Research

JAMA | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality

in Older Critically Ill Patients With Vasodilatory Hypotension
A Randomized Clinical Trial
François Lamontagne, MD; Alvin Richards-Belle, BSc; Karen Thomas, MSc; David A. Harrison, PhD;
M. Zia Sadique, PhD; Richard D. Grieve, PhD; Julie Camsooksai, BSc; Robert Darnell, BA; Anthony C. Gordon, MD;
Doreen Henry, MSc; Nicholas Hudson, BA; Alexina J. Mason, PhD; Michelle Saull, BSc; Chris Whitman, BSc;
J. Duncan Young, DM; Kathryn M. Rowan, PhD; Paul R. Mouncey, MSc; for the 65 trial investigators

Visual Abstract
IMPORTANCE Vasopressors are commonly administered to intensive care unit (ICU) patients Editorial
to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge,
particularly in older patients. Video and Supplemental
content
OBJECTIVE To determine whether reducing exposure to vasopressors through permissive
hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality
at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.

DESIGN, SETTING, AND PARTICIPANTS A multicenter, pragmatic, randomized clinical trial was
conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged
65 years or older with vasodilatory hypotension (assessed by treating clinician). The study
was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.

INTERVENTIONS Patients were randomized 1:1 to vasopressors guided either by MAP target
(60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the
discretion of treating clinicians) (n = 1307).

MAIN OUTCOME AND MEASURES The primary clinical outcome was all-cause mortality
at 90 days.

RESULTS Of 2600 randomized patients, after removal of those who declined or had
withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome
(mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive
hypotension group had lower exposure to vasopressors compared with those in the usual
care group (median duration 33 hours vs 38 hours; difference in medians, –5.0; 95% CI, –7.8
to –2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference
in medians, –8.7 mg; 95% CI, –12.8 to −4.6 mg). At 90 days, 500 of 1221 (41.0%) in the
permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died
(absolute risk difference, −2.85%; 95% CI, −6.75 to 1.05; P = .15) (unadjusted relative risk,
0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for
90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for
79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care
group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33
[2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).

CONCLUSIONS AND RELEVANCE Among patients 65 years or older receiving vasopressors for
vasodilatory hypotension, permissive hypotension compared with usual care did not result in
a statistically significant reduction in mortality at 90 days. However, the confidence interval Author Affiliations: Author
affiliations are listed at the end of this
around the point estimate for the primary outcome should be considered when interpreting
article.
the clinical importance of the study.
Group Information: 65 Trial
TRIAL REGISTRATION isrctn.org Identifier: ISRCTN10580502 investigators are listed at the end of
the article.
Corresponding Author: François
Lamontagne, MD, Université de
Sherbrooke, Sherbrooke, Quebec J1H
5N4, Canada (francois.lamontagne@
usherbrooke.ca).
Section Editor: Derek C. Angus, MD,
JAMA. doi:10.1001/jama.2020.0930 MPH, Associate Editor, JAMA
Published online February 12, 2020. (angusdc@upmc.edu).

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

V
asopressors are commonly administered to patients in
intensive care units (ICUs)1,2 to avoid hypotension as- Key Points
sociated with myocardial injury, kidney injury, and
Question What is the effect on mortality at 90 days of reducing
death.3,4 Vasopressors, however, may reduce blood flow in va- the exposure to vasopressors through permissive hypotension
soconstricted vascular beds and are associated with effects on (mean arterial pressure target of 60-65 mm Hg) in intensive care
cardiac, metabolic, microbiome, and immune function.5 Bal- unit (ICU) patients aged 65 years or older receiving vasopressors
ancing risks of hypotension with risks from vasopressors is, for vasodilatory hypotension?
therefore, a challenge when managing patients in ICUs. Findings In this randomized clinical trial that included 2600
Blood pressure is used to guide administration of vasopres- patients aged 65 years or older with vasodilatory hypotension,
sors. The 2012 Surviving Sepsis Campaign Guidelines recom- treatment with permissive hypotension resulted in death at 90 days
mended an initial mean arterial pressure (MAP) target of 65 among 41.0% of patients compared with 43.8% of those receiving
mm Hg with a higher target for older patients, and for those with usual care, a difference that was not statistically significant.
chronic hypertension and coronary artery disease.6 Although the Meaning Reducing the exposure to vasopressors through
2016 update7,8 acknowledged no evidence for targeting MAP val- permissive hypotension did not significantly reduce mortality at
ues greater than 65 mm Hg in any patient group, MAP values re- 90 days.
ported in observational studies are systematically higher than
65 mm Hg,9,10 possibly because clinicians also use other targets.
Results from an individual patient data meta-analysis of 2 posure to vasopressors prior to randomization) for vasodilatory
trials evaluating MAP targets, the SEPSISPAM (Sepsis and Mean hypotension, with adequate fluid resuscitation (as assessed by
Arterial Pressure) trial,11 and the OVATION (Optimal Vasopressor the treating clinician) completed or ongoing and vasopressors
Titration) pilot trial,12 suggest that increased exposure to were expected to continue for 6 hours or more. In an earlier ver-
vasopressors resulting from higher MAP targets is potentially sion of the protocol, randomization was permitted from the point
associated with an increased risk of death in a subgroup of older of making the decision to commence a vasopressor infusion
patients (≥65 years).13 In this subgroup, 28-day mortality was (Figure 1). Exclusion criteria included contraindications to per-
37.2% compared with 45.8% (odds ratio, 1.42; 95% CI, 0.98- missive hypotension (eMethods in Supplement 2).
2.04). This led to the biological rationale that greater exposure Screening was conducted by the clinical-research teams
to vasopressors may harm older patients by overwhelming their at each ICU. Randomization occurred as soon as possible once
more limited physiological reserve. eligibility was confirmed. Patients were allocated in a 1:1 ra-
This randomized clinical trial tested the hypothesis that tio, via a concealed central 24-hour telephone-web random-
reducing vasopressor exposure through permissive hypoten- ization system, to permissive hypotension or usual care. Ran-
sion (using a MAP target of 60-65 mm Hg) among patients domization was stratified by site using permuted blocks with
treated in the ICU aged 65 years or older with vasodilatory variable block lengths (of 4, 6, and 8).
hypotension and receiving vasopressors compared with usual
vasopressor exposure reduces 90-day mortality (Video). Trial Interventions
Patients in the permissive hypotension group received vasopres-
sors with administration guided by a MAP target of 60 to 65
mm Hg to reduce or discontinue exposure to vasopressors. The
Methods MAP target was reinforced through trial-specific prompts on in-
Trial Design and Oversight fusion pumps and in medical notes and setting of upper MAP
The 65 trial14 was a pragmatic, open, multicenter, parallel alarms. Patients in the usual care group received vasopressors at
group, randomized clinical trial. The South Central–Oxford C the discretion of treating clinicians allowing a more personalized
Research Ethics Committee and the United Kingdom Health approach (eg, in function of patient characteristics and markers
Research Authority approved the trial protocol, which is avail- of perfusion). Choice of vasopressor, as well as all other interven-
able in Supplement 1. The research ethics committee granted tions, were also at the discretion of treating clinicians. Norepi-
an emergency waiver of consent. The UK National Institute for nephrine, vasopressin, terlipressin, phenylephrine, epinephrine,
Health Research (NIHR) convened an independently chaired dopamine, and metaraminol were considered as vasopressors.
(and majority independent) trial steering committee and an in-
dependent data monitoring and ethics committee. The Clini- Monitoring of Adherence
cal Trials Unit at the UK Intensive Care National Audit & Adherence was defined as appropriate reduction in dose (or dis-
Research Centre (ICNARC) managed the trial. continuation) of vasopressors when the MAP was higher than
the upper target limit (65 mm Hg). Deviation was defined by fail-
Sites and Patients ure to reduce (or discontinue) vasopressors while the MAP re-
The trial was conducted in 65 UK National Health Service (NHS) mained higher than 65 mm Hg for 3 consecutive hours.
adult, general, ICUs that participate in the Case Mix Programme—
the national clinical audit for adult ICUs across England, Wales, Consent Procedures
and Northern Ireland. Patients aged 65 years or older admitted For patients who did not have the mental capacity to give ver-
to a participating ICU were eligible if they were randomized within bal consent prior to randomization, a “research without prior
6 hours of commencing a vasopressor infusion (to minimize ex- consent” approach was used. Agreement was obtained from

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 Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension Original Investigation Research

Figure 1. Screening, Randomization, and Follow-up of Patients in the 65 Trial

10 755 Patients ≥65 y with vasodilatory

hypotension and receiving
vasopressors assessed for eligibilitya

4271 Excluded
1808 Started vasopressor >6 h before
1482 Receiving <0.1 μg/kg/min noradrenaline
981 Expected to continue vasopressors >6 h

6484 Met inclusion criteria

3066 Met exclusion criteriab

1033 Ongoing treatment for brain injury
776 Vasopressors only for acute ventricular failure
690 Death appeared imminent
496 Vasopressors only for bleeding
131 Ongoing treatment for spinal cord injury
60 Previously enrolled in the 65 trial
32 Vasopressors only for postcardiopulmonary
bypass vasoplegia
330 Eligible did not undergo randomization
122 Needed higher MAP target
30 Treatment limitations on record
20 Refused consent
11 Family member refused consent
5 Enrolled in another study
142 Other reasons

