Articles

Balanced crystalloids versus saline for critically ill patients

(BEST-Living): a systematic review and individual patient
data meta-analysis
Fernando G Zampieri, Alexandre B Cavalcanti, Gian Luca Di Tanna, Lucas P Damiani, Naomi E Hammond, Flavia R Machado, Sharon Micallef,
John Myburgh, Mahesh Ramanan, Balasubramanian Venkatesh, Todd W Rice, Matthew W Semler, Paul J Young, Simon Finfer

Summary
Background The effect of balanced crystalloids compared with that of saline in critically ill patients overall and in Lancet Respir Med 2024;
specific subgroups is unclear. We aimed to assess whether use of balanced solutions, compared with 12: 237–46

0·9% sodium chloride (saline), decreased in-hospital mortality in adult patients in intensive care units (ICUs). Published Online
November 30, 2023
https://doi.org/10.1016/
Methods For this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, and S2213-2600(23)00417-4
CENTRAL databases from inception until March 1, 2022 (updated Sept 1, 2023) for individually randomised and See Comment pages 187 and 188
cluster-randomised trials comparing balanced solutions with saline for adult patients in the ICU. Eligible trials were HCor Research Institute, São
those that allocated patients to receive balanced solutions or saline for fluid resuscitation and maintenance fluids, or Paulo, Brazil (F G Zampieri PhD,
for maintenance fluids only; and administered the allocated fluid throughout ICU admission or, for trials using A B Cavalcanti PhD,
landmark mortality as their primary outcome, until the timepoint at which mortality was assessed (if ≥28 days). L P Damiani MSc); Brazilian
Research in Intensive Care
Authors of eligible trials were contacted to request individual patient data. Data obtained from eligible trials were Network—BRICNet, São Paulo,
merged, checked for accuracy, and centrally analysed by use of Bayesian regression models. The primary outcome Brazil (F G Zampieri,
was in-hospital mortality. Prespecified subgroups included patients with traumatic brain injury. This study was A B Cavalcanti,
F R Machado PhD); Department
registered with PROSPERO (CRD42022299282).
of Critical Care Medicine,
Faculty of Medicine and
Findings Our search identified 5219 records, yielding six eligible randomised controlled trials. Data obtained for Dentistry, University of
34 685 participants from the six trials, 17 407 assigned to receive balanced crystalloids and 17 278 to receive saline, Alberta, Edmonton, AB,
Canada (F G Zampieri); The
were included in the analysis. The mean age of participants was 58·8 years (SD 17·5). Of 34 653 participants with
George Institute for Global
available data, 14 579 (42·1%) were female and 20 074 (57·9%) were male. Among patients who provided consent to Health, Sydney, NSW, Australia
report in-hospital mortality, 2907 (16·8%) of 17 313 assigned balanced solutions and 2975 (17·3%) of 17 166 assigned (Prof G L Di Tanna, PhD,
saline died in hospital (odds ratio [OR] 0·962 [95% CrI 0·909 to 1·019], absolute difference –0·4 percentage N E Hammond PhD,
S Micallef BN,
points [–1·5 to 0·2]). The posterior probability that balanced solutions reduced mortality was 0·895. In patients with
Prof J Myburgh MD,
traumatic brain injury, 191 (19·1%) of 999 assigned balanced and 141 (14·7%) of 962 assigned saline died (OR 1·424 M Ramanan MMed,
[1·100 to 1·818], absolute difference 3·2 percentage points [0·7 to 8·7]). The probability that balanced solutions Prof B Venkatesh MD,
increased mortality in patients with traumatic brain injury was 0·975. In an independent risk of bias assessment, Prof S Finfer MD); University of
New South Wales, Sydney,
two trials were deemed to be at low risk of bias and four at high risk of bias.
NSW, Australia
(Prof G L Di Tanna,
Interpretation The probability that using balanced solutions in the ICU reduces in-hospital mortality is high, although N E Hammond, Prof J Myburgh,
the certainty of the evidence was moderate and the absolute risk reduction was small. In patients with traumatic brain Prof B Venkatesh, Prof S Finfer);
Department of Business
injury, using balanced solutions was associated with increased in-hospital mortality. Economics, Health and Social
Care, University of Applied
Funding HCor (Brazil) and The George Institute for Global Health (Australia). Sciences and Arts of Southern
Switzerland, Lugano,
Switzerland (Prof G L Di Tanna);
Copyright © 2023 Elsevier Ltd. All rights reserved. Malcolm Fisher Department of
Intensive Care Medicine, Royal
Introduction crystalloids are constituted with use of alternative anions North Shore Hospital, Sydney,
During an admission to the intensive care unit (ICU), to reduce the chloride concentration in the fluid, and NSW Australia (N E Hammond);
Anesthaesiology, Pain and
most patients receive intravenous fluid therapy as include compound sodium lactate (Ringer’s lactate, Intensive Care Department,
supportive therapy for the presenting critical illness.1 Hartmann’s solution) or acetate-containing solutions Hospital São Paulo, Federal
Crystalloid solutions are the fluids used most commonly (Plasma-Lyte 148, Ringer’s acetate). Potential benefits of University of São Paulo,
to correct symptomatic hypovolaemia due to fluid losses, balanced crystalloid solutions include the reduction of São Paulo, Brazil (F R Machado);
St George Hospital, Sydney,
improve haemodynamic function to optimise vital organ development of an iatrogenic hyperchloraemic metabolic NSW, Australia
function and as an intravenous vehicle to administer acidosis.2 (Prof J Myburgh); Intensive Care
medications.2 Widely used intravenous crystalloid Randomised clinical trials have compared the effects of Unit, Caboolture and The
solutions include 0·9% sodium chloride (saline) and balanced solutions with those of saline on patient-centred Prince Charles Hospitals, Metro
North Hospital and Health
solutions characterised by an electrolyte profile similar outcomes in critically ill patients.3−8 One study reported Services, Brisbane, QLD,
to extracellular fluid. These buffered, or balanced, that the use of balanced solutions was associated with a Australia (M Ramanan); School

