The Efficacy of Albumin with Diuretics in the Mechanically Ventilated Patients with Hypoalbuminemia: Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-200244/v1

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The Efficacy of Albumin with Diuretics in the Mechanically Ventilated Patients with Hypoalbuminemia: Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-200244/v1

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Background

Hypoalbuminemia is associated with fluid overload, the development of acute respiratory distress syndrome, and mortality. Co-administration of albumin and diuretics for treatment of patients with hypoalbuminemia is expected to increase urinary output, without hemodynamic instability, and improve pulmonary function; however, these effects have not been systematically investigated. Here, we aimed to clarify the benefits of co-administration of albumin and diuretics for mechanically ventilated patients.

Methods

We searched for randomized, placebo-controlled trials that investigated the effects of co-administration of albumin and diuretics compared with placebo and diuretics, in mechanically ventilated patients with hypoalbuminemia. We searched these trials via the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed and EMBASE. Primary outcomes were hypotensive events after intervention, all-cause mortality, and the length of mechanical ventilation. Secondary outcomes were improvement in the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio) at 24 h, total urine output (mL/d), and the clinical requirement of renal replacement therapy (RRT).

Results

Among 1574 records identified, we included three studies for quantitative analysis. The results of albumin administration were as follows: hypotensive events [risk ratio (RR) -1.05 (95% confidence interval (CI): 0.15 to 0.81], all-cause mortality [RR 1.0 (95% CI: 0.45 to 2.23], the length of mechanical ventilation in days [mean difference (MD) -1.05 (95% CI: -3.35 to 1.26)], improvement of P/F ratio [RR 2.83 (95% CI: 1.42 to 5.67)]. None of the randomized controlled trials reported the total urine output, whereas one reported that no participants required RRT. Adverse events were not reported during the trials. The certainty of evidence was low (in the hypotensive events after intervention, all-cause mortality) to moderate (in the length of mechanical ventilation in days, improvement of P/F ratio, clinical requirement of RRT, and adverse events).

Conclusions

Although this treatment combination reduced the number of days for which mechanical ventilation was required, it did not reduce the all-cause mortality at 30 days. Taken together, co-administration of albumin and diuretics may reduce hypotensive events and improve the P/F ratio at 24 h.

Critical Care & Emergency Medicine

Albumin

hypoalbuminemia

diuretics

mechanical ventilation

fluid overload

systematic review

meta-analysis

Hypoalbuminemia is frequently observed in critically ill patients [1–3], in whom severe inflammation can increase capillary permeability, leading to albumin exudation from intravascular to extravascular compartments [1]. Furthermore, hypoalbuminemia is also correlated with fluid overload and the development of acute respiratory distress syndrome (ARDS) [2, 3].

Albumin is one of the major determinant factors of vascular colloid oncotic pressure (COP), and as such, the administration of albumin in critically ill patients with hypoalbuminemia is reasonable to maintain or increase intravascular volume. Therefore, colloids such as albumin, may suppress the amount of infusion volume required, compared with crystalloids [4]. A meta-analysis concluded that the use of albumin for resuscitation of patients with sepsis was associated with lower mortality than that observed using other fluid resuscitation [5].

The ARDS Clinical Trials network reported a randomized controlled trial, (RCT) which showed that conservative fluid management and diuretics improve lung function and reduce the length of mechanical ventilation [6]. While diuretic administration can improve ARDS by volume reduction, there is a risk of hemodynamic instability in critically ill patients. However, combined use of albumin and diuretics may negate the effect of diuretics alone by maintaining hemodynamical stability. It has also been hypothesized that when the plasma albumin complex is bound to furosemide, it reaches the proximal tubular cells to act in the ascending limb of the loop of Henle [7]. Thus, albumin, in combination with diuretics, may contribute to an increased urine output.

The effects of co-administration of albumin and diuretics for critically ill patients with hypoalbuminemia have been investigated in several RCTs [8–13]. However, to-date, no systematic review and meta-analysis of this treatment in mechanically ventilated patients has been carried out.

In the present study, we aimed to clarify the benefits of co-administration of albumin and diuretics for mechanically ventilated patient. The findings of this systematic review and meta-analysis provide frontline physicians with efficacy information for co-administration of albumin and diuretics in the respiratory critical care patients with hypoalbuminemia.

Compliance with reporting guidelines

We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14] and the recommendations listed in the Cochrane Handbook [15].

Research question and eligibility criteria

The research question of the present study was “effectiveness of co-administration of albumin and diuretics in mechanically ventilated patients with hypoalbuminemia.” A patient was defined as mechanically ventilated when there was a possibility of fluid overload and confirmed hypoalbuminemia (serum albumin under 3.0 mg/dL). The intervention was defined as co-administration of albumin and diuretics. Control groups were defined as those administered placebo or no intervention with diuretics. We did not consider the length of albumin administration or concentration. We included only RCTs and did not consider publication status, publication date, publication language or country. We excluded quasi RCT, cross-over trials, and cluster randomized trials.

