10.1007/s00134-017-5016-5

[8] Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial [published online ahead of print, 2020 Feb 12]. JAMA. 2020;323(10):938-949. doi:10.1001/jama.2020.0930

ABOUT THE AUTHOR

Dr. DeLaney is an associate professor and the associate residency program director in the Department of Emergency Medicine at the University of Alabama at Birmingham. He is a co-host of Urgent Care Reviews and Perspectives and Lit Matters.

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