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of Medicine, University of
Queensland, Brisbane, QLD,
Australia (M Ramanan);
Intensive Care Unit, Wesley and
Princess Alexandra Hospitals,
Woolloongabba, QLD, Australia
(Prof B Venkatesh); Division of
Allergy, Pulmonary, and Critical
Care Medicine, Vanderbilt
University Medical Center,
Nashville, TN, USA
(Prof T W Rice MD,
M W Semler MD); Department
of Intensive Care, Wellington
Regional Hospital, Wellington,
New Zealand (P J Young PhD);
Medical Research Institute of
New Zealand, Wellington, New
Zealand (P J Young); Australian
and New Zealand Intensive
Care Research Centre, Monash
University, Melbourne, VIC,
Australia (P J Young);
Department of Critical Care,
University of Melbourne,
Melbourne, VIC, Australia
(P J Young); School of Public
Health, Imperial College
London, London, UK
(Prof S Finfer)
Correspondence to:
Prof Simon Finfer, The George
Institute for Global Health,
Sydney, NSW 2042, Australia
sfinfer@georgeinstitute.org.
au
Research in context
Evidence before this study
Randomised clinical trials have compared the effects of
balanced crystalloid solutions and 0·9% sodium chloride
(saline) in patients treated in intensive care units (ICUs). One
cluster-randomised trial reported that the use of balanced
solutions was associated with a reduction in the composite
outcome of death, new renal replacement therapy, or persistent
kidney dysfunction. No individual trial reported a statistically
significant effect on mortality. A Bayesian trial-level
meta-analysis of randomised trials reported a probability of
0·895 that, compared with saline, use of balanced solutions in a
heterogeneous population of ICU patients was associated with
reduced mortality. However, existing data suggest that the
treatment effect might be heterogeneous, with differing effects
in different subgroups of patients. An individual patient data
meta-analysis not only provides an overall estimate of the
treatment effect, but allows patients to be categorised into
subgroups of interest to clinicians on the basis of pre-
randomisation characteristics that were not examined or
reported in publications from the original individual trials or
trial-level meta-analyses.
Added value of this study
This systematic review and individual patient data meta-
analysis included six randomised trials with 34 685 patients
analysed within a Bayesian framework to provide a more
nuanced interpretation of its findings. The probability that
balanced crystalloid solutions were associated with reduced in-
hospital mortality overall was 0·895. The probability that
balanced solutions were associated with lower mortality
exceeded 0·90 in patients without traumatic brain injury
(>0·97), patients who did not receive 0·9% saline before
enrolment (>0·98), and female patients (0·95). The probability
that balanced solutions were associated with higher mortality
in patients with traumatic brain injury was 0·975. The effect of
balanced solutions versus saline on mortality was similar in
subgroups defined by serum sodium and chloride
concentration and blood pH. We assessed the certainty of the
evidence in relation to mortality as moderate. These results
support those of previous trial-level meta-analyses that there is
a high probability that balanced solutions are associated
reduced mortality overall, the exception being patients with
traumatic brain injury in whom mortality is increased. The
results add important information about effects in subgroups
of patients defined by diagnosis, demographics, and
biochemical parameters.
Implications of all the available evidence
The totality of existing evidence supports the use of balanced
crystalloid solutions in patients in ICUs, except for those with
traumatic brain injury, in whom saline should be preferred.

reduction in a composite outcome measure of death,
new renal replacement therapy, or persistent kidney
dysfunction.4 No trial reported a statistically significant
difference in mortality. A recent trial-level meta-analysis
of randomised clinical trials reported a 0·895 probability
that the use of balanced solutions was associated with
lower mortality than saline.9
To address the remaining uncertainty over the use of
balanced solutions in the ICU, we did an individual
patient-data meta-analysis of randomised clinical trials
analysed within a Bayesian framework to provide
estimates of the probability of benefits associated with
use of balanced solutions compared with saline in
a heterogeneous population of adult patients and in
prespecified subgroups. Bayesian methods were used as
they allow a more nuanced interpretation of the results,
compared with traditional frequentist null hypothesis
testing that relies on a dichotomised interpretation of a
p value to accept or reject a hypothesis.
Methods
Overview
The BEST-Living Study is a living, individual patient-data
meta-analysis with a prespecified protocol and statistical
analysis plan designed to compare the effects of using
balanced solutions with those of saline in the ICU on
patient-centred outcomes in critically ill adult patients.10,11
Given the results of a recent aggregated meta-analysis,
which were close to traditional statistical significance,
we chose to use a Bayesian framework to provide a more
comprehensive analysis of the effect of balanced
solutions. Bayesian analyses provide an assessment of
the probability of benefit for situations in which benefit
is considered probable, but the results are not
statistically significant on the basis of traditional
frequentist null hypothesis testing.12 They also provide a
more nuanced approach to the effect sizes that are
compatible with data (and prior information, if
available). Reviews of Bayesian methods in critical care
can be found elsewhere.13,14
In relation to the use of individual patient data in meta-
analyses, the Cochrane handbook states, “In most cases
participants will not have specifically consented to
inclusion in the meta-analysis. However, as the meta-
analysis is posing the same research question, and is
essentially updating the trial they did consent to, the
usual view is that separate consent is not required.
However, it is advisable that data received are
anonymised.” In keeping with this principle, our meta-
analysis addressed the same question as the trials for
which we have data, and all data were anonymised before
transfer.
This systematic review is reported in accordance with
PRISMA-IPD guidelines.15,16

