Analytic Reviews

Journal of Intensive Care Medicine

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Different Concentrations of Albumin Versus © The Author(s) 2023
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Crystalloid in Patients with Sepsis and Septic DOI: 10.1177/08850666231170778
journals.sagepub.com/home/jic
Shock: A Meta-Analysis of Randomized
Clinical Trials

Li Geng, PhD1,* , Xiaoxue Tian, PhD1,*, Zifeng Gao, PhD1,

Aiqin Mao, PhD1, Lei Feng, PhD1, and Chao He, MD2

Abstract
Objective: The best type of resuscitation fluids for sepsis and septic shock patients remains unclear. The aim of this study was to
evaluate the efficacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis.
Materials and Methods: PubMed, EMBASE, and Web of Science databases were used for screening the relevant studies.
Randomized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in patients
with sepsis and septic shock. Data were examined and extracted by two reviewers independently. Any disagreements were
resolved by consensus with or without the help from a third reviewer. Data including mortality, sample size of the patients,
and resuscitation endpoints were extracted. Meta-analysis was carried based on the corresponding odds ratios with 95% confi-
dence intervals.
Results: Eight studies with a total of 5124 septic patients and 3482 septic shock patients were included in this study. Compared
with crystalloid, the use of albumin may represent a trend toward reduced the 90-day mortality of septic patients (OR 0.91 [0.80,
1.02]; P = .11) and significantly improved the outcome of septic shock patients (OR 0.85 [0.74, 0.99]; P = .04). Further analysis
showed a potentially beneficial role of both 4% to 5% and 20% albumin on reducing the mortality of septic patients. The use of
20% albumin significantly decreased the 90-day mortality of septic shock patients (OR 0.81 [0.67, 0.98]; P = .03), which was better
than 4% to 5% albumin and crystalloid.
Conclusions: Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients.
Both 4% to 5% and 20% of albumin may work better than crystalloid in improving the survival rate of patients with sepsis, but
more relative RCTs are required for validation.

Keywords
albumin, crystalloid, randomized controlled trials, meta-analysis, mortality, septic shock, sepsis

