Mean arterial pressure, Elderly, Hypertension

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory HypotensionA Randomized Clinical Trial

François Lamontagne, MD^1,2; Alvin Richards-Belle, BSc³; Karen Thomas, MSc³; et al

Introduction-

Vasopressors are commonly administered
to patients in intensive care units (ICUs) to treat in order to prevent
hypotension associated myocardial injury, kidney injury, and death.
Vasopressors, however, may reduce blood flow in vasoconstricted vascular beds
and are associated with effects on cardiac, metabolic, microbiome, and immune
function. Balancing risks of hypotension with risks from vasopressors is,
therefore, a challenge when managing patients in ICUs.

Blood pressure is used to guide the administration of vasopressors. The norm is to use MAP as reference rather than SBP.

The 2012 Surviving Sepsis Campaign Guidelines recommended an initial mean arterial pressure (MAP) target of 65 mmHg with a higher target for older patients and for those with chronic hypertension and coronary artery disease.  Although the 2016 update acknowledged no evidence for targeting MAP values greater than 65 mmHg in any patient group, MAP values reported in observational studies are systematically higher than 65 mmHg, possibly because clinicians also use other targets.

What’s known so
far?

SEPSISPAM Trial – 2014 NEJM

Authors randomly assigned 776 patients with
septic shock to undergo resuscitation with a mean arterial pressure target of
either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group).
The primary end point was mortality at day 28. Targeting a mean arterial
pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with
septic shock undergoing resuscitation did not result in significant differences
in mortality at either 28 or 90 days. The occurrence of serious adverse events
did not differ significantly between the two groups (74 events [19.1%] and 69
events [17.8%], respectively; P=0.64). However, the incidence of newly
diagnosed atrial fibrillation was higher in the high-target group than in the
low-target group. Among patients with chronic hypertension, those in the
high-target group required less renal-replacement therapy than did those in the
low-target group, but such therapy was not associated with a difference in
mortality.

Ovation Trial 2016 Intensive Care Medicine
– Canadian Critical Care Group.

Optimal Vasopressor Titration (OVATION)
pilot trial was performed to inform the design of a larger trial examining the
effect of lower versus higher mean arterial pressure (MAP) targets for
vasopressor therapy in shock.

We randomly assigned critically ill
patients who were presumed to suffer from vasodilatory shock regardless of admission
diagnosis to a lower (60–65 mmHg) versus a higher (75–80 mmHg) MAP
target. The primary objective was to measure the separation in MAP between
groups.

A total of 118 patients were enrolled from
11 centres.

This pilot study supports the feasibility of a large trial comparing lower versus higher MAP targets for the shock.

Risks of cardiac arrhythmias (20 versus
36 %, p = 0.07) and hospital mortality (30 versus
33 %, p = 0.84) were not different between lower and
higher MAP arms. Among patients aged 75 years or older, a lower MAP target
was associated with reduced hospital mortality (13 versus 60 %, p = 0.03)
but not in younger patients.

The
Question?

What is the effect on mortality at 90
days of reducing the exposure to vasopressors through permissive hypotension
(mean arterial pressure target of 60-65mmHg) in intensive care unit (ICU)
patients aged 65 years or older receiving vasopressors for vasodilatory
hypotension?

Setting

The trial was conducted in 65 UK National
Health Service (NHS) adult, general lCUs across England, Wales, and Northern
Ireland.

Design

Open, multicenter, parallel group,
randomized clinical trial. Patients were allocated in a 1:1 ratio, via a concealed
central 24-hour telephone-web randomization system, to permissive hypotension
or usual care. Randomization was stratified by site using permuted blocks with
variable block lengths

Population

Inclusion criteria

Patients aged 65 years or older admitted to
a participating ICU were eligible if they were randomized within 6 hours of
commencing a vasopressor infusion.

Adequate fluid resuscitation (as assessed
by the treating clinician) was completed or ongoing and vasopressors were
expected to continue for 6 hours or more.