2600 Randomized 2 Duplication patients (only first

randomization included in the analysis)

1291 Randomized to permissive hypotension 1307 Randomized to usual care

1291 Received treatment as randomized 1307 Received treatment as randomized

70 Withdrew or lost to follow-up 65 Withdrew or lost to follow-up

8 Requested all trial data be removed 7 Requested all trial data be removed
61 Refused retrospective consent 56 Refused retrospective consent
before 90 d before 90 d
1 Withdrew consent 1 Withdrew consent
1 Lost to follow-up

1221 Included in the primary analysis 1242 Included in the primary analysis
533 Returned 90-d questionnaire 493 Returned 90-d questionnaire a
As assessed by the treating clinician.
261 Returned 1-y questionnaire 255 Returned 1-y questionnaire b
Some patients met more than 1
criterion.

a personal or nominated consultee as soon as appropriate fol- related quality of life (QOL), assessed using the EuroQoL 5-
lowing randomization. Informed consent was obtained from dimension 5-level (EQ-5D-5L) questionnaire,16 in survivors, at
patients if they regained mental capacity. Data collected up to 90 days and 1 year. IQCODE scores are calculated as the mean
refusal or withdrawal of consent were retained. All proce- of the scores from the 16 items that range from 1 (much im-
dures are provided in the eMethods section in Supplement 2. proved) to 5 (much worse). The EQ-5D-5L utility scale ranges
from −0.285 to 1 with lower scores indicating worse health-
Outcome Measures related QOL, anchored at 0 (death) and 1 (perfect health). No
The primary outcome was all-cause mortality at 90 days after studies have been conducted to establish a minimally clini-
randomization. cally important difference (MCID) for critically ill patients aged
Secondary outcomes were mortality at discharge from ICU 65 years or older with vasodilatory hypotension on either the
and from the treating acute care hospital; duration of sur- IQCODE or EQ-5D-5L. Adverse events were monitored to ICU
vival to longest available follow-up; duration of advanced re- discharge. All definitions are in listed in the eMethods sec-
spiratory and renal support during ICU stay; days alive and free tion in Supplement 2. The integrated economic evaluation for
of advanced respiratory support and renal support within first the trial will be reported separately.
28 days; duration of ICU and treating acute care hospital stay;
cognitive decline assessed using the Informant Question- Data Collection
naire on Cognitive Decline in the Elderly (IQCODE, short Patients’ trial data were linked to both Case Mix Programme
version)15 in survivors at 90 days and 1 year; and health- data, including baseline data and ICU outcomes, and NHS death

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

registrations, for survival data. Data not contained in the Case sion for continuous outcomes (duration of advanced respira-
Mix Programme—such as hourly vasopressor dose and MAP— tory and renal support, days alive and free of advanced respi-
were collected prospectively. Detailed vasopressors and MAP ratory and renal support at day 28, duration of ICU and treating
data are based on the first episode of vasopressors, with the acute care hospital stay, cognitive decline, and health-related
end of an episode defined as a 24-hour period without re- QOL at 90 days and 1 year), Fisher exact test and multilevel
ceipt of vasopressors, discharge from the ICU, or death (which- logistic regression for binary outcomes (mortality at dis-
ever occurred first). Cognitive decline and health-related QOL charge from ICU and treating acute care hospital), and log-
were ascertained by mailed questionnaires, with telephone rank test and Cox proportional-hazard models with shared
follow-up. Follow-up for patient-reported 1-year outcomes was frailty at the site level for duration of survival from random-
stopped when the last patient reached 90 days. ization to longest available follow-up (proportionality was as-
sessed visually using Kaplan-Meier curves).
Statistical Analysis Prespecified, subgroup analyses of the primary outcome
Using Case Mix Programme data, the final sample size calcu- testing interactions for age, chronic hypertension, chronic heart
lation assumed a 90-day mortality of 35% for usual care with failure, atherosclerotic disease, ICNARC risk of death, 19
a 2.5% withdrawal or loss to follow-up; a sample size of 2600 Sepsis-3,20 and receipt of vasopressors at randomization were
patients (1300 per group) had 90% power to detect a 6% ab- conducted. Likelihood ratio tests were used to compare mod-
solute risk reduction—approximately two-thirds of the ob- els, with and without the relevant interaction terms. One sub-
served absolute risk reduction in the individual patient data group, chronic hypertension, was also tested (prespecified) for
meta-analysis13—to 29% for permissive hypotension. An ini- interaction with the effect of permissive hypotension across
tial sample-size calculation based on the same assumptions the in-hospital secondary outcomes.
but powered to detect an 8% absolute risk reduction was up- Missing values were imputed using multivariate imputa-
dated following the internal pilot phase on the recommenda- tion by chained equation (MICE)21 for all baseline variables in-
tion of the trial steering committee (eMethods in Supple- cluded in the adjusted model and for cognitive decline and
ment 2). A single interim analysis on the primary end point was health-related QOL at 90 days and at 1 year (in patients known
conducted after recruitment and 90-day follow-up of 500 pa- to be alive at each relevant time point). Models were fitted
tients, using a Peto-Haybittle stopping rule (P < .001) for early across all the imputed data sets and results combined using
termination due to either effectiveness or harm. the Rubin rules.22 Further details of variables considered for
Patients were analyzed according to their randomized imputation are provided in eTable 1 in Supplement 2. Stata/SE
group, following a prespecified statistical analysis plan.17 version 14.2 was used for all effectiveness analyses, and
A P value of less than .05 was considered statistically signifi- Stata/SE version 16.0 for multiple imputation (StataCorp LP).
cant. All tests were 2-sided with no adjustment for multiple Post hoc analyses included estimation of the absolute risk
comparisons. Doses for each vasopressor, except metarami- difference for the primary outcome adjusted for site only, using
nol, were converted to norepinephrine equivalents.18 a generalized estimating equations (GEE) model with a bino-
The Fisher exact test was used to compare between-group mial link and robust standard error estimates, estimation of
differences in the primary outcome. Absolute risk reduction is the adjusted relative risk for the primary outcome, adjusted
reported with 95% CIs without adjustment as the primary ef- for the same baseline variables as previously specified, and cal-
fect estimate. Secondary analyses of the primary outcome in- culation of the adjusted relative risk by prespecified sub-
cluded unadjusted relative risk reduction; and adjusted analy- groups, which was done using a GEE model with a Poisson link
sis (using multilevel logistic regression) for prespecified baseline and robust standard error estimates. Mortality at days 28 and
variables (age, sex, chronic hypertension, chronic heart fail- 60 was also reported as a binary outcome using only patients
ure, atherosclerotic disease, dependency on assistance for daily with nonmissing primary outcome data.
activities, location prior to ICU admission and urgency of sur-
gery, ICNARC physiology score,19 Sepsis-3,20 receipt of vaso-
pressors at randomization, and duration of vasopressors prior
to randomization), and site (as a random effect). Sensitivity
Results
analyses repeating the primary analysis including only pa- Sites and Patients
tients deemed eligible in the final version of the protocol; best- Across 65 sites, a total of 10 755 patients aged 65 years or older
and worst-case scenario analysis assuming all patients with with vasodilatory hypotension and receiving vasopressors were
missing primary outcome data had survived if randomized to screened and 6484 deemed to have met the inclusion crite-
permissive hypotension and died if randomized to usual care, ria. After applying the exclusion criteria, 2930 were poten-
and vice versa; and adherence-adjusted analysis defining ad- tially eligible and 2600 were enrolled between July 3, 2017, and
herence as a binary variable, 0 for all patients allocated to per- March 16, 2019. Two patients were randomized twice (in error)
missive hypotension with 1 or more deviation, or 1 if not, and leaving 2598 unique patients (1291 permissive hypotension,
using a structural mean model with an instrumental variable 1307 usual care) (Figure 1; and eFigures 1 and 2 in Supple-
of allocated treatment to estimate the complier average causal ment 2). Randomization occurred 24 hours a day, 7 days a week
effect of treatment. (eFigure 3 in Supplement 2). Deferred consent was used, and
Secondary outcomes were analyzed using unadjusted retrospective consent was obtained for 2461 (95%) of pa-
t tests or Wilcoxon rank sum test and multilevel linear regres- tients (eFigures 4 and 5 in Supplement 2), of whom 2 later

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 Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension Original Investigation Research