Introduction various amounts of substances, for instance, albumin, hydrox-

yethyl starch, dextran, and gelatin.5 Although the current
Sepsis is defined as life-threatening organ dysfunction caused
by a dysregulated host response to infection.1 Septic shock is
a subset of sepsis with circulatory and cellular/metabolic abnor- 1
Wuxi School of Medicine, Jiangnan University, Wuxi, China
malities.1,2 Sepsis and septic shock are global health problems, 2
Department of Emergency and Critical Care, Changzheng Hospital, Naval
leading to a high mortality rate.3 They are often associated with Medical University, Shanghai, China
extremely low blood pressure and multiple organ dysfunctions, *
Li Geng and Xiaoxue Tian contributed equally to this work.
which are the main causes of death in critically ill patients. Fluid
resuscitation is one of the most critical treatments for patients with Received November 15, 2022. Received revised March 30, 2023.
sepsis and septic shock. An early administration of an appropriate Accepted April 4, 2023.
fluid to patients is considered the most effective way to increase Corresponding Authors:
blood pressure, improve tissue perfusion, and save their lives.3,4 Lei Feng, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue,
Resuscitation fluids are divided into crystalloid and colloid 214122 Wuxi, Jiangsu, China.
solutions. Crystalloid fluids are a subset of intravenous solu- Email: feng2008lei@163.com
tions composed of mineral salts and other small, water-soluble
Chao He, Department of Emergency and Critical Care, Changzheng Hospital,
molecules, including normal, isotonic or hypertonic saline, and Naval Medical University, 200003 Shanghai, China.
various buffered solution. Colloid solutions are composed of Email: hechao19820110@163.com
2 Journal of Intensive Care Medicine 0(0)
international guidelines from the Surviving Sepsis Campaign
recommend crystalloids to perform the initial resuscitation,
and the replacement with albumin on patients who require sub-
stantial amounts of crystalloids, the choice of the best type of
resuscitation fluids is still under debate. A few large-scale ran-
domized controlled trials (RCTs) are available comparing the
therapeutic effects of albumin and crystalloids on patients
with sepsis or septic shock. The SAFE and EARSS study con-
cluded that the administration of human albumin solution does
not significantly change the rate of mortality, compared with
crystalloids.6,7 Another RCT such as the Albumin Italian
Outcome Sepsis (ALBIOS) study reported the positive effects
of albumin resuscitation on reducing the mortality.8
Additionally, some meta-analyses revealed the contradictory
conclusions on the effects of albumin treatment. Some studies
showed that albumin significantly improved the survival rate
of patients with sepsis or septic shock,9 while some others
found no differences between albumin and crystalloid treatment
in the reduction of the rate of mortality.10,11 Therefore, the
results of the above studies did not show a unanimous
conclusion.
Since 2018, no meta-analyses focusing on the comparison of
albumin with crystalloid solutions on reducing the mortality
rate of patients with sepsis or septic shock have been performed,
although some related RCTs have been conducted.12,13 Thus,
our meta-analysis aims to provide an update to further evaluate
the efficacy of albumin treatment versus that of crystalloids.
More importantly, various concentrations (ie, 4%, 5%, and
20%) of albumin solution are used in RCTs for sepsis and
septic shock patients. However, no comparisons among these
concentrations have been made. Therefore, this work is a sys-
tematic review and meta-analysis of RCTs performed to fill
this gap, focusing on the assessment of the concentration of
albumin associated to a better effect on reducing the mortality
in patients with sepsis and septic shock.
Materials and Methods
The protocol of this work was submitted to the International
Prospective Register of Systematic Reviews (PROSPERO)
(CRD42022362272). This meta-analysis followed the
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines. The PRISMA checklist
is provided in the supplementary materials.
Identification and Selection of Relevant
