Different concentrations of albumin versus crystalloid in patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials

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Different concentrations of albumin versus crystalloid in patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials

https://doi.org/10.21203/rs.3.rs-1434369/v1

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Background

The best type of resuscitation fluids for severe sepsis and septic shock patients remains unclear. The aim of this study was to evalute the effacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis.

Methods

PubMed, EMBASE and Web of Science databases were used for screening the relevant studies. Ramdonized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in severe sepsis and septic shock patients. 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 out using STATA version 16.0, based on the corresponding odds ratios with 95% confidence intervals.

Results

Eight studies with a total of 5124 severe sepsis patients and 3482 septic shock patients were included in this study. Compared with crystalloid, the use of albumin slightly reduced the 90-day mortality of severe sepsis patients [OR 0.91 (0.80, 1.02); P = 0.11] and significantly improved the outcome of septic shock patients [OR 0.85 (0.74, 0.99); P = 0.04]. Further analysis showed a potentially benenifical role of both 4–5% and 20% albumin on reducing the mortality of severe sepsis patients. The use of 20% albumin significantly decreased the 90-day mortality of septic shock patients [OR 0.81 (0.67, 0.98); P = 0.03], which was better than 4–5% albumin and crystalloid.

Conclusions

Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients. Either 4–5% or 20% of albumin may work better than crystalloid in improving the survival rate of patients with severe sepsis, but more relative RCTs are required for validation.

Albumin

crystalloid

ramdonized controlled trials

meta-analysis

mortality

septic shock

severe sepsis.

Sepsis is an infection-induced systemic inflammatory syndrome that is a global health problem[1, 2]. Severe sepsis and septic shock are often associated with extremely low blood pressure and multiple organ dysfunctions, which are the main causes of death in critically ill patients with sepsis. Fluid resuscitation is one of the most critical treatments for patients with severe sepsis and septic shock. An early administration of an appropriate fluid to patients is considered the most effective way to increase blood pressure, improve tissue perfusion, and save their lives [3, 4].

Resuscitation fluids are divided into crystalloid or colloid solutions. Crystalloid solutions are composed of 0.9% normal saline and balanced solutions (e.g., Ringer's lactate). Colloid solutions are composed of various amounts of substances, for instance, albumin, hydroxyethyl starch, dextran, and gelatin[5]. Although the current international guidelines from the Surviving Sepsis Campaign recommend crystalloids to perform the initial resuscitation, and the replacement with albumin on patients who require substantial amounts of crystalloids, the choice of the best type of resuscitation fluids is still under debate. A few large-scale randomized controlled trials (RCTs) are available comparing the therapeutic effects of albumin and crystalloids on patients with severe sepsis or septic shock. The SAFE and EARSS study concluded 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 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 severe 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 severe 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 (i.e., 4%, 5% and 20%) of albumin solution are used in RCTs for severe sepsis and septic shock patients. However, no comparisons among these concentrations have been made. Therefore, this work is a systematic 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 severe sepsis and septic shock.

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 supplementary appendices of the relevant studies were also screened. No language restrictions were considered during the search. 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 disagreements were resolved by consensus with or without the help from a third reviewer.

Eligibility criteria

The following inclusion criteria were considered:

Adult patients aged over 16 years critically suffering from severe sepsis or septic shock and admitted to a critical or intensive care unit.
Clinical RCTs reporting patients who required fluid therapy.
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.
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:

Unavailability of full-text articles.
Articles not published in English.
Articles that were not original research.
Articles with no adult patients.
Articles with patients not confirmed as suffering from severe sepsis or septic shock.
Articles not comparing human albumin with crystalloid.
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 severe 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 were 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 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% confidence intervals (95% CIs). A direct comparison between albumin (4-5% and 20%) and crystalloids, as well as an indirect comparison between 4-5% and 20% albumin on the effects on all-cause mortality was performed. The statistical heterogeneity was evaluated in the direct comparisons by estimating the variance among studies, using the chi-square test and the I² test[16, 17]. Heterogeneity was considered when P <0.05 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].

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 duplicates. The screening of the titles and abstracts of the remaining 4204 records revealed that 79 articles were potentially eligible for the assessment of the full text. Finally, 8 articles with a total of 5124 severe sepsis 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 review or meta-analysis. Sixteen studies analyzed the same data. Two studies were conference 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, 5 studies used 4-5% albumin for fluid resuscitation, whereas 2 studies used 20% albumin treatment. One RCT included both concentrations. Normal saline was used as crystalloid in 4 studies. Ringer’s lactate solution was used as crystalloid in 2 trials. The remaining 2 trials used various type of crystalloid solutions. Data of mortality were extracted and included two time points, 28-day and 90-day mortality rates for both severe 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 severe 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, 1.07); P= 0.35]. The heterogeneity was not-significant (P= 0.53, I²= 0%).

Information of 90-day mortality in patients with severe sepsis was extracted from 8 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= 0.64, 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 significant [OR 0.91 (0.80, 1.02); P= 0.11].

The effects on 90-day mortality in patients with septic shock were evaluated in 7 trials (Figure 2C). The heterogeneity was not significant (P= 0.60, 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= 0.04]. Thus, our analysis showed that albumin might be effective in reducing all-cause mortality for septic shock, but not that for severe sepsis.