Table 1. Patient Baseline Characteristics

No./Total (%) of Patients

Permissive Hypotension Usual Care
Characteristic (n = 1283)a (n = 1300)a
Age, median (IQR), y 75.2 (70.4-80.5) 74.8 (70.1-80.8) Abbreviations: ICU, intensive care
unit; IQR, interquartile range.
Sex a
Excludes 15 patients who refused
Women 520/1216 (42.8) 547/1239 (44.1) permission of data use.
Men 696/1216 (57.2) 692/1239 (55.8) b
Comorbidities were selected a priori
Comorbiditiesb because they may constitute effect
modifiers.
Chronic hypertension 590/1283 (46.0) 597/1299 (46.0)
c
The Acute Physiology and Chronic
Atherosclerotic disease 187/1283 (14.6) 189/1299 (14.5)
Health Evaluation (APACHE) II score
Chronic heart failure 143/1283 (11.1) 143/1298 (11.0) (range, 0-71; higher scores indicate
Chronic renal replacement therapy at ICU admission 16/1204 (1.3) 18/1224 (1.5) greater severity) was calculated
using physiology readings in the
Daily activities status before admission to acute hospital
first 24 hours of ICU admission.23
No assistance 794/1211 (65.6) 850/1230 (69.1) d
The Intensive Care National Audit &
Minor or major assistance 409/1211 (33.8) 375/1230 (30.5) Research Centre (ICNARC) score
Total assistance with all activities 8/1211 (0.7) 5/1230 (0.4) (range, 0-100; higher scores indicate
greater severity) was calculated using
Location prior to ICU admission and urgency of surgery
physiology readings in the first 24
Emergency department and not in hospital 432/1219 (35.4) 420/1239 (33.9) hours of ICU admission.24
Operating room e
ICNARCH-2015 predicted risk is
Elective and scheduled surgery 53/1219 (4.3) 60/1239 (4.8) calculated using physiology reading
in the first 24 hours of ICU
Emergency and urgent surgery 259/1219 (21.2) 264/1239 (21.3)
admission with age, comorbidities,
Other ICU 14/1219 (1.1) 22/1239 (1.8) dependency, and location before
Ward or intermediate care area 461/1219 (37.8) 473/1239 (38.2) and reason for admission.
f
APACHE II score, mean (SD) [No.]c 20.9 (6.5) [1218] 20.6 (6.1) [1239] Sepsis-3 criteria requires evidence
of infection and 2 or more points on
ICNARC physiology score, mean (SD) [No.]d, 23.9 (8.8) [1213] 23.5 (8.8) [1239] the Sequential Organ Failure
ICNARCH-2015 predicted risk of death, median (IQR) [No.]e 0.33 (0.15-0.60) [1213] 0.32 (0.14-0.61) [1239] Assessment (SOFA) score, which is
Sepsis-3f based on data in the first 24 hours
of ICU admission.
No sepsis 263/1216 (21.6) 275/1239 (22.2) g
Patients starting vasopressors or
Sepsis (not in shock) 364/1216 (29.9) 369/1239 (29.8) receiving metaraminol or
Septic shock 589/1216 (48.4) 595/1239 (48.0) terlipressin boluses could be
Mean arterial pressure at randomization, mm Hgg, recruited for the protocol’s version
2.0, which specified their starting a
Mean (SD) 69.9 (10.1) 71.1 (11.5) vasopressor infusion at least 1 hour
Median (IQR) [No.] 69 (64-75) [1281] 70 (64-77) [1300] before randomization.
h
Vasopressor infusion(s) received at time of randomization Norepinephrine equivalent doses
were calculated according to the
Norepinephrine only 761/1265 (60.2) 766/1280 (59.8)
method described in Khanna et al,18
Metaraminol only 406/1265 (32.1) 409/1280 (32.0) using the conversion factors:
Phenylephrine only 37/1265 (2.9) 38/1280 (3.0) epinephrine μg/kg/min (× 1),
dopamine μg/kg/min (/150),
Epinephrine only 3/1265 (0.2) 5/1280 (0.4)
phenylephrine μg/kg/min (× 0.1)
Vasopressin only 0/1265 (0.0) 2/1280 (0.2) and vasopressin U min –1 ( × 2.5).
Dopamine only 0/1265 (0.0) 1/1280 (0.1) i
Both groups had 118 patients
Other or combination 43/1265 (3.4) 34/1280 (2.7) receiving less than 0.1 μg/kg/min of
norepinephrine were eligible for
Noneg 15/1265 (1.2) 25/1280 (2.0)
recruitment prior to the protocol’s
Norepinephrine equivalent doseh version 2.0, which specified that, for
<0.1 μg/kg/mini 153/1265 (12.1) 155/1280 (12.1) patients receiving norepinephrine,
then they must fulfill a minimum
≥0.1 μg/kg/min 676/1265 (53.4) 677/1280 (52.9)
dose of 0.1 μg/kg/min at the time of
Duration of vasopressor infusion prior to randomization, 186 (102-277) [1247] 186 (104-284) [1262] randomization. A minimum dose was
median (IQR), min [No.]j not required for other vasopressors.

withdrew consent, and 1 was lost to follow-up by 90 days, leav- The randomized groups were well matched at baseline
ing 2458 patients. Five patients declined retrospective con- (Table 1), except for the proportion of patients dependent on
sent after 90 days and were included in the analysis until that assistance for daily activities (417 [34.4%] in permissive hy-
point. As a result, 2463 patients (1221 permissive hypoten- potension, 380 [30.9%] in usual care group). Immediately prior
sion, 1242 usual care) were included in the analysis of the pri- to randomization, the mean MAP was 69.9 mm Hg in the per-
mary outcome. Follow-up was completed in August 2019. missive hypotension and 71.1 mm Hg in the usual care group.

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

Table 2. Vasopressor Use After Randomization by Group

Permissive Hypotension Usual Care Difference
(n = 1261)a (n = 1276)a (95% CI)
Total duration of vasopressors 33.0 (15.0 to 56.0) 38.0 (19.0 to 67.0) –5.0 (–7.8 to –2.2)
after randomization,
median (IQR), h
Vasopressor usage, No. (%)
Norepinephrine 992 (78.7) 997 (78.1) 0.9 (−2.3 to 4.1)
Metaraminol 395 (31.3) 418 (32.8) −1.3 (−4.9 to 2.4)
Vasopressin 123 (9.8) 126 (9.9) −0.1 (−2.4 to 2.3)
Epinephrine 40 (3.2) 42 (3.3) −0.1 (−1.5 to 1.3)
Phenylephrine 32 (2.5) 33 (2.6) −0.0 (−1.3 to 1.2)
Terlipressin 10 (0.8) 14 (1.1) −0.3 (−1.1 to 0.5)
Dopamine 1 (0.1) 2 (0.2) −0.1 (−0.3 to 0.2)
Norepinephrine equivalentsb
Total dose, mg
Median (IQR) [No.] 17.7 (5.8 to 47.2) [1008] 26.4 (8.9 to 65.6) [1021] −8.7 (−12.8 to −4.6)
Mean dose rate, μg kg−1 min−1
Median (IQR) 0.12 (0.06 to 0.23) 0.15 (0.08 to 0.26) −0.03 (−0.04 to −0.02)
Highest dose rate, μg kg−1 min−1
Median (IQR) 0.26 (0.13 to 0.57) 0.32 (0.16 to 0.63) −0.06 (−0.09 to −0.02)
Metaraminolb
Total dose, mg
Median (IQR) [No.] 22.0 (9.3 to 60.0) [395] 35.0 (12.7 to 79.8) [420] −13.0 (−19.5 to −6.5)
Mean dose rate, mg h−1
Abbreviations: IQR, interquartile
Median (IQR) 2.35 (1.44 to 4.25) 2.83 (1.95 to 4.88) −0.48 (−0.78 to −0.18) range; MAP, mean arterial pressure.
Highest dose rate, mg h−1 a
Total number of patients with
Median (IQR) 4.00 (3.00 to 6.50) 5.00 (3.50 to 7.00) −1.00 (−1.48 to −0.52) treatment data recorded until
completion of the first treatment
Terlipressin
episode. In the permissive
Total dose, U hypotension group, the proportions
Median (IQR) [No.] 2.5 (1.0 to 10.8) [10] 3.3 (1.0 to 6.0) [14] −0.8 (−8.5 to 6.9) of the way in which the first episode
ended were 72.8% were free of
Time receiving vasopressor
vasopressors for 24 continuous
with recorded MAP
hours, 11.0% were discharged from
≤65 mm Hgc
ICU prior to being free of
Median (IQR) h 12 (5 to 25) 6 (2 to 13) vasopressors for 24 continuous
>65 mm Hgc hours, and 16.2% died while
receiving vasopressors. In the usual
Median (IQR) h 12 (5 to 25) 27 (13 to 49)
care group, the same proportions
Mean MAP while receiving were 69.0%, 12.3%, and 18.7%,
vasopressors, mm Hgd respectively.
Median (IQR) [No.] 66.7 (64.5 to 69.8) [1247] 72.6 (69.4 to 76.5) [1267] −5.9 (−6.4 to −5.5) b
See eFigure 6 in Supplement 2.
Peak MAP while receiving c
See eFigure 9 in Supplement 2.
vasopressors, mm Hgd
d
See eFigures 8 and 10 in
Median (IQR) 83.0 (75.0 to 92.0) 92.0 (85.0 to 100.0) −9.0 (−10.4 to −7.6)
Supplement 2.

