Vasopressor and inotrope treatment for septic shock: An umbrella review of reviews
Introduction
Systematic reviews (SRs) and meta-analyses are believed to provide high-quality evidence [1] and as such are often relied upon by clinicians for making important therapeutic decisions.
The construct of a SR includes important components. These include clarity regarding the question at hand (population, intervention, comparator and outcome definitions), a publicly available protocol, duplicate data selection and extraction processes, detailed and standardized reporting, address of risks of bias (study level, outcome level), address of potential bias incurred by omission of data at various levels, investigation and reporting of heterogeneity and ethical transparency [2].
As data may be conflicting and often confusing, the expectation is for a rigorous approach and adherence to all of these components. Decisions regarding data pooling are made based on the inherent characteristics of the data. The summary of the data, whether synthesized or not, is presented in standard manner with the statistical findings translated into language that every clinician should be able to understand. Or so it should be.
In 2016 Page et al. analysed more than 650 SRs published in the biomedical literature during a randomly selected month [3]. Multiple flaws were identified in many these studies. The annual number of SRs published in MEDLINE was calculated to be three times higher than a decade ago when compared to a similar study published in 2006 [4] and the authors concluded with a warning regarding waste of research resources and effort as poorly conducted SRs may mislead clinicians, thwarting even the best of efforts to improve patient outcomes.
Vasopressors and inotropes have been used for symptomatic treatment of septic shock for several decades. For a long time, the effects of these drugs were not studied in human trials. However, at the turn of the century, shortly after standardization of the definition of sepsis and septic shock, the first human trials on the use of vasopressors for septic shock began to appear [5,6]. The Surviving Sepsis campaign, initiated in 2002 at the European Society of Intensive Care annual meeting with the Barcelona Declaration, revealed the paucity of medical literature on the relation between the use of vasopressors and catecholamines and patient outcomes [7], citing only 4 articles on the topic [5,6,8,9]. This finding triggered a series of publications of trials on the topic. Because patients with sepsis are very complex, it seemed only logical that this literature be reviewed systematically and indeed a series of SRs have now also been published.
For this review we systematically searched the literature for SRs studying the effect of vasopressors and inotropes on the outcomes of adult patients with sepsis. We aimed to review the PICO (populations, interventions, comparators and outcomes) questions these SRs have addressed, their characteristics, findings and quality in order to provide insights for future research on this topic. We hypothesized we would identify multiple, poor-quality reviews with inconsistent findings, based on few, high-quality studies.
Section snippets
Materials and methods
The study protocol for this SR was registered in the Open Science Framework platform (osf.io/a4jfp).We also followed the Joanna Briggs Institute recommendations for umbrella reviews [10].
Search result
The electronic search resulted in 2148 hits. After the addition of 2 references from other sources, removal of duplicates with bibliographic software and screening of titles we identified 236 potentially relevant articles which also underwent screening of abstracts. Based on the abstracts, we selected 33 potentially relevant articles for full text review. One SR was not retrievable [15]. Of the remaining 32 articles 4 did not meet our inclusion criteria after closer inspection for the following
Discussion
We sought to systematically describe SRs investigating the effect of vasopressors on the outcomes of adult patients with sepsis when compared with either no treatment, another vasopressor or fluids. Our most important findings are the large number of SRs published on this topic in the last decade in relation to the paucity of new studies added to these SRs and the quality of these SRs which can be improved. Our study, focused on the evidence for a very specific clinical condition, confirms the
Conclusions
This review was intended to serve as a clinical tool for practicing clinicians. Although 28 SRs were identified, only one of three was judged to be of moderate to high quality. Publication bias was judged to be minimal. However, domination of SRs by a single study was not uncommon. Pooling of patients with diverse characteristics, lack of blinding and attrition bias may have affected mortality and additional outcomes sought in many of the SRs. When taken together, this large body of SRs leads
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors' contribution
All authors read and approved the final manuscript.
All the authors agreed to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Declaration of Competing Interest
SE is associate editor of Intensive Care Medicine and a Cochrane Editor. AC is an advisory board member of Critical Care and an associate Editorial Board member of BJA. The other authors declare that they have no competing interests.
Acknowledgements
Our thanks to Dr. Iris Arad for assisting with the search of the literature.
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