Outcomes of interest

The primary outcomes of interest were hypotensive events after intervention (duration of the event was defined within 7 days after intervention; considerable range for analysis is 0-10 days), all-cause mortality at 30 days and the length of the mechanical ventilation (from tracheal intubation to extubation). Initially, we defined a hypotensive event as a systolic blood pressure ≤ 90 mmHg, however to include paediatric patients we redefined hypotensive events. Martin et al (2005) reported the number of free days during the 30 day follow up period where the patient was not ventilated, and from this we calculated the remaining days where they would have been under mechanical ventilation. The secondary outcomes were the improvement of the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio) at 24 h, the total urine output (mL/d), the clinical requirement of renal replacement therapy (RRT) within 7 days and all other adverse events.

Search strategy and selection of studies

The following databases were searched: 1. the Cochrane Central Register of Controlled Trials (CENTRAL); 2. MEDLINE via PubMed; and 3. EMBASE. The following databases were also searched for ongoing or unpublished trials: 1. the World Health Organization International Clinical Trials Platform Search Portal (ICTRP); and 2. ClinicalTrials.gov. The detailed search strategy is shown in Protocols.io (https://www.protocols.io/view/the-efficacy-of-albumin-with-diuretics-in-the-mech-bpadmia6). Researchers also searched for other relevant studies to include. After the removal of duplicate studies, articles were independently screened by checking title and abstract information using Rayyan [16].

Data extraction

The extraction of data was performed by two reviewers independently, and any disagreement was resolved by a third reviewer, if required. We asked the relevant author for further data on unreported outcomes, if the data was unavailable.

In studies where the authors reported the continuous data as median and the interquartile range, we converted the indicated values to mean ± SD according to the Cochrane Handbook for Systematic Reviews of Interventions [15].

Dealing with missing data

For missing data, we contacted the relevant author within a period of two weeks via email. If no response was received, we followed up the initial email a maximum of two times. We did not include the studies which lacked information that we were unable to source from the author.

Quality assessment

Two researchers independently used a tool for assessing risk of bias in randomized trials (RoB2) [17]. To summarize the evidence, we followed the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and Summary of Findings (SoF) tables [18] for the outcomes of interest.

Statistical analysis

The Review Manager software (RevMan 5.4, Nordic Cochrane Centre, Cochrane Collaboration) was used to carry out the meta-analysis [19]. We used a random-effects model and reported the results of outcomes as mean difference (MD) and risk ratio (RR). Effect sizes are reported as 95% confidence intervals (CI) and results are reported graphically by forest plot. Simultaneously, we calculated I² (I² values of 0% to 40%: may not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity). Cochrane Chi² test (Q-test) was used to investigate I². Statistical differences were considered significant at p-value <0.10.

Ethics and dissemination

According to the nature of this study, no ethical approval was required. This study was registered with Protocols.io (https://www.protocols.io/view/the-efficacy-of-albumin-with-diuretics-in-the-mech-bpadmia6).

Search results and characteristics of included trials

We identified 1,574 records during the search conducted in October 2020. Seven RCTs were identified and assessed for their eligibility for this study, one article was excluded as no outcome of interest was included (Figure 1). We finally included three RCTs (n=129) that fulfilled all the eligibility criteria [11-13].

As shown in Table 1, the RCTs were carried out in the USA, Canada, and India. The mean age of the patients ranged from 3.6 to 48.9 years, with sample sizes of 40 to 45 per study. One of the studies included only children [13].

Albumin used in these studies were 20% or 25% albumin. Furosemide was the diuretic used in these studies, although doses and intravenous infusion method (continuous or bolus) were different among the trials (Table 1).

Figures 2 and 3 show the risk of bias for each outcome in included studies, ranging from low to high.

Primary outcomes

Table 2 shows the SoF of the present study. Although there was low certainty and risk of bias of missing outcomes, hypotensive events were recorded in all three RCTs [11-13]. Compared with placebo, albumin reduced hypotensive events [RR 0.33 (95% CI: 0.15 to 0.81)] (Figure 4a). Number of mechanical ventilation days was measured in two of the RCTs with moderate certainty of the evidence [12, 13]. The result of the meta-analysis did not clarify the effect of albumin in reducing the number of mechanical ventilation days [MD -1.05 (95% CI: -3.35 to 1.26)] (Figure 4b). All-cause mortality was recorded in all trials and the results were not different [RR 1.0 (95% CI: 0.45 to 2.23)] (Figure 4c). We were not able to carry out pre-specified sensitivity analyses for the primary outcomes, or subgroup analysis because the number of the RCTs was insufficient.