Clinical Management and eFigure 10 in Supplement 2). The number of episodes of va-
Patients in the permissive hypotension group had a lower ex- sopressors were not significantly different between groups, with
posure to vasopressors compared with those in the usual care 86.8% of patients in the permissive hypotension and 86.3% in
group—median duration 33 hours compared with 38 hours (dif- the usual care group having a single episode.
ference, –5.0; 95% CI, –7.8 to –2.2), mean duration, 46.0 hours
compared with 55.9 hours (mean difference, –9.9 hours; 95% Adherence to Protocol
CI, –14.3 to –5.5), and median total dose (norepinephrine equiva- The number of patients with one or more occurrence of non-
lent), 17.7 mg compared with 26.4 mg (difference, –8.7 mg; 95% adherence was 153 (11.3%) (permissive hypotension group).
CI, –12.8 to –4.6 mg) (Table 2; eTable 2 and eFigures 6 and 7 in Overall, nonadherence represented 6% of the total time receiv-
Supplement 2). Clinical management diverged immediately af- ing vasopressors. The main reasons for nonadherence were
ter randomization (eFigure 8 in Supplement 2), and there was concerns regarding the patient’s clinical condition (renal, 36;
a clear difference in management of vasopressors between the cardiac, 4; history of chronic hypertension, 2; gastrointesti-
groups (eFigure 9 in Supplement 2). Mean and peak MAP val- nal, 2; other, 7); and logistical staff-related issues (trial aware-
ues were lower in the permissive hypotension group (Table 2; ness, 54; other clinical priorities, 42; no reason documented, 6).

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 Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension Original Investigation Research

Table 3. Primary and Secondary Mortality Outcomes

No./Total (%)
Unadjusted Unadjusted Relative Adjusted Difference
Outcome Intervention Group Usual Care Group Absolute Difference P Value Difference (95% CI) (95% CI)a
Primary Outcome
90-d mortality 500/1221 (41.0) 544/1242 (43.8) −2.85 (−6.75 to 1.05) .15
Relative risk 0.93 (0.85 to 1.03) 0.92 (0.83 to 1.01)b
Odds ratio 0.89 (0.76 to 1.04) 0.82 (0.68 to 0.98)
Secondary Outcomes
Discharge mortality
ICU 362/1212 (29.9) 380/1237 (30.7) −0.85 (−4.49 to 2.79) .66
Relative risk 0.97 (0.86 to 1.10) 0.95 (0.78 to 1.17)b
Odds ratio 0.96 (0.81 to 1.14) 0.90 (0.73 to 1.10)
Acute hospital 484/1232 (39.3) 519/1250 (41.5) −2.23 (−6.09 to 1.63) .27
Relative risk 0.95 (0.86 to 1.04) 0.94 (0.85 to 1.03)b
Odds ratio 0.91 (0.78 to 1.07) 0.86 (0.71 to 1.03)
Abbreviation: ICU, intensive care unit. Intensive Care National Audit & Research Centre (ICNARC) physiology score,
a
Adjusted for age, sex, comorbidities, prior dependency, vasopressor infusions Sepsis-3, and random effect of site. For comparison, the unadjusted OR for the
received at randomization, duration of vasopressor infusion prior to primary outcome is 0.89 (95% CI, 0.76-1.04).
b
randomization, location prior to admission to ICU and urgency of surgery, Post hoc analysis.

Figure 2. Kaplan-Meier Survival Curves

0.5
Usual care
Permissive hypotension
0.4

All randomized patients are included

when calculating survival, excluding
0.3
Mortality

8 patients in the permissive

hypotension group and 7 in the usual
care group who did not consent to
0.2
the trial and refused permission for
data use. Other surviving patients
were censored at the last known date
0.1
alive or at date of withdrawal or
Unadjusted HR, 0.96 (95% CI, 0.86-1.07) refusal of consent (from whom trial
Adjusted HR, 0.94 (95% CI, 0.84-1.05) consent was not obtained). The
0
0 1 2 3 4 5 6 7 8 9 10 11 12 median follow-up time (using the
Months reverse Kaplan-Meier method) was
14.3 months (interquartile range
No. at risk
Permissive hypotension 1283 794 743 721 699 667 631 596 545 509 480 442 409 [IQR], 8.8-19.3) for the permissive
Usual care 1300 772 727 697 677 642 604 569 525 489 459 435 395 hypotension group and 14.2 months
(IQR, 8.5-19.4) for the usual care
group. HR indicates hazard ratio.

Targeting a lower MAP in the permissive hypotension group did lute risk difference, −2.85%, 95% CI, −6.75 to 1.05; P = .15).
not significantly increase the number of hours with MAP val- When adjusted for prespecified baseline variables, the odds
ues lower than 60 mm Hg (eFigure 9 in Supplement 2). ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98) com-
pared with an unadjusted odds ratio of 0.89 (95% CI, 0.76 to
Cointerventions 1.04) (Table 3). For each baseline variable that was used in the
During the first episode of vasopressors, there was no clinically adjusted analysis, data were missing for fewer than 0.1% of pa-
important difference in fluid balance, urine output, or the use tients (eTable 1 in Supplement 2). Best- and worst-case sensi-
of pure inotropes. Corticosteroids were administered to 31.6% tivity analyses yielded unadjusted odds ratios of 0.74 (95% CI,
of patients in the permissive hypotension and 33.9% in the usual 0.63 to 0.87) and 1.08 (0.93 to 1.27), respectively. Adherence-
care group (eFigure 11 and eTables 3 and 4 in Supplement 2). adjusted analysis did not alter the primary results (eTable 5 in
Supplement 2).
Effectiveness Mortality at ICU and treating acute care hospital dis-
At 90 days, there was no statistically significant difference in charge were not significantly different, and there was no sig-
all-cause mortality, with 500 deaths (41.0%) among of 1221 pa- nificant difference in time to death between groups (adjusted
tients in the permissive hypotension group compared with 544 hazard ratio, 0.94; 95% CI, 0.84 to 1.05; Figure 2). The mean
(43.8%) among 1242 patients in the usual care group (abso- duration of ICU and treating acute care hospital stay and

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

Table 4. Secondary Outcomes

Unadjusted Adjusted Mean Difference
Intervention Group Usual Care Absolute Difference P Value (95% CI)
Advanced Respiratory Supporta
Receipt, No./total (%) 708/1218 (58.1) 691/1239 (55.8)
Duration among those 4 (2 to 10) 4 (2 to 10) 0.0 (-0.7 to 0.7) .64
receiving support,
median (IQR), d
Duration among all patients, 4.5 (8.3) 4.8 (10.0) −0.3 (−1.1 to 0.4) .40 −0.3 (−1.0 to 0.4)
mean (SD), d
Days alive and free of advanced 15.7 (12.8) 15.1 (13.0) 0.6 (−0.4 to 1.7) .26 0.9 (0.0 to 1.8)
respiratory support to day 28,
mean (SD)
Renal Supportb
Receipt, No./total (%) 302/1218 (24.8) 306/1239 (24.7)
Duration among those receiving 4 (2 to 7) 4 (2 to 8) 0.0 (-1.1 to 1.1) .93
support, median (IQR), d
Duration among all patients, 1.4 (3.6) 1.5 (4.1) −0.1 (−0.4 to 0.2) .47 −0.2 (−0.4 to 0.1)
mean (SD), d
Days alive and free of renal 17.4 (13.2) 16.7 (13.4) 0.6 (−0.4 to 1.7) .25 0.9 (0.0 to 1.9)
support to day 28, mean (SD)
Duration of ICU Stay, Median (IQR) [No. of Patients], d
Survivors 5.2 (2.9 to 10.5) [850] 5.4 (3.0 to 9.9) [865] −0.2 (−0.7 to 0.3) .61
Nonsurvivors 3.2 (0.9 to 8.1) [632] 2.7 (0.9 to 8.7) [380] 0.5 (−0.4 to 1.4) .97
Duration of Acute Hospital Stay, Median (IQR) [No. of Patients], d
Survivors 18 (10 to 34) [732] 18 (10 to 36) [721] 0 (−2.1 to 2.1) .27
Nonsurvivors 6 (1 to 15) [484] 5 (1 to 14.5) [519] 1 (−0.8 to 2.8) .92
Cognitive Decline (IQCODE Score) Among Survivors, Mean (SD) [No. of Patients]c
At 90 d 2.97 (0.72) [497] 2.99 (0.76) [458] −0.01 (−0.09 to 0.07) .80 −0.01 (−0.09 to 0.07)
At 1 y 2.93 (0.81) [254] 2.80 (0.96) [247] 0.13 (−0.00 to 0.25) .05 0.12 (−0.00 to 0.25)
Health-Related QOL (EQ-5D-5L Utility Score) Among Survivors, Mean (SD) [No. of Patients]d
At 90 d 0.677 (0.274) [504] 0.683 (0.272) [464] −0.006 (−0.038 to 0.026) .71 −0.000 (−0.031 to 0.031)
At 1 y 0.706 (0.264) [253] 0.716 (0.245) [241] −0.010 (−0.050 to 0.030) .62 −0.011 (−0.050 to 0.028)
Safety Monitoring, No/Total (%)
Any serious adverse evente 79/1283 (6.2) 75/1300 (5.8)
Abbreviations: EQ-5D-5L, European quality of life-5 dimensions 5-level scores on the 16 items and range from 1 (much improved) to 5 (much worse).
questionnaire; ICU, intensive care unit; IQCODE, Informant Questionnaire on No studies have been conducted to establish a minimum clinical important
Cognitive Decline in the Elderly; IQR, interquartile range. difference (MCID) for critically ill patients aged 65 years or older with
a
Defined as receiving 1 or more of the following: invasive mechanical vasodilatory hypotension. Patients without completed IQCODE data had
ventilatory support applied via a translaryngeal tube or applied via a missing data imputed.
d
tracheostomy; BPAP (bilevel positive airway pressure) applied via a Utility scale ranges from −0.285 to 1 with lower scores indicating worse
translaryngeal tracheal tube or via a tracheostomy; CPAP (continuous positive health-related QOL. The scale is anchored at 0 (death) and 1 (perfect health).
airway pressure) via a translaryngeal tracheal tube; extracorporeal respiratory Health utilities were assigned using the EQ-5D-5L value set for England.25 No
support. Mask or hood CPAP or BPAP and high–flow nasal canula are not studies have been conducted to establish an MCID for critically ill patients
considered advanced respiratory support. aged 65 years or older with vasodilatory hypotension. Patients without
b
Either receiving acute renal replacement therapy (eg, hemodialysis, completed EQ-5D-5L data had missing data imputed.
e
hemofiltration etc) or renal replacement therapy for chronic renal failure. See the Methods section for the most serious adverse events.
c
Cognitive decline scores on the IQCODE are calculated as the mean of the