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Search strategy and selection criteria
The initial search was done on March 1, 2022, in
MEDLINE, Embase, and the Cochrane Central Register
of Controlled Trials (CENTRAL). Key search terms were
balanced crystalloids[Title] OR (balanced solution[Title]
OR (balanced multielectrolyte solution[Title] OR
plasmalyte[Title] OR plasma-lyte[Title] OR “plasma lyte
148”[Title] OR “lactated ringer”[Title] OR “ringer
lactate”[Title] OR “normal saline”[Title]”. Full search
details are provided in the appendix (p 3) and in the
statistical analysis plan.11 The eligibility of identified
studies was assessed independently by two reviewers
(FGZ and LPD), with disagreement resolved by a third
reviewer (ABC).
Eligible randomised clinical trials were those that
enrolled adults treated in an ICU; allocated individuals
or clusters to receive balanced solutions or saline for
fluid resuscitation and maintenance fluids, or for
maintenance fluids only; and administered the allocated
study fluid for the duration of the ICU admission or, for
trials using landmark mortality as their primary
outcome, until the timepoint at which mortality was
assessed, provided mortality was assessed at 28 days or
later. A priori, we defined balanced solutions as any
intravenous crystalloid solution in which the difference
between the sodium and chloride concentrations was at
least 15 mmol/L.
We excluded trials that mandated the use of study
fluids for only part of participants’ ICU stays (other than
trials assessing landmark mortality beyond day 28 that
did not mandate use of study fluids after that timepoint);
that enrolled only surgical patients; in which study fluids
were used for resuscitation only; that did not report in-
hospital mortality or mortality at a landmark timepoint
of at least 28 days; and that had loss to follow-up for in-
hospital mortality of more than 10%.
Data collection and data items
The review was sponsored by the HCor Research
Institute (São Paulo, Brazil) with formalised collaborative
research agreements between the sponsor and respective
author investigators and their associated institutions.
A data skeleton (appendix p 4) was sent to corresponding
authors for populating respective trial information,
which was housed on a secure server at the HCor
Research Institute. Complete cases were included in the
analysis, with no imputation for missing data. Data
quality was assured by replicating the primary analysis
of each trial, the results of which were compared with
the published results of each trial; trialists were informed
about any discrepancies and allowed to respond or
update their uploaded results.
Risk of bias assessment and certainty of evidence
Risk of bias in the included studies and certainty of the
review evidence was assessed by independent experts
using the Cochrane Risk of bias and tool and the
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Articles
GRADE (Grading of Recommendations Assessment,
Development and Evaluation) approach for assessing
certainty.17,18
Outcomes
The primary outcome was all-cause in-hospital mortality
censored at 90 days. Secondary outcomes were survival
at last follow-up, treatment with renal replacement
therapy commenced during the index ICU admission,
and days alive and out of hospital and out of ICU within See Online for appendix
28 days.
Prespecified subgroup analyses were done for the
primary outcome and for treatment with renal
replacement therapy in subgroups of patients identified
by baseline characteristics of sex (male or female),
presence or absence of sepsis (as defined by each trial),
presence or absence of traumatic brain injury, baseline
serum chloride concentration (categorised as low
[<100 mmol/L], normal [100–110 mmol/L], or high
[>110 mmol/L]), acid-base status as defined by baseline
pH (severe acidaemia [pH <7·20], mild acidaemia
[pH 7·20 to <7·35], normal [pH 7·35 to 7·45], or
alkalaemia [pH >7·45]), volumes of intravenous saline
received before randomisation (none, 1–999 mL, or
≥1000 mL of saline received), and study design (cluster
versus individual randomisation). Hypotheses for each
prespecified subgroup are presented in the appendix
(p 7) and in the statistical analysis plan.11 One planned
subgroup analysis estimating effects in patients with
non-traumatic acute brain injury was planned but could
not be done due to an absence of prospective
classification of patients in the included trials (appendix
p 8).
A post-hoc analysis based on serum sodium con­
centration at baseline (<135, 135–145, or >145 mmol/L)
was also added during the review process.
Statistical analysis
The statistical analysis plan was finalised before data
were merged or analysed.11 The primary analysis was
based on a one-step meta-analysis using a Bayesian
hierarchical model with the intervention of interest
(balanced solution vs saline) as a fixed-effect covariate
and two layers: the ICU (or cluster) nested within trial
as hierarchical effects.
The primary model used for this and future iterations
is a non-informative prior for the effect size of the
intervention (prior for the log odds ratio [OR] of the
intervention defined as normal with mean 0 and
SD 0·355).19 Alternative analyses for the primary
endpoint included an adjusted model (adjusted for age,
sex, surgical vs non-surgical admission, and sepsis),
different prior analyses (including optimistic and
pessimistic priors), and a frequentist mixed model.
Survival analyses were done with time-to-event models
following a Bayesian semiparametric survival time with
a non-informative prior for the intervention
239
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mean of 0 and SD of 4. The proportion of patients
treated with new renal replacement therapy initiated
during the index ICU admission was assessed using the
same model as the primary outcome. Length of hospital
stay was analysed with a cumulative logistic model for
days alive and free of hospital or ICU admission (both
truncated at 28 days, with patients who died given a
score of –1 using non-informative priors). Exploratory
analyses were assessed with frequentist generalised