Excluded

Contraindication to permissive hypotension

Vasopressors being used solely for
bleeding, cardiac failure, post-CABGs vasoplegia

Treatment for brain or spinal cord injury

Death perceived as imminent

Previous enrolment in 65 trial

Intervention

Vasopressor administration was guided by a
MAP target of 60 to 65 mm Hg.

Control

Vasopressors were administered at the
discretion of treating clinicians

Common

Choice of vasopressor left to clinician
discretion (Norepinephrine, vasopressin, terlipressin, phenylephrine,
epinephrine, dopamine, and metaraminol)

All other interventions according to
clinician judgement

Sample size calculation based on a 90-day mortality of 35% for usual care. 90% power to detect a 6% absolute risk reduction (from 35–29%). 2600 patients (1300 per group) allowing a 2.5% withdrawal or loss to follow-up. (2/3 of the observed risk reduction observed in a previous meta-analysis).

The groups were well matched at baseline except
for the proportion of patients dependent on assistance for daily activities
(417 [34.4%] in permissive hypotension, 380 [30.9%] in usual care group). Mean
and peak MAPs were significantly different between groups. Significantly less
vasopressors in the permissive hypotension group.

Outcomes

Primary outcome:

90-d mortality: 500/1221 (41%) vs. 544/1242 943.8%). Absolute difference -2.85
(-6.75–1.05). Relative risk and odds ration not significantly different

Secondary outcomes

ICU mortality: 362/1212 (29.9%) vs. 380/1237 (30.7%) not different

Hospital mortality: 484/1232 (39.3%) vs. 519/1250 (41.5%) not different

Duration of survival at the longest
available follow-up

Duration of advanced respiratory and renal
support during ICU stay

Days alive and free of advanced respiratory
support in within first 28 d

Days alive and free of advanced renal
support within first 28 d

Duration of ICU stay

Duration of hospital stay

Cognitive decline in survivors at 90 days
and 1 year (assessed using the Informant Questionnaire on Cognitive Decline in
the Elderly (IQCODE, short version)

Health-related QOL among survivors at 90
days and 1 year [assessed using the EuroQoL 5- dimension 5-level (EQ-5D-5L)
questionnaire]

Pre-specified subgroup analysis:  for age, chronic hypertension, chronic heart
failure, atherosclerotic disease, ICNARC risk of death, Sepsis-3, and receipt
of vasopressors at randomization were conducted. (The tests for interaction
were not statistically significant for the subgroups defined by age, chronic
heart failure, atherosclerotic disease, predicted risk of death, sepsis status,
or vasopressor dose)

Chronic hypertension: Higher 90-d mortality
with usual care: permissive hypotension (38.2%) and usual care group (44.3%)

Post hoc analysis: hypertensive patients,
improved 90-d survival with permissive hypotension

Serious adverse events: no different

Strengths –

1. Multicentre
   Pragmatic RCT
2. First, it was set in a representative sample of 65 ICUs in NHS
   hospitals across the UK.
3. Site set-up was rapid, and the trial recruited 2600 patients in 21
   months with recruitment being 24 hours a day, 7 days a week.
4. Collateral benefits – use of “research without prior consent”
   model; nesting of the trial within routinely collected data (reducing burden);
   and the increasing maturity of the UK Critical Care Clinical Research Network,
   funding and enabling trained research nurses to deliver such trials.
5. Third, both cognitive decline and quality of life among survivors
   were assessed—important outcomes valued by patients.
6. The usual care comparator avoided risk of artificially increasing
   harm in the control group the population was enriched by enrolling older
   patients considered to have a greater chance of benefiting from the
   intervention.

Limitations –

1. Non-blinded
2. Non-consent
   and withdrawals were slightly higher.
3. no mechanistic data were collected, and attributable mortality was
   not adjudicated

Summary –

Practice changing trial

Challenged the dogma of more vasopressors for patients with chronic hypertension