duration and days alive and free from advanced respiratory and potension, 41; usual care, 33), supraventricular cardiac ar-
renal support to day 28 were not significantly different be- rhythmia (permissive hypotension, 12; usual care, 13),
tween groups. Cognitive decline (IQCODE) and health- ventricular cardiac arrhythmia (permissive hypotension, 12;
related QOL (EQ-5D-5L) scores also were not significantly dif- usual care, 5), myocardial injury (permissive hypotension, 8;
ferent between groups at 90 days or at 1 year (Table 4; and usual care, 12), mesenteric ischemia (permissive hypoten-
eFigure 12 and eTables 6 and 7 in Supplement 2). sion, 8; usual care, 12), and cardiac arrest (permissive hypo-
The number of serious adverse events was not signifi- tension, 11; usual care, 10).
cantly different between groups with 79 patients (6.2%) hav- The tests for interaction were not statistically significant for
ing a serious adverse event in the permissive hypotension com- the subgroups defined by age, chronic heart failure, atheroscle-
pared to 75 (5.8%) in the usual care group (Table 4 and eTable 8 rotic disease, predicted risk of death, sepsis status, or vasopres-
in Supplement 2). The most commonly reported serious ad- sor dose (Figure 3). However, for the chronic hypertension sub-
verse events were severe acute renal failure (permissive hy- group, the difference in 90-day mortality observed between the

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 Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension Original Investigation Research

Figure 3. Subgroup Analyses of the Primary Outcome

90-d Mortality, No./Total (%) Post Hoc Planned Analysis Favors Favors
Permissive Analysis Relative P Value for Odds Ratio Permissive Usual P Value for
Subgroup Hypotension Usual Care Risk (95% CI)a Interactionb (95% CI)a Hypotension Care Interactionc
Age (quintiles), y
65-69d 108/289 (37.4) 124/304 (40.8) 0.93 (0.78-1.13) 0.87 (0.60-1.27)
70-72 62/194 (32.0) 70/224 (31.3) 1.06 (0.83-1.35) 1.13 (0.71-1.81)
73-77 127/304 (41.8) 121/274 (44.2) 0.89 (0.73-1.08) .13 0.76 (0.52-1.11) .11e
78-82 115/243 (47.3) 111/219 (50.7) 0.90 (0.77-1.06) 0.72 (0.48-1.10)
>82 88/191 (46.1) 118/221 (53.4) 0.84 (0.69-1.02) 0.66 (0.43-1.01)
Chronic hypertension
No 286/661 (43.3) 291/671 (43.4) 0.98 (0.88-1.11) 0.97 (0.76-1.24)
.12 .047
Yes 214/560 (38.2) 253/571 (44.3) 0.84 (0.71-0.99) 0.67 (0.51-0.88)
Chronic heart failure
No 431/1085 (39.7) 467/1104 (42.3) 0.92 (0.83-1.02) 0.82 (0.68-1.00)
.69 .81
Yes 69/136 (50.7) 77/137 (56.2) 0.88 (0.72-1.08) 0.77 (0.45-1.31)
Atherosclerotic disease
No 424/1047 (40.5) 458/1062 (43.1) 0.90 (0.82-1.00) 0.79 (0.65-0.96)
.34 .38
Yes 76/174 (43.7) 86/180 (47.8) 0.99 (0.82-1.21) 1.00 (0.62-1.60)
Predicted risk of death (quintiles)
<0.11 33/238 (13.9) 34/252 (13.5) 1.01 (0.67-1.53) 0.99 (0.59-1.68)
0.11-0.24 55/240 (22.9) 63/250 (25.2) 0.90 (0.69-1.18) 0.86 (0.56-1.31)
0.24-0.42 79/234 (33.8) 114/257 (44.4) 0.76 (0.60-0.97) .88 0.63 (0.43-0.92) .69f
0.42-0.68 135/259 (52.1) 124/231 (53.7) 1.00 (0.84-1.19) 0.99 (0.69-1.43)
>0.68 195/242 (80.6) 209/248 (84.3) 0.94 (0.87-1.02) 0.75 (0.47-1.21)
Sepsis-3
No sepsis 124/263 (47.1) 117/275 (42.5) 1.04 (0.85-1.26) 1.15 (0.77-1.71)
Sepsis 112/364 (30.8) 138/368 (37.5) 0.77 (0.63-0.95) .07 0.62 (0.44-0.86) .06
Septic shock 262/589 (44.5) 289/595 (48.6) 0.94 (0.84-1.04) 0.83 (0.64-1.08)
Infusion at randomizationg
None 7/15 (46.7) 9/22 (40.9) 1.20 (0.70-2.05) 1.61 (0.35-7.54)
Norepinephrine, μg/kg/min
<0.1 44/142 (31.0) 57/148 (38.5) 0.77 (0.57-1.03) 0.63 (0.36-1.09)
.45 .36
≥0.1 308/648 (47.5) 324/653 (49.6) 0.96 (0.86-1.06) 0.88 (0.69-1.13)
Metaraminol 131/385 (34.0) 139/387 (35.9) 0.89 (0.73-1.09) 0.80 (0.57-1.11)
Other/combination 5/15 (33.3) 8/13 (61.5) 0.61 (0.28-1.31) 0.20 (0.03-1.25)

0.1 1 8
Odds Ratio (95% CI)

a e
Adjusted for age, sex, comorbidities, prior dependency, vasopressor infusions Test of continuous linear interaction with age: adjusted OR, 0.82 (95% CI,
received at randomization, duration of vasopressor infusion prior to 0.69-0.99) at age 75 years (mean value), interaction OR, 0.90 (95% CI,
randomization, location prior to admission to intensive care unit (ICU) or 0.78-1.02) per 5-year increase in age.
urgency of surgery, Intensive Care National Audit & Research Centre f
Test of continuous linear interaction with predicted log odds of acute hospital
physiology score, Sepsis-3, and random effect of site. mortality: adjusted OR, 0.82 (95% CI, 0.68 to 0.99) at predicted log odds of
b
P value for test of interactions of risk ratio in adjusted generalized estimating –0.64 (mean value) (predicted risk of 35%), interaction OR, 0.97 (95% CI,
equation (GEE) Poisson regression model. 0.84-1.12) per increase of 1 in predicted log odds.
c g
P value for test of interactions in the odds ratio (OR) in adjusted multilevel Norepinephrine equivalent doses were calculated according to the method
logistic regression model. described in Khanna et al,18 using the following conversion factors:
d
Three patients in the usual care group were identified after randomization to epinephrine μg/kg/min (× 1), dopamine μg/kg/min (/150), phenylephrine
be younger than 65 years and are included in this subgroup. μg/kg/min (× 0.1), and vasopressin U min –1 ( × 2.5).

permissive hypotension (38.2%) and usual care group (44.3%) CI, −7.00 to 1.36), consistent with the primary effect esti-
was more pronounced (adjusted odds ratio, 0.67; 95% CI, 0.49- mate. In addition to the prespecified subgroup analyses of the
0.85) than for patients without chronic hypertension (43.3% vs primary outcome (adjusted odds ratios), adjusted relative risks
43.4%; adjusted odds ratio, 0.97; 95% CI, 0.73-1.21; test of in- were also calculated. The relative risks for 90-day mortality
teraction, P = .047, not adjusted for multiple testing). Second- were consistent with the odds ratios. In patients with chronic
ary outcomes for patients with and without chronic hyperten- hypertension, the adjusted relative risk was 0.84 (95% CI, 0.71
sion are detailed in eTable 9 in Supplement 2. to 0.99) and in patients without chronic hypertension, the ad-
justed Sepsis-3 was 0.98 (95% CI, 0.88 to 1.11); test of interac-
Post Hoc Analyses tion, P = .12, not adjusted for multiple testing (Figure 3). Mor-
Adjustment of the primary outcome model for the effect of site tality at 28 and 60 days can also be found in eTable 10 in
(only) resulted in an absolute risk difference of −2.82% (95% Supplement 2.