mixed models with interaction between time and
intervention and with patients as a random intercept.
We did a two-stage individual patient data meta-
analysis for the primary outcome: effect sizes obtained
from each trial were aggregated using a Bayesian meta-
analysis. In addition, we did a Bayesian meta-analysis of
aggregated trial-level data for hospital mortality and use
of renal replacement therapy.
Results for the primary outcome are presented as
median OR (95% credible intervals [CrI]) and the
probability of direction, defined as the posterior
5920 records identified
4797 from databases
1123 from registers
701 records removed before screening
267 duplicates
434 marked as ineligible by automation
tools
5219 records screened
5138 records excluded
81 records retrieved and assessed for eligibility
75 records excluded
19 surgical patients only
12 registry of included trial
12 secondary analysis of RCT
8 not an RCT
7 fluids used for resuscitation only
6 recruiting or not yet recruiting
4 truncated fluid use
3 unable to obtain status
2 not critically ill patients
1 study in children
1 use of colloids
6 studies included*
Figure 1: Study identification and selection
Flow diagram shows identification, screening, and selection of studies from the
initial search (concluded on March 1, 2022). On repeat search (Sept 1, 2023), we
identified 691 new records, among which 37 were duplicates; 20 of the
remaining 654 were retrieved and assessed for eligibility, but none met our
study’s eligibility criteria. *Two further records were identified by citation
searching, of which two were retrieved and assessed for eligibility but were
excluded as fluids were used for resuscitation only. No records were found
through searches of websites or organisations.
240
probability of the intervention (use of balanced
solutions) being associated with an OR less than 1·0.
We also present relative risks and absolute risk
differences obtained from posterior expected
probabilities. As described in the statistical analysis
plan, a region of practical equivalence (ROPE) for the
effect of the intervention on the primary outcome as an
OR was defined as 0·955–1·046,11 shown as the
percentage of the posterior probability distribution
contained in the ROPE. For further details see appendix
(p 6).
Results for the survival outcome are presented as
hazard ratio (HR) and corresponding 95% CrI. Results
for secondary binary outcomes are presented similarly
to the primary endpoint, with exception of ROPE, which
was not defined for all secondary endpoints. Results for
subgroup analyses are presented as forest plots for the
OR, probability of benefit, and probability of direction of
the interaction for each subgroup; other measurements
of effect size including relative risk and absolute risk
reduction are also shown. A list of deviations from
original plans to performed analysis is summarised in
appendix (p 8).
All analyses were done with R version 4.2.2 with
packages brms and bayesmeta.20,21
This study was registered with PROSPERO
(CRD42022299282).
Role of the funding source
The funders of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report.
Results
The initial search was concluded on March 1, 2022. Of
the 5219 records screened, 81 were assessed for eligibility,
and six met the eligibility criteria and were selected for
analysis (figure 1).3–8 All investigators agreed to share
data. Characteristics of the included studies, including
the type of balanced fluid used and volumes received
after randomisation, are shown in table 1. Of the
six included studies, four were cluster-randomised trials
and two were individually randomised. Two studies were
conducted in the USA, one in Australia, one in New
Zealand, one in Australia and New Zealand combined,
and one in Brazil. In all trials, patients received balanced
solutions or saline for resuscitation, and all received
compatible intravenous crystalloid therapy during their
ICU stay.
The search was repeated on Sept 1, 2023. We identified
691 new records; 37 were duplicates, 634 were ineligible
on initial review, the remaining 20 were retrieved and
underwent full-text review to assess for eligibility. None
met our study’s eligibility criteria.
A total of 34 685 patients were included in the meta-
analysis: 17 407 assigned to receive balanced crystalloids
and 17 278 to receive saline. The mean age was 58·8 years
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Number of Centres; Randomisation Masking Population Primary outcome Median fluid use, mL Balanced fluid
patients intensive care
units
Balanced Saline
solution
SPLIT (2015)3 2278 4 Cluster Masked Critically ill patients Acute kidney injury* 2000 2000 Plasma-Lyte 148
SALT (2017)4 974 1 Cluster Unmasked Critically ill patients Feasibility, MAKE30† 1617 1424 Plasma-Lyte A or
lactated Ringer solution
SMART (2018)5 15 802 1; 5 Cluster Unmasked Critically ill patients MAKE30† 1000 1020 Plasma-Lyte A or
lactated Ringer solution
BaSICS (2021)6 10 520 75 Individual Masked Critically ill patients 90-day survival 2900‡ 2900‡ Plasma-Lyte 148
PLUS (2022)7 5037 53 Individual Masked Critically ill patients 90-day survival 3900 3700 Plasma-Lyte 148
SCOPE-DKA (2021)8 93 7 Cluster Unmasked Patients with diabetic Ketoacidosis 6798¶ 6574¶ Plasma-Lyte 148
ketoacidosis resolution§
The 19-patient difference between the sum of each trial and the individual participant data meta-analysis results reflects the use of a complete case analysis in this Article. 15 patients from the BaSICs trial and
191 from the PLUS trial were excluded from the primary analysis as consent to use of their data was either withheld or withdrawn. Additionally, four patients from the SCOPE-DKA trial were excluded from the
survival analysis as date of hospital discharge was unknown. *Doubling of serum creatinine concentration, or a serum creatinine concentration of ≥3·96 mg/dL with an increase of ≥0·5 mg/dL. †Composite
endpoint of mortality, doubling of serum creatinine, or treatment with renal replacement therapy during hospitalisation, truncated at 30 days. ‡Fluid used up to 3 days after enrolment. §Base excess to at least
−3 mEq/L at 48 h post-ICU admission. ¶Mean value.