Studies
The relevant articles were collected using PubMed, EMBASE,
and Web of Science. The selected articles were published from
the inception until December 2021. The relevant citations of the
previously published meta-analyses were analyzed. The supple-
mentary appendices of the relevant studies were also screened.
The terms used for the search are listed in Table S1. The titles
and abstracts of all articles were examined by two reviewers
independently, to determine the potential eligibility. Any dis-
agreements were resolved by consensus with or without the
help from a third reviewer.
Eligibility Criteria
The following inclusion criteria were considered:
1. Adult patients aged over 16 years critically suffering
from sepsis or septic shock and admitted to a critical
or intensive care unit. Sepsis was defined referring to
The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3).1 Severe sepsis
was applied if articles were published before the
Sepsis-3 definition.
2. Clinical RCTs reporting patients who required fluid
therapy.
3. After randomization, patients who received intravenous
human albumin solution of any concentration or type in
any vehicle were compared with those who received
intravenous crystalloids of any strength or type in any
vehicle.
4. Availability of data of all-cause mortality, including
28-day mortality, 90-day mortality or mortality at
other time points.
The following exclusion criteria were considered:
1. Unavailability of full-text articles.
2. Articles not published in English.
3. Articles that were not original research.
4. Articles with no adult patients.
5. Articles with patients not confirmed as suffering from
sepsis or septic shock.
6. Articles not comparing human albumin with crystalloid.
7. Articles without all-cause mortality data.
Data Extraction
Two independent reviewers extracted the data using a pre-
defined extraction table. Any disagreements were resolved
through discussion with a third clinician until the consensus
was reached. The study characteristics were collected, including
the year of the studies, the number of patients with sepsis or
septic shock, the endpoint of each trial, and the mortality
data. The 28-day and 90-day mortality data were extracted
when available, otherwise, mortality at hospital or other time
points was collected. The authors were contacted in case of
uncertain information in the publications.
Risk of Bias Assessment
The risk of bias of each study was independently assessed by
two reviewers, using the revised version of the Cochrane tool,
following the Cochrane Handbook for Systematic Reviews of
Interventions.14,15 Any disagreements were resolved through
Geng et al
discussion with a third clinician. The domains of the assessment
included the randomization process, deviations from intended
interventions, missing outcome data, measurement of the
outcome, selection of the reported result, and overall bias.
Statistical Analysis
This meta-analysis was carried out using STATA version 16.0,
based on the corresponding odds ratios (ORs) with 95% confi-
dence intervals (95% CIs). A direct comparison between
albumin (4%-5% and 20%) and crystalloids, as well as an indi-
rect comparison between 4% to 5% and 20% albumin on the
effects on all-cause mortality was performed. The statistical het-
erogeneity was evaluated in the direct comparisons by estimat-
ing the variance among studies, using the chi-square test and the
I2 test.16,17 Heterogeneity was considered when P < .05 with the
chi-square test or I2 > 50% with the I2 test. The random-effects
model was applied in case of heterogeneity, otherwise, the
fixed-effects model was used. Rank plots based on probabilities
were performed to estimate the best treatment.18
Results
Study Selection and Characterization
A total of 5791 studies were identified, in which the latest study
was from 2021. A total of 1587 articles were excluded as dupli-
cates. The screening of the titles and abstracts of the remaining
4204 records revealed that 4125 articles were removed as satis-
fying at least one condition listed in the exclusion criteria.
Seventy-nine articles were potentially eligible for the assess-
ment of the full text. Finally, 8 articles with a total of 5124