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

use of renal replacement therapy was not increased in pa-

Discussion tients with chronic hypertension randomized to a lower MAP
target group. The suggestion of a greater benefit associated with
In this multicenter, pragmatic, randomized clinical trial, among permissive hypotension in patients with chronic hyperten-
patients aged 65 years or older, receiving vasopressors for va- sion, compared with those without, should be interpreted with
sodilatory hypotension, permissive hypotension compared caution. Significant subgroup comparisons with no adjust-
with usual care did not result in a statistically significantly re- ment for multiple testing alongside a nonsignificant primary
duction in mortality at 90 days. The absolute reduction in analysis must be deemed exploratory. Although this suggests
90-day mortality associated with permissive hypotension was that it may be safe to tolerate lower MAP, even in patients with
2.9% with 95% CI, from a 6.8% reduction to a 1.1% increase. chronic hypertension, further research is required to better un-
This trial has several strengths. First, it was set in a repre- derstand the interaction between this chronic comorbidity and
sentative sample of 65 ICUs in NHS hospitals across the UK. vasopressors. In future studies, consideration should be given
Second, site set-up was rapid, and the trial recruited 2600 to the fact that blood pressure may vary considerably among
patients in 21 months with recruitment being 24 hours a day, patients identified as chronically hypertensive and that pa-
7 days a week. Sites embedded the trial within routine clini- tients identified as being normotensive may experience un-
cal care due to a simple intervention delivered by bedside recognized severe hypertension. In addition, patients who ex-
nurses; a use of “research without prior consent” model; perience chronic hypertension are also at risk of other
nesting of the trial within routinely collected data (reducing comorbidities potentially rendering them more vulnerable to
burden); and the increasing maturity of the UK Critical Care vasopressor-induced adverse effects.
Clinical Research Network, funding and enabling trained
research nurses to deliver such trials. Third, both cognitive Limitations
decline and quality of life among survivors were assessed— This trial has several limitations. First, the intervention was not
important outcomes valued by patients. 26,27 Fourth, the blinded, but the risk of bias was minimized through central ran-
usual care comparator avoided risk of artificially increasing domization, to try to ensure concealment of group assign-
harm in the control group. Fifth, the population was enriched ment, and use of a primary outcome not subject to observer
by enrolling older patients considered to have a greater bias. Second, the 90-day mortality in the usual care group was
chance of benefiting from the intervention. Sixth, careful higher than anticipated using data derived from the Case Mix
sensitivity analyses were conducted, including different Programme, plausibly because trial eligibility hinged on clini-
approaches to handling missing data. cal teams’ assessment that vasopressors would be required for
The confidence intervals for the absolute risk difference, as at least 6 hours. Third, nonconsent and withdrawals were
well as for the adjusted analyses, indicate that minimizing ex- slightly higher than anticipated in the sample-size calculation.
posure to vasopressors in older patients with vasodilatory hy- Fourth, in this pragmatic trial, no mechanistic data were col-
potension was unlikely to be harmful and might have been ben- lected, and attributable mortality was not adjudicated. Other
eficial. Usual care, which allowed expert clinicians to adjust trials comparing permissive hypotension with usual care are
vasopressors on many parameters (eg, patient characteristics ongoing and may shed light on the effect of vasopressors on sur-
and markers of tissue perfusion), did not outperform use of a rogate end points (NCT03431181).
single parameter, MAP, to systematically minimize exposure to
vasopressors. While the results of the adjusted analysis might
suggest that minimizing exposure to vasopressors in older pa-
tients with vasodilatory hypotension may be beneficial, the sur-
Conclusions
vival analysis and post hoc analyses using alternative ap- Among patients age 65 years or older receiving vasopressors
proaches to adjustment support the primary analysis. for vasodilatory hypotension, permissive hypotension com-
The results suggest that there may be no harm associated pared with usual care did not result in a statistically signifi-
with permissive hypotension and the corresponding signifi- cant reduction in mortality at 90 days. However, the confi-
cant reductions in exposure to vasopressors, but the study in- dence interval around the point estimate for the primary
terpretation must be limited because this was not designed as outcome should be considered when interpreting the clinical
a noninferiority trial. In contrast to the SEPSISPAM trial,11 the importance of the study.

ARTICLE INFORMATION Darnell, Hudson, Saull, Rowan, Mouncey); London (Henry, Whitman); Kadoorie Centre for Critical Care
Accepted for Publication: January 23, 2020. School of Hygiene and Tropical Medicine, Research and Education, University of Oxford,
Department of Health Services Research and Policy, John Radcliffe Hospital, Oxford, United Kingdom
Published Online: February 12, 2020. London, United Kingdom (Sadique, Grieve, Mason); (Young).
doi:10.1001/jama.2020.0930 Critical Care, Poole Hospital NHS Foundation Trust, Author Contributions: Ms Thomas and Dr Harrison
Author Affiliations: Université de Sherbrooke, Poole, Dorset, United Kingdom (Camsooksai); had full access to all of the data in the study and
Sherbrooke, Quebec, Canada (Lamontagne); Division of Anaesthetics, Pain Medicine and take responsibility for the integrity of the data and
Centre de Recherche du Centre Hospitalier Intensive Care, Imperial College London, London, the accuracy of the data analysis.
Universitaire de Sherbrooke, Sherbrooke, Quebec, United Kingdom (Gordon); Intensive Care Unit, Concept and design: Lamontagne, Harrison,
Canada (Lamontagne); Clinical Trials Unit, Intensive Imperial College Healthcare NHS Trust, St Mary’s Sadique, Grieve, Gordon, Henry, Young, Rowan,
Care National Audit & Research Centre, London, Hospital, Paddington, London, United Kingdom Mouncey.
United Kingdom (Richards-Belle, Thomas, Harrison, (Gordon); Patient representative, United Kingdom

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 Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension Original Investigation Research