Table 1: Characteristics of included trials

(SD 17·5). Among patients with available data,

Balanced n=17 407 Saline n=17 278
20 074 (57·9%) of 34 653 patients were male,
14 579 (42·1%) were female, 20 919 (60·6%) of 34 520 were Age, years 58·6 (17·5), n=17 407 58·9 (17·4), n=17 278
non-surgical admissions, and 6585 (19·1%) of 34 427 had Sex
an admission diagnosis of sepsis (table 2; appendix Male 10 043/17 383 (57·8%) 10 031/17 270 (58·1%)
pp 10–11). For analyses adjusted for age, sex, and admission Female 7340/17 383 (42·2%) 7239/17 270 (41·9%)
type (surgical vs non-surgical) and sepsis, complete case Admission type
data were available for 17 293 assigned to receive balanced Surgical 6791/17 325 (39·2%) 6810/17 195 (39·6%)
crystalloids and 17 153 assigned to receive saline. Non-surgical 10 534/17 325 (60·8%) 10 385/17 195 (60·4%)
Consent to report in-hospital mortality was obtained Days from ICU admission to study 0·38 (2·72), n=17 323 0·37 (3·57), n=17 196
for 17 313 participants assigned balanced crystalloids enrolment
and 17 166 assigned saline. Among these patients, Sepsis 3286/17 276 (19·0%) 3299/17 151 (19·2%)
2907 (16·8%) assigned balanced crystalloids and Traumatic brain injury 999/17 325 (5·8%) 962/17 195 (5·6%)
2975 (17·3%) assigned saline died in hospital (OR 0·962 Vasopressor use at enrolment 5927/16 162 (36·7%) 5965/16 076 (37·1%)
[95% CrI 0·909 to 1·019], absolute difference Inotrope use at enrolment 5236/7656 (68·4%) 5310/7723 (68·8%)
–0·4 percentage points [–1·5 to 0·2]). The posterior Mechanical ventilation at enrolment 7905/17 325 (45·6%) 7904/17 195 (46·0%)
probability that the use of balanced crystalloid solutions Fluid use before enrolment 10 801/15 599 (69·2%) 10 687/15 490 (69·0%)
decreased the risk of in-hospital death compared with Saline, mL 426·9 (951·6), n=17 214 544·7 (1026·0), n=17 096
saline use was 0·895; 58·8% of the probability mass was Balanced solution, mL 1018·8 (1555·1), n=17 214 884·0 (1500·5), n=17 096
concentrated in the defined ROPE (table 3; figure 2A). Renal replacement therapy 496/17 320 (2·9%) 529/17 192 (3·1%)
Using alternative priors, the posterior probability of Sodium, mmol/L 138·0 (5·1), n=12 657 138·1 (5·2), n=12 630
benefit for balanced solutions could be as low as 0·821 Chloride, mmol/L 104·7 (6·3), n=12 049 105·0 (6·2), n=11 967
(pessimistic prior) and as high as 0·932 (optimistic prior; Creatinine, mmol/L 0·121 (0·125), n=16 301 0·122 (0·127), n=16 231
table 3). From the frequentist model, the OR for in- pH 7·34 (0·11), n=6136 7·34 (0·10), n=6112
hospital death with balanced crystalloids compared with Base excess, mmol/L –4·7 (6·3), n=2300 –4·5 (6·0), n=2294
saline was 0·962 (95% CI 0·908 to 1·020; absolute Data are mean (SD) or n/N (%). ICU=intensive care unit.
difference –0·4 percentage points [95% CI –1·1 to 0·2];
p=0·192; table 3). Table 2: Aggregated patient characteristics according to randomisation group
The two-stage, individual patient data meta-analysis
yielded an OR for in-hospital death for balanced solutions
versus saline of 0·956 (95% CrI 0·878 to 1·040; New use of renal replacement therapy occurred in
probability of benefit of 0·870; appendix p 16). 934 (5·6%) of 16 628 participants assigned balanced
The HR for survival to longest available follow-up for solutions and 993 (5·9%) of 16 803 assigned saline
patients assigned balanced crystalloid solutions versus (OR 0·931 [95% CrI 0·849 to 1·020], absolute risk
saline was 0·964 (95% CrI 0·918 to 1·010; table 3, difference –0·4 percentage points [–1·3 to 0·1],
figure 2B). probability of benefit 0·930; table 3).

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In the trial-level meta-analysis using non-informative

Data are n/N (%) or mean (SD), unless otherwise specified. ICU=intensive care unit. HR=hazard ratio. OR=odds ratio. RR=relative risk. ROPE=region of practical equivalence. CrI=credible interval. *Represents the proportion of the posterior probability of
benefit that is contained in a ROPE, defined as an OR between 0·955–1·046. †Represents the probability that the posterior for the OR favours the intervention (an OR <1 for all columns, except for the cumulative odds models for “free-days” outcomes
Absolute risk difference,

priors for heterogeneity and a neutral prior for the

¶Sensitivity analysis excluding SCOPE-DKA (post-hoc analysis). ||Adjusted for age, sex, sepsis, and admission type. **Values in parentheses are 95% CI; generalised mixed model with random intercept for study or site; p=0·192. ††HR (95% CrI). ‡‡In
where the OR for benefit is >1). ‡A random slope for the effect of the intervention within the site in the trial was added (post-hoc analysis). §Includes all patients, including those receiving renal replacement therapy at enrolment (post-hoc analysis).
effect of the intervention, the OR for mortality with
percentage points

–0·4 (–1·5 to 0·2)

use of balanced solutions versus saline was

–0·4 (–1·1 to 0·2)

–0·4 (–1·3 to 0·1)

–0·5 (–1·5 to 0·3)
–0·3 (–1·2 to 0·3)

–0·5 (–2·6 to 1·1)

–0·3 (–1·3 to 0·3)

–0·5 (–1·5 to 0·1)
0·94 (95% CrI 0·86–1·03; probability of benefit of 0·92).
(95% CrI)

The corresponding OR for renal replacement therapy

was 0·94 (0·82 to 1·09; probability of benefit of 0·82;

··

··
··
··

appendix pp 17–18).
Subgroup results for in-hospital mortality are shown in
0·978 (0·930 to 1·026)
0·968 (0·921 to 1·016)

0·936 (0·857 to 1·020)

0·963 (0·914 to 1·012)

0·972 (0·920 to 1·025)

0·967 (0·917 to 1·016)
0·970 (0·924 to 1·017)
0·961 (0·821 to 1·072)

figure 3 and in the appendix (p 12), and those for use of

renal replacement therapy are shown in the appendix
RR (95% CrI)

