First, there were slight methodological differences and exclusion criteria across the four cohorts analysed.
The first author extracted data from full texts into an Excel spreadsheet, comprising author, year, type of study, aim, population, participant age-group, methodological approach, methodology, inclusion and exclusion criteria, included and excluded participants, findings, limitations, conclusions, and directions for future research.
Methodological strengths include the exclusion of samples with <80% successful genotypes and by 100% concordant genotypes in 270 duplicate samples.
With septic shock, some measurements, such as blood pressure and lactate levels, are likely to have reasonably high inter-observer, intra-observer and intra-subject reliability subject to certain caveats and exclusion of methodological errors.
The methodological flaws of this study (exclusion of a substantial number of patients after randomization limiting the benefits of randomization) should have been specifically highlighted in my opinion.
Methodological differences in subject recruitment, exclusion criteria, frequency and nature of procedures for follow-up, types of observations made, method of recording, methods of analysis and large intersite variability in some studies, make it difficult to evaluate the published data.
We extracted data including trial demographics (author, year of publication, country, funding source, publication status, duration of follow-up, number of centers involved, inclusion and exclusion criteria, and methodological quality using the Cochrane Collaboration Risk of Bias tool) [ 20, 21].
This criterion limited our ability to compare funding, conflicts of interest, methodological quality, and post-randomisation exclusions between trials that report using standard intention to treat analyses and those that report using modified intention to treat.
This exclusion may have multiple methodological causes (Visser et al., 2010; Lambon Ralph, 2014).
Excluded studies were considered eligible for the external validation gold standard set if exclusion was based on methodological, rather than topical, grounds.