Secondary outcomes

There was a moderate certainty of evidence in the secondary outcomes (Table 2). One RCT recorded the change of P/F [11]. They found that compared with placebo, albumin infusion improved the P/F ratio [RR 2.83 (95% CI: 1.42 to 5.67)] (Figure 5). No RCTs reported the total urine output (mL/d) after intervention. One RCT reported that no participants required RRT. Adverse events were not reported during any of the trials. We were not able to carry out pre-specified sensitivity analyses for the secondary outcomes, or subgroup analysis because the number of the RCTs were insufficient.

The results of this systematic review and meta-analysis covered three RCTs and showed that albumin treatment in combination with diuretics may result in a large reduction in the number of hypotensive events. It also likely results in an improvement in the P/F ratio at 24 h (considerable range for analysis is 12 h to 7 d) after the intervention. Albumin with diuretics likely reduced the number of mechanical ventilation days. However, the evidence suggests that albumin with diuretics does not decrease all-cause mortality at 30 d.

A large reduction in hypotensive events following the co-administration of albumin and diuretics may result from maintaining the intravascular volume by albumin administration. As albumin determines the vascular colloid oncotic pressure, the exudation of the intravascular fluids might be reduced by albumin.

P/F improvement and a reduction in the number of days of mechanical ventilation were found following the co-administration of albumin and diuretics. We speculate that this result is strongly related to the reduced number of hypotensive events. Albumin administration might maintain the intravascular volume by increasing the vascular colloid oncotic pressure. Therefore, the hypotensive events and the total amount fluid infused were reduced. This volume reduction may have improved the oxygenation of the mechanically ventilated patient.

Although co-administration of albumin and diuretics reduced the number of mechanical ventilation days, all-cause mortality rate did not improve. We speculate that due to the patients having various underlying diseases and complications, co-administration of albumin and diuretics could not directly improve the all-cause mortality. However, the reduction in the number of ventilation days seems to be effective for minimising complications such as ventilator associated pneumoniae or deep vein thrombosis [20, 21].

The variability of certainty of evidence from low to moderate is attributed to the small sample size and the concerns about risk of biases. In the future, further large and well-designed RCTs should be performed.

The present systematic review and meta-analysis has several limitations. First, we included only three RCTs, each with various quality in terms of risk of bias. Larger RCTs are required to establish a more thorough review. Second, we were unable to carry out sensitivity analyses for outcomes due to imprecision. However, preparing a heterogenic mechanically ventilated population is difficult due to the nature of intensive care, which consists of many clinical variables and situations.

In conclusion, the present study indicates that albumin, when administered alongside diuretics, reduced hypotensive events and led to an improvement in the P/F ratio at 24 h. Although it is likely that the co-administration reduced the number of mechanically ventilated days, the intervention did not decrease all-cause mortality at 30 d. Further large and well-designed RCTs are required to confirm the effectiveness of co-administration of albumin and diuretics in mechanically ventilated patients.

ARDS Acute respiratory distress syndrome

COP Colloid oncotic pressure

RCT Randomized controlled trial

RoB2 Risk of bias in randomized trials

RRT Renal replacement therapy

SOF Summary of Findings

Ethics Approval and Consent to participate

According to the nature of this study, no ethical approval and consent to participate were required.

Consent for publication

Not applicable.

Availability of data and materials

All relevant data are presented in the published manuscript.

Competing interests

None.

Funding

None.

Author contributions

YI is the guarantor. YI, NY, KY, MB, RM, MH drafted the manuscript. All authors contributed to the development of the selection criteria, the risk of bias assessment strategy and data extraction criteria. YI, NY, KY, MB, RM developed the search strategy. YI, NY, KY, MB, RM and YK provided statistical expertise. MB, RM provided expertise on YI. All authors read, provided feedback, and approved the final manuscript. Support: Self-funding.

Acknowledgments

The authors thank Yuki Kataoka MD. MPH. PhD for his contribution in searching the database.

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The Efficacy of Albumin with Diuretics in the Mechanically Ventilated Patients with Hypoalbuminemia: Systematic Review and Meta-Analysis

Status:

Version 1

Abstract

Figures

Background

Methods

Compliance with reporting guidelines

Research question and eligibility criteria

Outcomes of interest

Search strategy and selection of studies

Data extraction

Dealing with missing data

Quality assessment

Statistical analysis

Ethics and dissemination

Results

Search results and characteristics of included trials

Primary outcomes

Secondary outcomes

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Supplementary Files

Status:

Version 1