(pp 13, 15). Denominators are reported for each subgroup

as the baseline data needed to classify participants into
subgroups was not available for all participants. The
··

··
··
··

probability that balanced solutions were associated with

lower mortality exceeded 0·90 in the following
Probability
of benefit†

subgroups: patients without traumatic brain injury

0·689
0·895

0·854

0·483
0·903

0·930
0·814
0·932
0·821

(0·975), patients who did not receive 0·9% saline before

··
··
··

enrolment (0·988), and female patients (0·950). In

patients with traumatic brain injury, 191 (19·1%) of 999
ROPE %*

assigned balanced solutions died and 141 (14·7%) of 962

50·6%
58·8%
74·8%

66·0%
44·5%
60·3%

··
··
··
··
··

assigned saline died (OR 1·424 [95% CrI 1·100–1·818],

··

absolute difference 3·2 percentage points [0·7–8·7]). the

probability that balanced solutions increased mortality in
0·964 (0·918 to 1·010)††
0·967 (0·909 to 1·029)
0·962 (0·908 to 1·020)
0·962 (0·909 to 1·019)

0·999 (0·962 to 1·037)

0·954 (0·802 to 1·087)
0·963 (0·909 to 1·021)

0·931 (0·849 to 1·020)

0·956 (0·903 to 1·010)
0·973 (0·920 to 1·030)

1·010 (0·973 to 1·050)

patients with traumatic brain injury was 0·975.

Comparing patients with and without traumatic brain
injury, the interaction probability of direction was greater
OR (95% CrI)

than 0·99; for all other comparisons between subgroups,

including those based on baseline chloride concentration
··

and pH, the interaction probability of direction was less

than 0·80. The probability that balanced solutions were
2975/17 166 (17·3%)

associated with reduced risk of new treatment with renal

993/16 803 (5·9%)

replacement therapy exceeded 0·90 in the following

Saline solution

dialysis-free patients at baseline; data missing for 79 patients. §§Ordinal Bayesian proportional OR models.
19·2 (10·3)
14·7 (10·2)

subgroups: patients with sepsis (97·5), patients without

traumatic brain injury (93·3), patients with baseline
··
··
··
··
··
··
··
··

blood pH of 7·20–7·35 (91·0), patients who did not

receive saline before enrolment (90·4), female patients
(92·0), patients enrolled in cluster-randomised trials
2907/17 313 (16·8%)

(90·7), and patients with baseline serum sodium

934/16 628 (5·6%)
Balanced solution

concentration less than 135 mmol/L (98·5).

14·8 (10·1)
19·3 (10·2)

The independent risk of bias assessment for included

trials is shown in the appendix (p 9). Two trials were
··
··
··
··
··
··
··
··

deemed to be at low risk of bias6,7 and four at high risk of

bias.3–5,8
The evidence relating to in-hospital mortality and use
Days alive and out of hospital within 28 days§§

of renal replacement therapy was assessed to be of

Main model without SCOPE-DKA study§¶
Random slope for intervention in trial‡§

moderate certainty due to risk of bias (for in-hospital

In-hospital renal replacement therapy‡‡

Days alive out of ICU within 28 days§§

mortality) or inconsistency (for use of renal replacement

therapy; appendix p 14).
Table 3: Summary of effect sizes

Discussion
Frequentist model**

In this individual patient data meta-analysis

Adjusted model||
Pessimistic prior
Optimistic prior
In-hospital death

incorporating data from randomised clinical trials, the

Main model

use of balanced solutions for intravenous fluid therapy

in adults in the ICU was associated with a high
Survival

probability of reduced in-hospital mortality overall. The

main Bayesian analysis suggests the OR for in-hospital

242 www.thelancet.com/respiratory Vol 12 March 2024

 Articles

death for balanced solutions compared with saline

A
is 0·962 (ie, approximately a 4% reduction in the odds of
15
dying) with a 95% CrI of 0·909 to 1·019 (ie, around a Favours balanced solutions Favours saline
9% reduction or a 2% increase in the odds of dying,
respectively). These values are consistent with those

Posterior probability density

from the frequentist analysis (OR 0·962 10
[95% CI 0·908–1·020]). The point estimates and the CrIs
and CIs are consistent with the posterior probability
of 89·5% that the use of balanced solutions reduces
5
mortality by some amount, the converse of which is a
10·5% probability that it does not reduce mortality.
While the results of the Bayesian and frequentist
analyses are consistent, the inferences that can be drawn 0
from them might differ. A purely frequentist view would 0·84 0·88 0·92 0·96 1·00 1·04
be that there was no difference between balanced OR

solutions and saline, as the upper limit of the 95% CI

B
is 1·020. By contrast, the Bayesian analysis implies a
100 Saline solution
high probability that balanced solutions reduce mortality. Balanced solution
We defined a margin of practical equivalence, which can 36
be viewed as the range of ORs indicating that a treatment 32
Cumulative mortality (%)