septic patients and 3482 septic shock patients were included
in this meta-analysis. The details of the exclusion are shown
in Figure 1. Seventeen studies were reviewed or meta-analysis.
Sixteen studies analyzed the same data. Two studies were con-
ference abstracts containing no data on mortality. Thirteen
studies were clinical trials but not RCTs. Twenty-three
studies did not compare albumin with crystalloid. The included
studies are characterized in Table S2. Briefly, five studies used
4% to 5% albumin for fluid resuscitation, whereas two studies
used 20% albumin treatment. One RCT included both concen-
trations. Normal saline was used as crystalloid in four studies.
Ringer’s lactate solution was used as crystalloid in two trials.
The remaining two trials used various types of crystalloid solu-
tions. Data of mortality were extracted and included two-time
points, 28-day, and 90-day mortality rates for both sepsis and
septic shock. The bias assessment of the relevant studies is
described in Table S3.
Efficacy of Albumin Treatment on Mortality
Eight studies contained the data of 28-day mortality in patients
with sepsis (Figure 2A). Fluid therapy with human albumin did
not reduce the mortality compared with crystalloid therapy, as
the difference was not statistically significant (OR 0.94 [0.83,
3
1.07]; P = .35). The heterogeneity was not-significant (P =
.53, I2 = 0%).
Information on 90-day mortality in patients with sepsis was
extracted from eight trials (Figure 2B). The data of the longest
complete follow-up (90-day mortality) were used in the analysis
since two studies investigated the mortality rate for more than
one-time point.8,19 The heterogeneity was not significant (P =
.64, I2 = 0%). Although a trend toward reduced mortality was
found in patients who received albumin solution compared
with crystalloid, the difference was again not statistically signif-
icant (OR 0.91 [0.80, 1.02]; P = .11).
The effects on 90-day mortality in patients with septic shock
were evaluated in seven trials (Figure 2C). The heterogeneity
was not significant (P = .60, I2 = 0%). The resuscitation using
albumin significantly decreased the 90-day mortality in septic
shock patients, compared with the use of crystalloid solutions
(OR 0.85 [0.74, 0.99]; P = .04).
Impact of Different Concentrations of Albumin on
Mortality in Patients with Sepsis
The 28-day mortality in septic patients was reported in all
studies involving the direct comparisons between two concen-
trations of albumin and crystalloid. Five trials compared 4%
to 5% albumin with crystalloid, while two trials estimated the
impact of 20% albumin compared with crystalloid. One trial
included both concentrations of albumin without defining the
mortality rate for each group. No direct comparison between
4% to 5% albumin and 20% albumin was found in the literature.
Thus, finally, seven RCTs were included (Figure 3A). The
meta-analysis results showed that albumin of both concentra-
tions displayed no beneficial effect on 28-day mortality in
septic patients, compared with crystalloid (4%-5% albumin vs
crystalloid, OR 0.90 [0.74, 1.08]; P = .25; 20% albumin vs
crystalloid, OR 0.96 [0.81, 1.14]; P = .67). Figure 3B shows
the probability-based ranking results, indicating that 4% to
5% albumin ranked the highest and crystalloid ranked the
lowest in reducing the mortality rate.
Seven RCTs that considered the 90-day mortality in patients
with sepsis were included in the meta-analysis. Five RCTs com-
pared 4% to 5% albumin with crystalloid, and two trials com-
pared 20% albumin with crystalloid (Figure 4A). None of
them found a significant difference from the meta-analysis
(4%-5% albumin vs crystalloid, OR 0.90 [0.74, 1.08]; P =
.25; 20% albumin vs crystalloid, OR 0.90 [0.77, 1.06]; P =
.21). The probability-based ranking results are shown in
Figure 4B. The dose of 4% to 5% albumin ranked as similar
as 20% albumin, while crystalloid ranked the lowest in reducing
the mortality rate.
Impact of Different Concentrations of Albumin on
Mortality in Patients with Septic Shock
The 90-day mortality in patients with septic shock was
reported in six studies. Four compared 4% to 5% albumin
4 Journal of Intensive Care Medicine 0(0)

