The present study found a 96.4% probability that, of the fluid treatments assessed, albumin provides the highest survival benefit in patients with sepsis through lowering the risk of mortality. In this analysis, the longest follow-up mortality data in trials were included. The trials with longer observation periods found more cases of adverse effects such as renal toxicity in patients treated with HES [16
]. This finding is augmented by the sub-group analysis in this study, which showed that there is higher risk of mortality in the long term for patients treated with HES.
The recent meta-analyses compared HES either with other colloids or crystalloids in critically ill patients. Gattas et al.,
] concluded that with HES there is a 6% increase in relative risk of death and a significant 25% increase in relative risk of being treated with RRT. Zarychanski et al.,
] also showed in their analysis that removing the studies by boldt, there was a clear survival benefit with other control fluids in critically ill patients. Patel et al.,
] conducted a meta-analysis on trials with severe septic patients treated with 6% HES (130/0.4 or 130/0.42). The control fluid showed a higher survival benefit in the 90-day follow up period. Haase et al.,
] found higher rate of RRT and blood transfusion in patients treated with HES 130/0.38-0.45 but no significant difference in risk of death. Delaney et al.,
] compared albumin with any control fluid and found albumin to be superior in reducing the risk of mortality.
The methodology of these routine meta-analyses does not allow the assessment of comparative effectiveness and safety of specific treatments in the absence of direct head to head trials. The present study applied network meta-analysis using a Bayesian approach to compare and rank the different fluid therapies available for severe sepsis so as to inform clinical decision making. This approach has been used to compare therapies in similar circumstances, in areas including pain management, diabetic neuropathy [48
] and antifibrinolytic therapy in cardiac surgery [49
], and has been shown to be not increase the bias relative to routine meta-analysis [50
The inclusion of data from two recently reported large trials - ALBIOS and EARSS - which assessed the effect of albumin versus crystalloid in severe sepsis from the reported conference proceedings required caution as such data can lead to inconsistencies [51
], and sensitivity analysis without this data was performed and confirmed the robustness of the analysis. Similarly, further sub-group analysis was performed in order to assess the effect of including the trials of Maitland et al.,
on children with malaria [13
] which has a pathophysiology with many features in common with sepsis [44
]. The sub-group analysis confirmed that the outcomes of the base case were not affected by the incision of these trials. Maitland et al.,
also demonstrated a survival benefit in children receiving albumin compared to gelofusine [52
] but the present study was restricted to HES as this is the predominant synthetic colloid globally [9
An underlying presumption in comparing outcomes in different clinical trials through techniques like meta-analysis is that different therapeutic preparations within each arm are biopharmaceutically equivalent. Hence, the different compositions of HES and albumin are assumed to have the same therapeutic effect when compared in meta-analyses such as that in the present study. Crystalloids also form a very broad category with differently formulated solutions. Any differences in formulation, manufacturing method etcetera between different fluids within the same broad class (crystalloids, albumin and HES) are assumed to not affect their therapeutic properties. Equivalent efficacy and safety profiles have been shown for albumin produced by different methods [53
]. The most recent HES products have been claimed to be associated with fewer adverse events than earlier products [54
] but the outcomes of meta-analysis [30
] and recent trials [16
] have disputed this, and have led the US Food and Drug Administration (FDA) to conclude that in relation to these effects, all HES products behave as a class [40
]. This has led the European Medicines Agency to conclude that the negative risk-benefit balance associated with these products justifies the removal of their marketing authorization [56
]. Similarly, crystalloid solutions formulated to approximate physiological conditions have been claimed to be therapeutically superior to normal saline [57
]. This has not been supported in a systematic review of mortality and morbidity in patients [58
]. To test this assumption further, we performed the analysis with different formulations of albumin and HES and obtained similar results. Hence, we propose that the results of previous analyses, [30
] and the current study are not affected by any differences in the preparations within
each treatment arm.
Similarly, we acknowledge that variability in the patient populations recruited in the individual trials may influence the results of this analysis, although the populations studied, consisting of severe sepsis and septic shock patients, were very similar in terms of age (all populations in the different fluid arms were in the age group 61 to 68) with the exception of the pediatric populations studied in the malaria trials of Maitland et al., We have assessed the effect of variability resulting from patient population, follow up time, product composition and patient age through sub-group analyses which demonstrated no effect on the final result of this study (Table ), but it is possible that variability in these and other factors may influence the results, as with all meta-analyses.
Our sub-group analysis of trials with 28-day mortality showed a lower risk with HES than our analysis of trials with 90-day mortality outcomes. This suggests that more adverse outcomes from HES ensue after a prolonged period after use, as was shown in both the VISEP [45
] and 6S [16
] large clinical trials of different generation HES products. A high fraction of HES is taken up and deposited in tissues [59
], where its long-term toxic effects on the kidney, liver, and bone marrow [60
] may explain the relative time frame of the mortality outcomes. There is a lower risk of mortality with HES and crystalloid in older patients in as assessed through the sub-group analysis in the present study but the relative ranking in survival benefit is not affected. This could be speculatively attributed to a higher incidence of other comorbidities in elderly patients, thus diminishing the difference between the efficacies of the fluid treatments.
All the trials with RRT outcomes had a 90-day follow up period. The indication was severe sepsis or septic shock for all included trials except the CHEST study [17
] which assessed all the patients in the ICU setting. Sepsis was a sub-group in the CHEST trial, and the findings of the sub-group have not been published but have been reported (Myburgh J, Presentation at the International Symposium on Intensive Care and Emergency Medicine, Brussels March 2013). The need for RRT in all trials comparing albumin with other fluids did not show any increased risk with albumin, possibly due to albumin’s lack of renal toxicity [62
] compared to HES [64
Direct data on mortality in fluid resuscitation with sepsis, comparing albumin, HES and crystalloids, are minimal and thus the present study may inform therapeutic choice. Moreover, network meta-analysis and indirect comparison is receiving increased acceptance in health care decision making (Pharmaceutical Benefits Advisory Committee in Australia, Canadian Agency for Drugs and Technologies in Health [CADTH], National Institute for Health and Clinical Excellence [NICE] in the UK) [29
]. Even when direct evidence is available and conclusive, combining direct and indirect results may yield more refined and precise estimates of the interventions and broaden inference to the population sampled. Network meta-analysis links and maximizes existing information within the network of treatment comparisons [24
]. We propose that such an approach should assist policy makers, manufacturers, physicians and patients, when making a choice between fluid-resuscitation treatments.