should not be selected based on assessment of efficacy 28

alone, as an OR of 0·955–1·046. Thus, although our 24
analysis suggests a high probability that balanced 20
solutions reduce mortality by a small amount, other 16
factors such as acquisition cost might influence whether 12
clinicians choose to use them. When acquisition costs 8
are similar, clinicians might consider a 4% or less 4
reduction in risk of death sufficient evidence to choose 0
balanced solutions. However, the estimate for the 0 15 30 45 60 75 90
absolute reduction in mortality was 0·4 percentage Time (days)
Number at risk
points, meaning that 250 patients would have to be Saline solution 17166 7690 6393 6032 5872 5782 5717
Balanced solution 17313 7580 6357 6036 5878 5786 5726
treated with balanced solutions to prevent one death. In
situations where balanced solutions are more expensive Figure 2: Posterior probability distribution for in-hospital mortality and cumulative mortality
and health-care resources are limited, this possible (A) Plot of the posterior probability distribution for OR for in-hospital mortality for balanced solutions versus
benefit might not be considered compelling. saline. The vertical dotted line indicates an OR of 1·00 (point of equivalence between treatments). (B) Survival
curves according to fluid type. OR=odds ratio.
The use of balanced solutions was associated with
increased in-hospital mortality in patients with traumatic
brain injury and decreased in-hospital risk of death in concentration nor blood pH at enrolment could be used
patients without traumatic brain injury. These findings to identify patients in whom saline use was associated
support the use of balanced solutions in patients without with reduced mortality. These data do not support the
traumatic brain injury. There was also a high probability hypothesis that blood pH or chloride concentration are
that balanced solutions reduced treatment with renal the mechanism by which balanced solutions and saline
replacement therapy. are associated with differences in outcomes. We found
The direction of treatment effect replicates the findings no heterogeneity of treatment effect on the basis of
of a recent trial-level systematic review and meta- baseline serum sodium concentration.
analysis,9 but the ability of our analysis to separate Balanced solutions and saline are widely used in
patients with and without traumatic brain injury provides clinical practice. This study provides clinicians with
stronger evidence for both of those populations. In information that could inform choices about which fluid
addition, a probabilistic interpretation of the effect of to use for patients treated in an ICU.22 The combined
balanced solutions on treatment with renal replacement trials provide evidence that balanced solutions should be
therapy is also provided. The use of individual patient- favoured in critically ill patients without traumatic brain
level data from randomised clinical trials allowed for injury.
estimation of treatment effects in a range of subgroups This individual patient data meta-analysis has
of potential interest to clinicians. Apart from patients limitations. First, in an independent assessment, some
with traumatic brain injury, subgroups in which saline trials included in the analysis were judged to have a
use was associated with improved outcomes were not high risk of bias, predominantly due to cluster
identified. In particular, neither blood chloride randomisation, resulting in concerns over allocation

www.thelancet.com/respiratory Vol 12 March 2024 243

 Articles

In-hospital death, n/N (%) Odds ratio Probability Probability of

(95% credible of benefit* direction of
interval) interaction†

Balanced solution Saline solution

Sepsis3–8 0·60
No 1834/13 932 (13·2%) 1834/13 775 (13·3%) 0·981 (0·914–1·057) 0·682
Yes 1070/3370 (31·8%) 1136/3383 (33·6%) 0·935 (0·847–1·040) 0·893
Traumatic brain injury3–8 >0·99
No 2713/16 304 (16·6%) 2830/16 198 (17·5%) 0·942 (0·886–1·000) 0·975
Yes 191/999 (19·1%) 141/962 (14·7%) 1·424 (1·100–1·818) 0·003‡
Baseline serum chloride concentration, mmol/L5–8 0·54
<100 481/1992 (24·1%) 451/1867 (24·2%) 0·998 (0·864–1·153) 0·515
100 to 110 1060/7831 (13·5%) 1097/7724 (14·2%) 0·948 (0·865–1·043) 0·860
>110 408/2205 (18·5%) 462/2342 (19·7%) 0·917 (0·787–1·071) 0·867
pH6–8 0·66
<7·20 200/488 (41·0%) 221/494 (44·7%) 0·849 (0·642–1·119) 0·877
7·20 to <7·35 506/2424 (20·9%) 550/2527 (21·8%) 0·966 (0·837–1·121) 0·676
7·35 to 7·45 425/2457 (17·3%) 418/2368 (17·7%) 0·956 (0·821–1·119) 0·710
>7·45 216/747 (28·9%) 200/696 (28·7%) 1·014 (0·797–1·285) 0·458
Saline use before enrolment3–7 0·68
None 1865/11 903 (15·7%) 1819/10 618 (17·1%) 0·922 (0·856–0·990) 0·988
1 to 999 mL 410/1953 (21·0%) 399/2087 (19·1%) 1·097 (0·942–1·286) 0·128
≥1000 mL 621/3326 (18·7%) 747/4353 (17·2%) 0·996 (0·882–1·122) 0·521
Sex3–8 0·65
Female 1229/7305 (16·8%) 1299/7204 (18·0%) 0·928 (0·851–1·011) 0·950
Male 1673/9995 (16·7%) 1674/9956 (16·8%) 0·987 (0·914–1·068) 0·642
Study randomisation3–8 0·45
Cluster 1160/8510 (13·6%) 1172/8356 (14·0%) 0·964 (0·882–1·053) 0·786
Individual 1747/8803 (19·8%) 1803/8810 (20·5%) 0·961 (0·890–1·036) 0·841
Serum sodium concentration before enrolment, mmol/L5,6,8§ 0·51
<135 552/2407 (22·9%) 534/2307 (23·1%) 0·992 (0·871–1·133) 0·548
135 to 145 1394/9682 (14·4%) 1451/9735 (14·9%) 0·963 (0·883–1·041) 0·820
>145 230/566 (40·6%) 247/587 (42·1%) 0·953 (0·754–1·193) 0·666

0·6 0·7 0·8 0·9 1·0 1·1 1·2 1·3 1·4 1·6 1·8

Favours balanced solutions Favours saline

Figure 3: Forest plot of subgroup analysis of in-hospital mortality

Chloride and pH are the last recorded values before individual patient randomisation. The trials contributing data for each subgroup are indicated by reference numbers: SPLIT,3 SALT,4 SMART5 BaSICS,6
PLUS,7 and SCOPE-DKA.8 *Probability that balanced solution reduces the risk of in-hospital death compared with saline. †Estimate of the probability mass of the posterior for the interaction that points
towards an increase or decrease of effect. ‡The probability of harm (ie, increased mortality) was 0·975. §Post-hoc subgroup.