Figure 1. Flow diagram of the study selection process.

with crystalloid in 953 patients, and two trials compared
20% albumin with crystalloid in 1913 patients
(Figure 5A). The meta-analysis results indicated that 4%
to 5% albumin did not significantly decrease mortality com-
pared with crystalloid (OR 0.89 [0.68, 1.08]; P = 1.15).
However, 20% albumin markedly reduced the mortality, in
comparison to crystalloid (OR 0.81 [0.67, 0.98]; P = .03).
Figure 5B shows the probability-based ranking results,
which revealed that 20% albumin ranked the highest in
reducing the mortality rate.
Geng et al 5

Figure 2. The comparison between albumin and crystalloid on all-cause mortality of sepsis and septic shock patients at different endpoints.
(A) 28-day mortality rate of septic patients. (B) 90-day mortality rate of septic patients. (C) 90-day mortality rate of septic shock patients.
6 Journal of Intensive Care Medicine 0(0)

Figure 3. (A) The effects of different concentrations of albumin on 28-day mortality in septic patients. (B) The ranking of resuscitation fluid
based on the cumulative probability plots.

Discussion albumin treatment could reduce the 90-day mortality in patients

Previous meta-analyses investigated the efficacy of human
albumin on reducing the morality of patients with sepsis or crit-
ically ill patients.10,20–22 Nevertheless, only a few research
focused on the evaluation of the resuscitation with albumin in
patients with sepsis and septic shock. One study revealed that
with sepsis and septic shock compared with crystalloid.9
However, another study concluded that albumin is unable to
decrease the mortality.11 Our meta-analysis aimed to provide
an update on the impact of albumin in resuscitating patients
with sepsis and septic shock with inclusion of the most recent
Geng et al
Figure 4. (A) The effects of different concentrations of albumin on 90-day mortality in septic patients. (B) The ranking of resuscitation fluid
based on the cumulative probability plots.
RCTs. More importantly, to the best of our knowledge, no
meta-analysis was performed to compare 4% to 5% and 20%
albumin with crystalloid on the reduction of the mortality of
patients with sepsis and septic shock. Our results revealed
that resuscitation with albumin solutions may represent a
trend toward reduced the 90-day mortality of patients with
sepsis, compared with the effect of crystalloid. Resuscitation
with albumin significantly decreased the all-cause mortality in
7
septic shock patients. Moreover, the use of 4% to 5%
albumin for resuscitation might be associated with the lowest
28-day mortality in patients with sepsis, as indicated by of the
probability-based ranking tests. The application of 20%
albumin represented the best choice in reducing the 90-day
mortality in patients with septic shock.
Sepsis and septic shock are associated with unacceptably
high mortality.23 A large number of RCTs were performed to
8 Journal of Intensive Care Medicine 0(0)