Acquisition, analysis, or interpretation of data: PhD; Zia Sadique, PhD; Michelle Saull, BSc; Karen Hospital: (Georgina Randell, RGN; Stephen
Lamontagne, Richards-Belle, Thomas, Harrison, Thomas, MSc; Chris Whitman, BSc; Duncan Young, Hutchinson, FFICM; Deirdre Fottrell-Gould, RGN;
Sadique, Grieve, Camsooksai, Darnell, Gordon, DM; and previous members, Nicholas Hudson, BA, and Lisa Hudig, BSc); North Devon District Hospital:
Hudson, Mason, Saull, Whitman, Young, Rowan, and Akshay Patel, MSc. (Tracey Shanley, BSc; Guy Rousseau, MBChB; Max
Mouncey. Participating UK sites: Addenbrookes Hospital: Coupe King, MBBS; and Nicolas Stafford, MBBS);
Drafting of the manuscript: Lamontagne, (Petra Polgarova, MSc; Peter Featherstone, MBBCh; Northampton General Hospital: (Joy Grewcock,
Richards-Belle, Thomas, Harrison, Sadique, Grieve, and Sofia Teixeira, RN); Aintree University Hospital: MSc; Jonathan Wilkinson, MBChB; Kathryn Hall,
Darnell, Henry, Whitman, Young, Rowan, Mouncey. (Colette Jones-Criddle, DipHE; Ben Morton, Dip; and Lorraine Campey, BA); Northern General
Critical revision of the manuscript for important MBChB; Ian Turner-Bone, DipHE; and Laura Hospital, Sheffield: (Joanne Pons, BSc; Gary Mills,
intellectual content: Lamontagne, Richards-Belle, Wilding, DipHE); Altnagelvin Hospital: (Gail Quigley, PhD; Sarah Bird, BSc; and Joshua Cooper, BSc);
Harrison, Camsooksai, Darnell, Gordon, Hudson, PGDip; Noel Hemmings, FCARCSI; Adrian Donnelly, Peterborough City Hospital: (Alan Pope, BSc;
Mason, Saull, Young, Rowan, Mouncey. FFICM; and Aidan Campbell, FCAI); Antrim Area Matthew Davies, MBChB; Coralie Carle, BMBS; and
Statistical analysis: Lamontagne, Thomas, Harrison, Hospital: (Emma McKay, BSc; Paul Johnston, Nicola Butterworth-Cowin, BSc); Pinderfields
Sadique, Grieve, Mason, Rowan. FFARCSI; Orla O'Neill, BSc; and Emma Totten, Hospital: (Loran Davies, BSc, Alastair Rose, FRCA;
Obtained funding: Lamontagne, Harrison, Sadique, FCARCSI); Arrowe Park Hospital (Nadine Weeks, Sarah Buckley, BSc; Lucy Brooks, MBChB; and Sarah
Grieve, Rowan, Mouncey. BSc; Paul Jeanrenaud, MBChB; Cathy Jones, BSc; Smith, MSc); Poole Hospital: (Julie Camsooksai, BSc;
Administrative, technical, or material support: Reni Jacob, Dip; and Ron Mathew Jacob, MBBS.); Henrik Reschreiter, DrMed; Sarah Patch, BSc; and
Lamontagne, Richards-Belle, Camsooksai, Darnell, Basingstoke and North Hampshire Hospital: (Maria Sarah Jenkins, BSc); Princess Royal University
Gordon, Henry, Hudson, Saull, Young, Rowan, Alpuerto, BSn; Antony Ashton, MRCP; Denise Hospital, Farnborough; (Olivia Rowe, BSc; Tom
Mouncey. Griffin, RGN; and McDonald Mupudzi, BSc); Williams, MBBS; Emma Clarey, BSc; and Jane
Supervision: Lamontagne, Harrison, Young, Rowan, Blackpool Victoria Hospital (Jason Cuppitt, MBChB; Wilson, BSc); Queen Elizabeth Hospital, Gateshead:
Mouncey. Emma Stoddard, DipHE; Gemma Brown, BSc; and (Jenny Ritzema, MSc; Vanessa Linnett, MBBS; and
Conflict of Interest Disclosures: Dr Lamontagne Jazmine McCooey, FdA); Bristol Royal Infirmary: Amanda Sanderson, DipHE); Queen Alexandra
reported receiving grants from National Institute (Lisa Grimmer, RN; Jeremy Bewley, FFICM; Katie Hospital: (Steve Rose, BN; David Pogson, MSc; Zoe
for Health Research (NIHR) and grants from Fonds Sweet, RN; and Chloe Searles, RN); Broomfield Daly, BSc; and Aimi Collins, BSc) Queen Elizabeth
de recherche du Québec-Santé. Mr Richards-Belle Hospital: (Rebecca Keskeys, BSc; Jayachandran Hospital, Woolwich: (Amy Collins, BSc; Ashraf
reported receiving grants from The NIHR Radhakrishnan, DipHE; Fiona McNeela, BSc; and Roshdy, PhD; Ahmed Zaki, MD; Estefania Treus,
Technology Assessment Programme. Ms Thomas Sue Smolen MSc); Charing Cross Hospital: (Laura BSc; Yvonna Marasigan, RN); Queens Medical
reported receiving grants from the NIHR Health Curran, BN; David Antcliffe, PhD; Roceld Rojo, BSn; Centre: (Lucy Ryan, MSc; Daniel Harvey, BMBS;
Technology Assessment Programme. Dr Harrison and Kim Zantua, BSn); Countess of Chester Hospital; Megan Meredith, BSc; and Louise Hughes, BSc);
reported receiving grants from the NIHR (Helen Robertson, BSc; Lyndsay Cheater, MBChB; Royal Berkshire Hospital: (Nicola Jacques, MSc;
Technology Assessment Programme. Dr Grieve Maria Faulkner, BSc; and Laura Parry, PGDip); Andrew Walden, PhD; Parminder Bhuie, DipN; and
reported receiving grants from the NIHR Darent Valley Hospital: (Phillipa Wakefield, BN; Aoife Dowling, BSc); Royal Cornwall Hospital: (Sarah
Technology Assessment Programme. Zakaulla Belagodu, MBBS; Danielle Vosper, BSc; Bean, BSc; Jonathan Paddle, MSc; and Karen Burt,
Mrs Camsooksai reported receiving grants from the Carmel Stuart, BA; and Binu Ravindran, MBBS); RGN); Royal Blackburn Hospital: (Caroline Aherne,
NIHR Health Technology Assessment Programme. Darlington Memorial Hospital: (Amanda Cowton, Dip; Justin Roberts, MBChB; and Rebecca Crosby,
Mr Darnell reported receiving grants from the NIHR BSc; James Limb, BMBS; and Julie O'Brien. RGN); MBChB); Royal Devon and Exeter Hospital: (Carole
Technology Assessment Programme. Dr Gordon Derriford Hospital: (Rosalyn Squires, BSc; Sam Boulanger, MSc; Charly Gibson, MBChB; and Sinead
reported receiving grants from the NIHR Waddy, MA; Esme Elloway, BSc; and Helen Kelly PGCert); Royal Glamorgan Hospital: (Ceri
Technology Assessment Programme and other McMillan, PGDip); Dorset County Hospital: (Sarah Lynch, FFICM; Bethan Gibson, FFICM; Lisa Roche,
support from Bristol-Myers Squibb and Williams, MSc; Andrew Ball, FFICM; Patricia BSc; Keri Turner; and Kelly Thomas, BSc); Royal
GlaxoSmithKline. Ms Saull reported receiving grants Williams, AdvDip; Sharon Hiscox, Dip; and Sarah Gwent Hospital: (Gemma Hodkinson, MA; Tamas
from the NIHR Technology Assessment Horton, BA); Glangwili General Hospital: (Ulla Szakmany, PhD; and Una Gunter, RN); Royal
Programme. Dr Rowan reported receiving grants Chappell, PhD: Igor Otahal, PhD; Peter Havalda, Liverpool University Hospital: (Samantha Hendry,
from the NIHR Health Technology Assessment MD; and Samantha Coetzee, PGDip); BSc; Ingeborg Welters, PhD; Karen Williams, RGN;
Programme. Mr Mouncey reported receiving grants Gloucestershire Royal Hospital: (Kelly Matthews, and Victoria Waugh BA); Royal Oldham Hospital:
from the NIHR Technology Assessment DipHE; Andrew Foo, MBBS; Izzy King, BSc; and (Ian Angus, DipHE; Redmond Tully, MBBS; Karen
Programme. No other disclosures were reported. Kirsty Manns, BSc); Hammersmith Hospital: (Sonia Hallett, BSc; and Susan Dermody, AdvDip); Royal
Sousa Arias, BSn; Stephen Brett, MD; Leilani Preston Hospital: (Mark Verlander, MBA; Shondipon
Group Information: Chief investigator and Laha, MA; Alexandra Williams, MSc; and Donna
coinvestigators: Paul Mouncey, MSc (chief Cabreros, BSc; and Rhoda Rosal, BSc); Ipswich
Hospital: (Stephanie Bell, Dip; Kate Turner, MBBS; Doyle); Royal Stoke Hospital: (David Cartlidge, MSc;
investigator); François Lamontagne, MD (lead Moses Chikungwa, MBChB; Minnie Gellamucho,
clinical investigator); Julie Camsooksai, BSc; Vanessa Rivers, BA; and Susan Brixey, BA); James
Cook University Hospital: (Lindsay Garcia, MSc; BSc; and Ruth Salt RGN); Royal Victoria Infirmary:
Anthony Gordon, MD; Richard Grieve, PhD; David (Patricia Piercy, BSc; Ian Clement, DPhil; Leigh
Harrison, PhD; Doreen Henry, MSc; Kathryn Rowan, Judith Wright, FFICM; Keith Hugill, BSc; Susan
Mortimer, FFICM; and Nicola Cree, FFICM); King's Dunn, BSc; Carmen Bradshaw, BSc; and Abigail
PhD; Zia Sadique, PhD; Chris Whitman, BSc; and Harrison, BSc); Russells Hall Hospital: (Davinder
Duncan Young, DM. College Hospital: (Fiona Bartley, BSc; Philip Hopkins,
PhD; Su Jeffreys, PGCert; Harriet Noble, MSc; and Kaur, BSc; Mike Reay, MBBS; Vikram Anumakonda,
Trial Steering Committee: Tim Walsh, MD (chair, Clare Finney, BSc); Leicester Royal Infirmary: (Louise MBBS; Rachel Collins, DipHE; Angela Watts, BSc;
independent); Ben Creagh-Brown, PhD Houslip, MSc; Neil Flint, MBChB; Dawn Hales, MSc; and Julie Matthews); Salford Royal Hospital:
(independent); Tom Lawton, MSc (independent); Prematie Andreou, BSc; and Iain McLaren, MBChB); (Alexandra Larkin, MSc; Paul Ferris, MBChB;
Theresa Melody, RN (independent), Natalie Lister Hospital: (Carina Cruz, MRes; Sunil Kathryn Cawley, MRes; and Joy Dearden, BSc);
Pattison, PhD (independent); Donna Reid Jamadarkhana, FFICM; Naomi Brice, BSc; Katie Southmead Hospital: (Beverley Faulkner, MA, Matt
(independent), François Lamontagne, MD Goodyer, RN); Manchester Royal Infirmary: (Richard Thomas, MBChB; Kati Hayes, BSc; and Ruth Worner,
(nonindependent), and Paul Mouncey, MSc Clark, DipHE; Jonathan Bannard-Smith, MBChB; RGN); St Mary's Hospital, London: (Dorota Banach,
(nonindependent). Emma Connaughton, BSc; and Abigail Williams, BSc; Anthony Gordon, MD; John Adams, BSc; and
Data Monitoring and Ethics Committee: John Norrie, BSc); Medway Maritime Hospital: (Amanda Maie Templeton, MSc); St Thomas’ Hospital: (Aneta
MSc (chair); Andreas Laupacis, MD; Danny Cameron, DipHE; Rahuldeb Sarkar, MPH; Vongayi Bociek, BSc; Marlies Ostermann, PhD; Simon
McAuley, MD. Ogbeide, MSc; and Mary Everett); Morriston Sparkes, MBBS; Ruth Wan. MRes; and Andrea Kelly,
Hospital: (Ceri Battle, PhD; Milercy Oliveros, MD; BSc); Torbay Hospital: (Joanne Holman, BSc;
Trial Management Group: Paul Mouncey, MSc, Thomas Clark, MBChB; and Alison Cornwell,
François Lamontagne, MD, Alvin Richards-Belle, Tracy Owen, MSc; and Sharon Storton, DipHE);
Musgrove Park Hospital: (Patricia Doble, BSc; DipHE); Tunbridge Wells Hospital: (Ilona Cassar,
BSc; Julie Camsooksai, BSc; Robert Darnell, BA; BSc; David Golden, MBBS; Joanne Jones, BSc; and
Anthony Gordon, MD; Richard Grieve, PhD; David Richard Innes, MBBCh; Joanne Hutter, DipHE; and
Stephen Harris, MBChB.); Norfolk and Norwich Miriam Davey, BSc); University Hospital Coventry:
Harrison, PhD; Doreen Henry, MSc; Kathryn Rowan,

