Introduction
Severe sepsis and septic shock are major causes of death in critically ill patients, and fluid management can resuscitate patients in these conditions. Early adequate volume expansion is emphasized as the key elements to be focused on saving lives [
1]-[
3]. With the advantage of restoring effective volume and maintaining colloid osmotic pressure, albumin is considered to be administered in addition to crystalloid in the initial fluid management of patients with severe sepsis and septic shock [
4].
Whether albumin is associated with reduced mortality in the resuscitation of severe sepsis and septic shock compared with crystalloid is a matter of debate. The predefined subgroup analysis of the Saline versus Albumin Fluid Evaluation (SAFE) study suggested albumin potentially resulted in lower mortality in patients with severe sepsis [
5],[
6]. However, previous meta-analyses that focused on sepsis patients drew nonequivalent results [
7],[
8]. The large randomized controlled trial, the Albumin Italian Outcome Sepsis (ALBIOS) study also reported contradictory results that albumin provided no improvement at day 28 in patients with severe sepsis [
9], while the
post hoc analysis of the septic shock subgroup supported a survival benefit to albumin, given the target patient population in this meta-analysis.
As a result of few investigators emphasizing the use of albumin in patients with severe sepsis, let alone septic shock, a meta-analysis is needed to address the outcome of albumin as fluid therapy. Furthermore, as the most commonly used crystalloid, no study stressed the role of albumin when compared with saline in severe sepsis patients.
Our goal was to examine whether albumin reduced mortality when employed in the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid solutions and saline.
Material and methods
Search strategy for identification of relevant studies
A search of the following databases was conducted: Medline, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. The following keywords were used as searching terms: ‘albumin’ or ‘serum albumin’ or ‘albumin replacement’ or ‘colloid’ or ‘crystalloid’ or ‘crystalloid solution’ or ‘saline’ or ‘normal saline’ or ‘Ringer's solution’ or ‘bicarbonated Ringer’s solution’ or ‘lactated Ringer’s solution’ or ‘isotonic solution’ or ‘hypertonic saline’ and ‘sepsis’ or ‘severe sepsis’ or ‘septic shock’ or ‘shock’ or ‘critical ill’ or ‘critical illness’ or ‘intensive care units’ or ‘intensive care’ or ‘critical care’ or ‘ICU’. No language restrictions were placed on the search. All databases were searched for articles published from inception until March 31, 2014. Additional files and supplementary appendices of the relevant articles were also reviewed. Detailed search strategies are shown in Additional file
1: Search strategy.
Study selection
One reviewer screened the search results, and the full-text manuscripts of all potentially eligible studies were acquired. Then, all of the articles were reviewed by two reviewers independently in accordance with the inclusion criteria. Disagreements between the two reviewers were resolved by consensus and discussion including a third reviewer. When the ‘same author’ or ‘same data’ issue was confronted with, the latest published study was included.
Inclusion and exclusion criteria
We included trials with the following features:
1.
Type of trials: randomized controlled clinical and parallel trials.
2.
Population: trials including adult population with severe sepsis. Severe sepsis was defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion [
4].
3.
Intervention: patients submitted to albumin for fluid therapy.
4.
Comparison: crystalloid for fluid therapy.
5.
Outcome: the primary outcome was all-cause mortality, including 28-day mortality, 90-day mortality or mortality at other time points.
Trials with the following features were excluded:
1.
They were not published in English or Chinese.
2.
They were not published as original articles.
3.
They did not use adult patients.
4.
They did not compare albumin with crystalloid.
5.
They included no data on mortality in patients with severe sepsis.
6.
Full-text articles were not available.
Quality assessment
The quality of each article was assessed by two reviewers independently. Disagreements were resolved by consulting a third reviewer. The five-point Jadad scale was calculated to assess the quality of the trial [
10]. This scale includes the method of randomization, blinding, and loss to follow-up. In addition, sequences generation, allocation concealment, incomplete outcome data, selective reporting and other bias were also inspected to assess the risk of bias [
11]. The latter was reported as low risk, unclear risk, or high risk for each trial. Low risk was defined as low risk of bias in all domains. Unclear risk was defined as unclear risk of bias in at least one domain with no high risk of bias domains. High risk was defined as high risk of bias in one or more domains. The publication bias was assessed by funnel plot techniques.
Data extraction and management
Using a data extraction table, two reviewers independently extracted data. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Then, data were proofread by another reviewer. Mortality data, including 28-day or 90-day mortality, were recorded during the data extraction. When 28-day and 90-day morality values were both published in the article, the longest complete follow-up was preferentially used for evaluation in the meta-analysis. However, when 28-day or 90-day mortality values were not presented, ICU or hospital mortality or mortality at other time points were recorded. Other data including the population of each trial, sample size of the trial and patients with severe sepsis, and resuscitation endpoints were extracted. If there was insufficient information in the publications, the contact to the authors was performed.
For studies including a subgroup of septic shock patients, the sample size of septic shock patients and the number of non-survivals were extracted.
Statistical analysis
Data were analyzed by Review Manager 4.2 (The Nordic Cochrane Center, Rigshospitalet, Copenhagen, Denmark). The pooled odds ratio (OR) for dichotomous data and mean differences for continuous data with 95% confidence intervals (CIs) were calculated. The statistical heterogeneity of the data was explored and quantified using the Mantel-Haenszel chi-square test and the I2 test. Heterogeneity was predefined as P <0.05 with the Mantel-Haenszel chi-square test or an I2 value >50%. The random-effects model was used if heterogeneity was observed; otherwise, the fixed-effects model was used. P <0.05 was considered statistically significant.