Impact of different concentrations of albumin on mortality in patients with severe sepsis

The 28-day mortality in severe sepsis patients was reported in all studies involving the direct comparisons between two concentrations of albumin and crystalloid. Five trials compared 4-5% 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 4-5% albumin and 20% albumin was found in the literature. Thus, finally 7 RCTs were included (Figure 3A). The meta-analysis results showed that albumin of both concentrations displayed no benefical effect on 28-day mortality in severe sepsis patients, compared with crystalloid. [4-5% albumin vs. crystalloid, OR 0.90 (0.74, 1.08); P = 0.25; 20% albumin vs. crystalloid, OR 0.96 (0.81, 1.14); P = 0.67]. Figure 3B shows the probability-based ranking results, indicating that 4-5% albumin ranked the highest and crystalloid ranked the lowest in reduing the mortality rate. Thus, resuscitation with 4-5% albumin might be associated with the lowest 28-day mortality in patients with severe sepsis.

Seven RCTs that considered the 90-day mortality in patients with severe sepsis were included in the meta-analysis. Five RCTs compared 4-5% albumin with crystalloid, and 2 trials compared 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= 0.25; 20% albumin vs. crystalloid, OR 0.90 (0.77, 1.06); P= 0.21]. The probability-based ranking results are shown in Figure 4B. The dose 4-5% albumin ranked as similar as 20% albumin, while crystalloid ranked the lowest in reduing the mortality rate. Patients with severe sepsis resuscitated with either concentration of albumin may have lower 90-day mortality than those resuscitated with crystalloid.

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 6 studies. Four compared 4-5% albumin with crystalloid in 953 patients, and 2 trials compared 20% albumin with crystalloid in 1913 patients (Figure 5A). The meta-analysis results indicated that 4-5% albumin did not significantly decrease mortality compared 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= 0.03]. Figure 5B shows the probability-based ranking results, which revealed that 20% albumin ranked the highest in reducing the mortality rate. Thus, resuscitation with 20% albumin in patients with septic shock could represent the best choice in reducing the all-cause mortality.

Previous meta-analyses investigated the efficacy of human albumin on reducing the morality of patients with sepsis or critically ill patients[10, 20–22]. Nevertheless, only a few research focused on the evaluation of the resuscitation with albumin in patients with severe sepsis and septic shock. One study revealed that albumin treatment could reduce the 90-day mortality in patients with severe 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 severe sepsis and septic shock with inclusion of the most recent RCTs. More importantly, to the best of our knowledge, no meta-analysis was performed to compare the hypooncotic (4–5%) and hyperoncotic (20%) albumin with crystalloid on the reduction of the mortality of patients with severe sepsis and septic shock. Our results revealed that resuscitation with albumin solutions could potentially reduce the 90-day mortality of patients with severe sepsis, compared with the effect of crystalloid. The application of hyperoncotic albumin significantly decreased the 90-day mortality in patients with septic shock.

The mortality due to severe sepsis and septic shock is high in patients with sepsis[23]. A large number of RCTs were performed to 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 8 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]. Consequently, our study provided more updated evidence underlining that albumin was the better resuscitation fluid particularly in patients with septic shock, compared with crystalloid.

There are two colloid families of albumin solutions used in clinical trials, the hypooncotic and hyperoncotic albumin. However, the comparison of the impact of either concentration of albumin with crystalloid on the mortality of both severe sepsis and septic shock patients was not performed properly. Moreover, no trials directly compared hypooncotic with hyperoncotic albumin up to now. Thus, the probability-based ranking tests were added to the meta-analysis to predict the best resuscitation fluid. Our analysis demonstrated that 20% albumin significantly reduced the 90-day mortality in septic shock patients compared with crystalloid. The probability-based ranking results indicated that both concentrations of albumin worked better than crystalloid. Indeed, 20% albumin was the most effective solutions in reducing the 90-day mortality of septic shock patients, and 4–5% albumin was superior to other fluids in decreasing 28-day mortality of patients with severe 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.

Our study has some limitations that should be mentioned. First, 8 RCTs were included, with 2 involving a small number of patients. Therefore, more high-quality RCTs are further needed. Second, the CRISTAL study was excluded from the analysis, due to the unidentified distribution of patients in the 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 mortality data. This could affect the overall results. Finally, the volume of the resuscitation fluid was not investigated in our study. Thus, further analysis of different types and volumes of fluids should be considered due to their association with the clinical outcome.

In conclusion, our results suggested that either concentration of albumin was potentially more effective than crystalloid in improving the survival rate of patients with severe 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.

ALBIOS study

the Albumin Italian Outcome Sepsis study

confidence interval

ESRSS study

Early Albumin Resuscitation During Septic Shock study

odds ratio

RCT

Randomized controlled trial

SAFE study

the Saline versus Albumin Fluid Evaluation study

Ethics approval and consent to participate

As we collected and analysed data from previous published clinical trials in which informed consent has already been obtained by the trial investigators, this meta-analysis study does not require ethics approval.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this article and its supplementary information files.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by National Natural Science Foundation of China (82100416) and Shanghai Science Development Funds (21Y11902500).

Authors' contributions

LG and XT indepently reviewed all the articles, assessed the included studies and exatracted the data. Disagreements were resolved by consensus and discussion with ZG and CH. LG, XT and AM interpretated the data and carried out the analysis. LG, CH and LF drafted and edited the manuscript. LG and LF designed the study. All authors approved the final manuscript.

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No competing interests reported.

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Different concentrations of albumin versus crystalloid in patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials

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