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 Research Original Investigation Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension

(Thomas Billyard, BMBS; Geraldine Ward, MA; Laura 13(10):1760-1767. doi:10.1513/AnnalsATS.201604- 15. Jorm AF. A short form of the Informant
Wild, BSc; Pamela Bremmer, BSc; and Christopher 259OC Questionnaire on Cognitive Decline in the Elderly
Bassford, PhD); University Hospital Lewisham: 3. Varpula M, Tallgren M, Saukkonen K, (IQCODE): development and cross-validation.
(Rosaleeta Reece-Anthony, BSc; Waqas Khaliq, PhD; Voipio-Pulkki L-M, Pettilä V. Hemodynamic Psychol Med. 1994;24(1):145-153. doi:10.1017/
Jayson Clarke, MBChB; and Babita Gurung, BSc); variables related to outcome in septic shock. S003329170002691X
University Hospital of North Tees: (Michele Clark, Intensive Care Med. 2005;31(8):1066-1071. doi:10. 16. Herdman M, Gudex C, Lloyd A, et al.
MA; Farooq Brohi, MBBS; and Tracey Oldfield, 1007/s00134-005-2688-z Development and preliminary testing of the
MSc); Warwick Hospital: (Sophie Mason, RGN; Ben new five-level version of EQ-5D (EQ-5D-5L). Qual
Attwood, MBBChir; Camilla Stagg, RGN; and Penny 4. Maheshwari K, Nathanson BH, Munson SH, et al.
The relationship between ICU hypotension and Life Res. 2011;20(10):1727-1736. doi:10.1007/s11136-
Parsons, BSc); William Harvey Hospital: (Carl 011-9903-x
Boswell, RGN; Neil Anthony Richardson, FFICM; in-hospital mortality and morbidity in septic
Tracy Hazelton; Natasha Schumacher, BSc; and patients. Intensive Care Med. 2018;44(6):857-867. 17. Thomas K, Patel A, Sadique MZ, et al. Evaluating
Nicholas Dalmon, BSc); Worthing Hospital: (Jenny doi:10.1007/s00134-018-5218-5 the clinical and cost-effectiveness of permissive
Lord, BSc; David Helm, FFICM; Charalice Ramiro, 5. Lamontagne F, Marshall JC, Adhikari NKJ. hypotension in critically ill patients aged 65 years or
BSc; and Jordi Margalef, BSc); Yeovil District Permissive hypotension during shock resuscitation: over with vasodilatory hypotension: Statistical and
Hospital: (Liliana Silva, RGN; Agnieszka equipoise in all patients? Intensive Care Med. 2018; Health Economic Analysis Plan for the 65 trial
Kubisz-Pudelko, PhD; Alison Lewis, RGN; and 44(1):87-90. doi:10.1007/s00134-017-4849-2 [Published online July 3, 2019]. J Intensive Care Soc.
Johnyta Panakal RGN); York Hospital: (Danielle doi:10.1177/1751143719860387
6. Dellinger RP, Levy MM, Rhodes A, et al;
Wilcock, Jonathan Redman MBChB, Joseph Carter Surviving Sepsis Campaign Guidelines Committee 18. Khanna A, English SW, Wang XS, et al; ATHOS-3
MBChB, Kate Howard MSc). including the Pediatric Subgroup. Surviving sepsis Investigators. Angiotensin II for the treatment of
Funding/Support: This project was funded by campaign: international guidelines for management vasodilatory shock. N Engl J Med. 2017;377(5):419-
project number 15/80/39 from the NIHR HTA of severe sepsis and septic shock: 2012. Crit Care Med. 430. doi:10.1056/NEJMoa1704154
Programme. The Intensive Care National Audit & 2013;41(2):580-637. doi:10.1097/CCM. 19. Ferrando-Vivas P, Jones A, Rowan KM,
Research Centre (ICNARC) sponsored the trial. 0b013e31827e83af Harrison DA. Development and validation of the
Dr Gordon is funded by grant RP-2015-06-018, an 7. Rhodes A, Evans LE, Alhazzani W, et al. Surviving new ICNARC model for prediction of acute hospital
NIHR Research Professorship award and by the Sepsis Campaign: international guidelines for mortality in adult critical care. J Crit Care. 2017;38:
NIHR Comprehensive Biomedical Research Centre management of sepsis and septic shock: 2016. 335-339. doi:10.1016/j.jcrc.2016.11.031
(based at Imperial College Healthcare National Intensive Care Med. 2017;43(3):304-377. doi:10. 20. Singer M, Deutschman CS, Seymour CW, et al.
Health Service Trust and Imperial College London). 1007/s00134-017-4683-6 The Third International Consensus Definitions for
Dr Lamontagne is supported by a Fonds de Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315
recherche du Québec–Santé (FRQS) career award 8. Rhodes A, Evans LE, Alhazzani W, et al. Surviving
sepsis campaign: international guidelines for (8):801-810. doi:10.1001/jama.2016.0287
and holds the Université de Sherbrooke Research
Chair on Patient-Centred Research. The UK Critical management of sepsis and septic shock: 2016. Crit 21. White IR, Royston P, Wood AM. Multiple
Care Research Group and the NIHR Clinical Care Med. 2017;45(3):486-552. doi:10.1097/CCM. imputation using chained equations: issues and
Research Networks supported the trial. 0000000000002255 guidance for practice. Stat Med. 2011;30(4):377-399.
9. Lamontagne F, Cook DJ, Meade MO, et al. doi:10.1002/sim.4067
Role of the Funder/Sponsor: The sponsors had no
role in the design and conduct of the study; Vasopressor use for severe hypotension-a 22. Rubin D. Multiple Imputation for Nonresponse
collection, management, analysis, and multicentre prospective observational study. PLoS in Surveys. New York, NY: John Wiley & Sons; 1987.
interpretation of the data; preparation, review, or One. 2017;12(1):e0167840-e0167840. doi:10. 23. Knaus WA, Draper EA, Wagner DP,
approval of the manuscript; and decision to submit 1371/journal.pone.0167840 Zimmerman JE. APACHE II: a severity of disease
the manuscript for publication. 10. St-Arnaud C, Ethier JF, Hamielec C, et al. classification system. Crit Care Med. 1985;13(10):
Disclaimer: The views and opinions expressed Prescribed targets for titration of vasopressors in 818-829. doi:10.1097/00003246-198510000-
herein are those of the authors and do not septic shock: a retrospective cohort study. CMAJ 00009
necessarily reflect those of the HTA Programme, Open. 2013;1(4):E127-E133. doi:10.9778/cmajo. 24. Harrison DA, Parry GJ, Carpenter JR, Short A,
NIHR, NHS, or the Department of Health. 20130006 Rowan K. A new risk prediction model for critical
Data Sharing Statement: See Supplement 3. 11. Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM care: the Intensive Care National Audit & Research
Investigators. High versus low blood-pressure Centre (ICNARC) model. Crit Care Med. 2007;35(4):
Additional Contributions: We thank all of the target in patients with septic shock. N Engl J Med. 1091-1098. doi:10.1097/01.CCM.0000259468.
patients who participated in the trial and their 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173 24532.44
family members and also Joseph Collins, MSc; Sian
Martin, MSc; Abby Koelewyn, BSc; Laura Drikite, 12. Lamontagne F, Meade MO, Hébert PC, et al; 25. Devlin NJ, Shah KK, Feng Y, Mulhern B,
MSc; and Akshay Patel, MSc, for their support in Canadian Critical Care Trials Group. Higher versus van Hout B. Valuing health-related quality of life: An
data aquisition for the trial. They received grants lower blood pressure targets for vasopressor EQ-5D-5L value set for England. Health Econ. 2018;
from the National Institute for Health Research therapy in shock: a multicentre pilot randomized 27(1):7-22. doi:10.1002/hec.3564
(NIHR) Health Technology Assessment (HTA) controlled trial. Intensive Care Med. 2016;42(4): 26. Needham DM, Sepulveda KA, Dinglas VD, et al.
Programme while working on the trial at the 542-550. doi:10.1007/s00134-016-4237-3 Core outcome measures for clinical research in
Intensive Care National Audit & Research Centre 13. Lamontagne F, Day AG, Meade MO, et al. acute respiratory failure survivors. an international
(ICNARC). Pooled analysis of higher versus lower blood modified delphi consensus study. Am J Respir Crit
pressure targets for vasopressor therapy septic and Care Med. 2017;196(9):1122-1130. doi:10.1164/rccm.
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