Discussion
Although previous meta-analyses [
7],[
8],[
16]-[
19] have explored the impact of albumin in resuscitating critically ill and sepsis patients, few investigators focused on the use of albumin in patients with severe sepsis, especially with septic shock. Our analysis was the only meta-analysis focusing totally on severe sepsis and septic shock, which are the most important and specific subset of sepsis, and for that the analysis separated from previous meta-analyses studies. Furthermore, to our knowledge, no meta-analysis has compared albumin with saline in severe sepsis patients up to now. In this meta-analysis, the effect of albumin as a resuscitation fluid on mortality in severe sepsis and septic shock was investigated. The results suggested a trend toward reduced 90-day mortality in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the use of albumin for resuscitation significantly decreased the 90-day mortality in septic shock patients.
A meta-analysis is imminent for stressing the role of albumin in resuscitating patients with severe sepsis and septic shock. As the major and specific subsets of sepsis, it was reported the mortality of severe sepsis without shock was 14 to 30%, while in septic shock, the mortality rate raised to 22 to 40% [
20]. Therefore, multiple randomized controlled trials have attempted to identify effective treatments to improve the survival of patients with severe sepsis and septic shock, rather than sepsis. However, the latest ALBIOS study published a disappointing result. To determine whether severe sepsis and septic shock patient benefit from the use of albumin for resuscitation compared with crystalloid, and to explore a better solution to improve the outcome, we conducted this meta-analysis to observe the effect of albumin on mortality in the resuscitation of severe sepsis and septic shock patients.
Our results were not equivalent with the recent study published by Patel
et al. [
8], which showed albumin was ineffective at reducing all-cause mortality. The differences come from: the variant target study population, the more comprehensive included studies, the distinct comparison, the dissimilar results and conclusion. As a result, our manuscript might add new evidence to help guide albumin as an optimal resuscitation fluid for septic shock.
Although the study published by Patel et al. did assess the role of albumin in sepsis of any severity, they did not highlight its role in severe sepsis and septic shock. As a result, the study lacked the detailed description of the characteristics of the included studies. Moreover, the data of septic shock from some important studies (for example the SAFE study) were incomplete owing to the unsuccessful data requests.
The comparison was goals-explicit in our study. As the unsolved, fundamental challenge in resuscitating severe sepsis and septic shock, it is recommended that albumin should be added to the initial resuscitation with crystalloid, and the application of hydroxyethyl starches was against given their role in renal injury [
21],[
22]. However, there is concern about which agent would improve the outcome of the patients with severe sepsis and septic shock, especially the comparison between albumin and crystalloid. As the most commonly used crystalloid, we also compare albumin with saline.
Compared with the review published by Patel et al., our meta-analysis included more comprehensive studies, which might result a more accurate conclusion. There are four studies included in the British Medical Journal review comparing albumin with crystalloid in patients with septic shock, and half of the included studies were confronted with the ‘same author’ or ‘same data’ issue. Moreover, the data of septic shock in the well-powered SAFE study are not included.
Various reasonable explanations are available for the encouraging results using albumin in septic shock patients. Fluid expansion is a life-saving management for resuscitating septic shock patients. The goal of fluid resuscitation is to expand the intravascular space and restore effective volume. However, fluid often moves into the extravascular space and induces tissue edema in septic patients. While exploiting oncotic pressure gradients [
23] to counteract the movement [
24], albumin provides intravascular volume expansion more effectively and restores the fluid in the intravascular space. All these above factors affect fluid resuscitation in a more timely and efficient manner. In addition, albumin is a key transporter and binder of active molecules [
25],[
26]. Albumin also acts as a radical-scavenging antioxidant [
27], its role on inhibition of platelet aggregation [
28] and maintenance of the capillary membrane permeability [
29] also takes a great part in being beneficial to outcome.
This meta-analysis has some limitations that should be noted. First, only five trials were included, and two of these trials had small sample sizes. Second, some included trials were subgroups of large randomized controlled studies with variable methodological quality. Thus, the results are potentially overstated [
30]. In addition, the endpoint was different in each study. Some of the trials included both 28-day and 90-day mortality values, whereas one trial only reported 28-day mortality. The remaining trials reported hospital mortality. The mortality rates obtained from various time points may influence the overall results. Finally, the concentration of albumin used in each study was different, and contained two colloid families, the hypooncotic and hyperoncotic albumin. The differences in formulation potentially do not influence the results in the same manner.
There are two other highly anticipated ongoing studies of albumin in patients with septic shock. The Five Percent Albumin vs. Normal Saline as Fluid Resuscitation Strategies for the Management of Early Suspected Septic Shock (NCT00819416) study has enrolled 47 patients up to now. The Early Albumin Resuscitation during Septic Shock (NCT00327704) study completed enrollment of 794 patients in January 2011 though it has not been updated for three years. All the results of the studies above will contribute significantly more to further guidance of the optimal resuscitation fluid for septic shock.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JYX carried out the analysis and interpretation of data and participated in drafting, editing and submitting the manuscript. All of the articles were reviewed by two reviewers (JYX and QHC) independently in accordance with the inclusion criteria. Disagreements between the two reviewers were resolved by consensus and discussion including a third reviewer (CP). The quality of each article was assessed by JYX and JFX independently. Disagreements were resolved by consulting a third reviewer (CSY). Using a data extraction table, JYX and JFX independently extracted data. Disagreements were resolved by discussion with CP and SQL until a consensus was achieved. LL contributed to the design and coordination of the study. YZH contributed to the design and coordination of the study. FMG contributed to the design and coordination of the study. LWH contributed to study analysis and interpretation of data. YY was responsible for revising the manuscript for important intellectual content. HBQ was responsible for conception and design, and revising the manuscript for important intellectual content. All authors read and approved the final manuscript.