The Effects and Safety of Vasopressin Receptor Agonists in Patients With Septic Shock

A Meta-analysis and Trial Sequential Analysis

Libing Jiang; Yi Sheng; Xia Feng; Jing Wu


Crit Care. 2019;23(91) 

In This Article


The present meta-analysis was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA,

Registration and Protocol

This meta-analysis was registered on PROSPERO (CRD42018104027).

Inclusion Criteria

Patients: Adult septic shock patients

Intervention: Vasopressin or its analogues (e.g., terlipressin, selepressin) with or without concomitant catecholamines, irrespective of dose and duration

Comparison: Catecholamines use alone, irrespective of dose and duration

Outcomes: The primary endpoint was 28/30-day mortality, and hospital mortality and ICU mortality were equal for this analysis module. The secondary endpoints included ICU length of stay, duration of mechanical ventilation, and adverse events (total adverse events, digital ischemia, cardiovascular events, arrhythmia, mesenteric ischemia, diarrhea, cerebrovascular events, and hyponatremia).

Data Source and Literature Search

PubMed, EMBASE, and Cochrane library were searched from inception to July 31, 2018. The detailed search strategy is showed in Additional file 1: Table S1. The bibliography of relevant articles was searched for additional articles. In addition, was searched for ongoing or unpublished studies.

Study Selection and Data Extraction

Two reviewers performed literature selection independently. Firstly, we excluded duplicates through reference management tool. Then, we exclude clearly non-relevant articles by reading titles and abstracts. Finally, we decided the eligibility of each article by full-text reading.

The same two reviewers did the data extraction independently using a pre-defined datasheet. And we recorded basic information of each eligible study, characteristics of included patients, interventions, comparisons, endpoints, and other items which were essential for quality evaluation. Any discrepancy was solved by discussion or consulting with the third reviewer.

Study Quality Evaluation

Two reviewers evaluated the quality of each included study based on the following domains: sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessors, incomplete outcome data, and selective reporting. Each domain is classified as low risk, unclear risk, and high risk. Any discrepancy was solved by discussion or consulting with the third reviewer.

Statistical Analysis

Relative risk (RR) was used for dichotomous data, and mean difference (MD) was used for continuous data. The heterogeneity between studies was assessed using the I 2 test and chi-square test. P < 0.1 and I 2 ≥ 50% indicated significant heterogeneity, and the random effects model was used. Otherwise, the fixed effects model was used. A two-sided P value < 0.05 was considered statistically significant. Publication bias was assessed by funnel plot and Egger's test quantitatively. All statistical analyses were performed using STATA 12.0 software (SERIAL NO.40120519635) and RevMan 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

In the present study, we used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) to evaluate the quality of evidence. And evidences were categorized as high, moderate, low, and very low, according to two group factors (factors that can reduce the quality of the evidence and factors that can increase the quality of the evidence). This process was performed on GRADEpro GDT (

In the present study, we performed the trial sequential analysis (TSA) to decrease the risks of random errors due to sparse data and repetitive testing and calculate the optimal information size for this meta-analysis. In addition to the optimal information size, an adjusted boundary line for favoring vasopressin or its analogue use and an adjusted boundary line for favoring catecholamine use alone were generated to decide whether the meta-analysis should be terminated early or the confidence interval. In this TSA model, type I error was set at 5% and type II error was set at 20%. A 10% relative risk reduction (RRR) and baseline mortality calculated from the actual meta-analyses were used to calculate the optimal information size. TSA was performed using the trial sequential analysis v. beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark, available from