Figure 5. (A) The effects of different concentrations of albumin on 90-day mortality in septic shock patients. (B) The ranking of resuscitation
fluid based on the cumulative probability plots.

determine the most effective resuscitation fluid in the increase
of the survival rate. However, an up-to-date review of these
trials for the estimation of the role of albumin in the mortality
rate is missing. A total of eight RCTs from 1983 to 2021
were included in this meta-analysis. The results of our analysis
showed that the survival rate was improved by the resuscitation
using albumin, particularly in septic shock patients, although
one RCT (ALBIOS study) reported the opposite outcome.
These findings were consistent with those in a previous meta-
analysis published in 2014.9 Nevertheless, our results on the
beneficial effect of albumin in decreasing the mortality in
septic shock patients were contradictory to those from a study
published in 2018.11 This could be due to the variance of the
included studies and the corresponding patient number, since
one extra RCT published recently was added.13 Moreover, the
data on patients with septic shock from the RASP study were
incomplete, since the trial was not finished by that time.12
Notably, some analysis suggests a beneficial role of balanced
Geng et al
crystalloids in reducing mortality compared to saline.22,24,25 It
is plausible that albumin may have greater benefits comparing
to saline and fewer benefits comparing to balanced crystalloids.
However, this remains to be confirmed due to the lack of RCTs
that directly compare albumin with balanced crystalloid.
Conclusively, our study provided more updated evidence
underlining that albumin was the better resuscitation fluid par-
ticularly in patients with septic shock, compared with
crystalloid.
There are two types of albumin solutions used in clinical
trials, 4% to 5% and 20% albumin. Nevertheless, only one
study has investigated the effect of each concentration of
albumin compared to crystalloid on the mortality of septic
shock patients.11 No such comparisons have been made for
both sepsis and septic shock patients. Moreover, no trials
directly compared 4% to 5% with 20% albumin up to now.
Thus, the probability-based ranking tests were added to the
meta-analysis to predict the best resuscitation fluid. Our analy-
sis demonstrated that 20% albumin significantly reduced the
90-day mortality in septic shock patients compared with crystal-
loid. The probability-based ranking results indicated that both
concentrations of albumin worked better than crystalloid.
20% albumin was the most effective solutions in reducing the
90-day mortality of septic shock patients, and 4% to 5%
albumin was superior to other fluids in decreasing 28-day mor-
tality of patients with sepsis. Taken together, our work showed
that higher percentage of albumin might serve as an optimal
resuscitation fluid in patients with long-term increasing
severity.
Various hypothetical mechanisms are available for improv-
ing the outcome of patients with sepsis and septic shock by
albumin administration, compared with crystalloid. First,
albumin regulates plasma colloid osmotic pressure more effec-
tively, increasing interstitial fluid reabsorption into the intravas-
cular space, and resolves interstitial edema.26,27 Second,
albumin acts as a free radical scavenger, and attenuates glyco-
calyx degradation.26,28 Its role in restoring impaired vascular
permeability and regulating cell adhesion contributes to being
beneficial to outcome. Third, albumin acts as a key binder to
functional molecules and causes immunomodulatory and
anti-inflammatory effects.29 Finally, albumin was found to be
associated with reduced need for mechanical ventilation and
vasopressor therapy, which resulted in renal protection in criti-
cally ill patients.19
Septic shock is associated with excessive release of a multi-
tude of proinflammatory mediators, which leads to the induc-
tion of a profound inflammatory response causing
hemodynamic decompensation.30 The goal of fluid resuscita-
tion is to provide intravascular volume expansion and restore
effective volume. Compared with 4% to 5% albumin, our find-
ings suggest that 20% albumin is superior in achieving these
goals. The reason being that 20% albumin has a higher
plasma colloid osmotic pressure, which induces fluid reabsorp-
tion from the extravascular space, effectively restoring intravas-
cular volume and reducing interstitial edema. In contrast, 4% to
5% albumin has a lower concentration and requires a larger
9
fluid volume, increasing the risk of electrolyte imbalances
during intravascular volume expansion, leading to adverse out-
comes. Additionally, septic shock patients often suffer from
hypoalbuminemia due to increased body temperature and
metabolism, which exacerbates the loss of effective volume
and multiple organ dysfunction. Administering 20% albumin
effectively improves the prognosis of septic shock patients,
whereas for sepsis patients with mild conditions, the consump-
tion and complications of albumin are not as severe, and 20%
albumin may not significantly improve outcomes. Therefore,
based on the higher plasma colloid osmotic pressure, effective
intravascular volume restoration, and reduced interstitial
edema, 20% albumin infusion is superior to 4% to 5%
albumin, particularly for septic shock patients. However, addi-
tional clinical data such as the volume of fluids received, serum
albumin levels, and hemodynamic parameter improvements
would further strengthen this finding. For example, a compari-
son of 20% albumin and crystalloid showed that the former is
associated with higher mean arterial pressure, higher serum
albumin levels, lower net fluid balance, and lower heart rate.8
Conducting a formal analysis that considers these data in the
future could enhance the quality of our work.
Our study has some limitations that should be mentioned.
First, eight RCTs were included, with two involving a small
number of patients and two relating 20% albumin. Therefore,
more high-quality RCTs are further needed. Second, although
the CRISTAL study was included to evaluate the efficacy of
albumin treatment on mortality, it was excluded from compar-
ing 4% to 5% and 20% albumin, due to the unidentified distri-
bution of patients receiving two concentrations of albumin.
Knowing this information could help provide more accurate
conclusions. Third, different endpoints were found in different
RCTs, including hospital mortality, 28-day and 90-day mortal-
ity data. This could affect the overall results. Finally, the
volume of the resuscitation fluid and the timing of fluid admin-
istration were not investigated in our study, which may have
contributed to unrecognized heterogeneity. Thus, further analy-
sis of different types, volumes and administration timing of
fluids should be considered due to their potential association
with the clinical outcome.
Conclusions
In summary, our results suggested that compared with crystal-
loid, albumin resuscitation may present a trend toward
improved the survival rate of patients with sepsis. Albumin
treatment, particularly 20% albumin, significantly reduced the
90-day mortality in septic shock patients. However, more high-
quality studies are needed for a better evaluation of the effects
of albumin, due to the limitations of our study.
Acknowledgments
We very much thank Dr Tingting Zhou, Dr Hao Kan, Dr Ka Zhang,
and Ms Yanting Li (Wuxi School of Medicine, Jiangnan University,
China) for their knowledge in the clinical field and help in the
design of figures.
10
Author Contributions
LG and XT independently reviewed all the articles, assessed the
included studies, and extracted the data. Disagreements were resolved
by consensus and discussion with ZG and CH. LG, XT, and AM inter-
preted the data and carried out the analysis. LG, LF, and CH drafted
and edited the manuscript. LG and LF designed the study. All
authors approved the final manuscript and agreed to be accountable
for all aspects of the work.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This work was sup-
ported by National Natural Science Foundation of China (82100416) and
Shanghai Science Development Funds (21Y11902500).
ORCID iD
Li Geng https://orcid.org/0000-0002-4264-677X
Supplemental Material
Supplemental material for this article is available online.
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