concealment. Second, primary outcome data were not
available for some participants because, in critical care
trials of urgent interventions, institutional review
boards and ethics committees might allow participant
enrolment without previous informed consent; however,
participants or their legal surrogates can subsequently
withhold consent to the use of their data, leading to loss
of outcome data. This loss resulted in 15 patients from
the BaSICS trial6 and 191 patients from the PLUS trial7
being excluded from the primary analysis, and four
patients from the SCOPE-DKA trial8 being excluded
from the survival analysis due to missing follow-up
data. Third, in the cluster-randomised trials, patients
might have received both balanced solution and saline if
present in the ICU when the units changed from using
one fluid to the other, and this carryover effect might
have affected the results. SMART5 was the largest
cluster-randomised trial (representing 15 802 of the
19 147 cluster-randomised participants included in this
meta-analysis) and had multiple crossovers, and
therefore the highest risk of carryover effects. As a
secondary analysis to adjust for carryover effects did not
affect the SMART study results, we did not repeat that
analysis. Fourth, we planned to evaluate the subgroup
of patients with non-traumatic acute brain injuries;
however, extracting data on this subgroup of patients
was not possible due to lack of prospective
subclassification of patients in the included trials. Thus,
the relative risks and benefits of balanced solutions
versus saline in patients with non-traumatic acute brain
injury remains unclear, and further research in such
patients is warranted. Fifth, this study included data
from randomised clinical trials that compared a range
of balanced solutions with saline, but did not allow for
the effects of different balanced solutions to be
compared.

244 www.thelancet.com/respiratory Vol 12 March 2024


Our report is the first iteration of a living review in
which the search will be repeated each year and the
analysis updated when new eligible trial data become
available.
In conclusion, overall, there is a high probability that
use of balanced solutions compared with saline in the
ICU is associated with reduced in-hospital mortality and
reduced treatment with renal replacement therapy, with
the evidence being of moderate certainty. However, in
patients with traumatic brain injury, balanced solutions
probably increase mortality.
Contributors
FGZ wrote the initial draft of the systematic review protocol, and all
authors revised and approved it. FGZ, GLDT, and LPD wrote the statistical
analysis plan, and all authors revised and approved it. FGZ, LPD, and ABC
searched and selected studies. FGZ and LPD merged databases and
checked for accuracy. FGZ, GLDT, and LPD analysed the data. FGZ, ABC,
GLDT, LPD, and SF have directly accessed the data. FGZ and SF wrote the
first draft of the manuscript and all remaining authors revised it. All
authors commented on drafts of the manuscript, approved the final
manuscript for submission, and were responsible for the decision to
submit the manuscript. FGZ and SF had full access to all of the data and
the final responsibility to submit for publication.
Declaration of interests
FGZ reports receiving consulting fees from Baxter (USA) and
Bactiguard (Sweden), and grants, paid to his institution from Ionis
Pharmaceuticals (USA), and receiving logistical support and donation
of study materials from Baxter Hospitalar for the BaSICS trial.
ABC reports receiving logistical support and donation of study materials
from Baxter Hospitalar for the BaSICS trial. GLDT reports receiving
consulting fees from Gilead paid to his then employer (The George
Institute for Global Health) for work outside the scope of this paper.
LPD reports receiving fees for statistical analysis from Nestlé and
Endpoint Health, all unrelated to the scope of this study. NEH reports
research funding and donation of study materials from Baxter
Healthcare related to intravenous fluid therapy, research funding from
Endpoint Health, and consulting fees from RevImmune unrelated to
fluid therapy, all paid to her employer; and competitive research grants
from the Australian National Health and Medical Research Council and
Medical Research Future Fund. FRM reports receiving consulting fees
from Baxter and receiving logistical support and donation of study
materials from Baxter Hospitalar for the BaSICS trial. SM declares no
competing interests. JM reports research funding and donation of study
materials from Baxter Healthcare related to intravenous fluid therapy,
paid to his employer; research funding from Endpoint Health unrelated
to fluid therapy; and competitive research grants from the Australian
National Health and Medical Research Council and Medical Research
Future Fund. MR reports donation of study materials from Baxter
Healthcare related to intravenous fluid therapy and competitive
research grants from the Australian Medical Research Future Fund.
BV reports donation of study materials from Baxter Healthcare related
to intravenous fluid therapy, research funding from Endpoint Health
unrelated to fluid therapy, and consulting fees from RevImmune
unrelated to fluid therapy, all paid to his institution; and competitive
research grants from the Australian National Health and Medical
Research Council. TWR reports receiving consulting fees received from
Cumberland Pharmaceuticals and Cytovale and fees for serving as a
data safety and monitoring board member from Sanofi, all unrelated to
the scope of this paper; and grants from the US National Institutes for
Health, Centers for Disease Control, and Department of Defence, all
paid to his institution. MWS reports receiving grants from the US
National Institutes for Health and Department of Defence unrelated to
the current work; and consulting fees and honoraria from Baxter
Healthcare related to intravenous fluid therapy. PJY reports receiving
competitive grants from the Health Research Council of New Zealand
unrelated to this work; consulting fees from AM Pharma unrelated to
this work; and consulting fees from Baxter Healthcare related to
intravenous fluid therapy. SF reports competitive research grants from
www.thelancet.com/respiratory Vol 12 March 2024
Articles
the Australian National Health and Medical Research Council, research
funding and consulting fees from Baxter Healthcare related to
intravenous fluid therapy, research funding and consulting fees from
RevImmune unrelated to fluid therapy, and research funding from
Endpoint Health unrelated to fluid therapy, all paid to his institution;
and owning stock options in Sepsis Scout, unrelated to fluid therapy.
Data sharing
Requests for access to data should be directed to the investigators of the
included trials who retain ownership of their data. The authors do not
have legal authority to share those data.
Acknowledgments
The independent risk of bias assessment for this study was done by
Caroline Kamp Jørgensen and Johan Holgersson.
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