Adverse effects of bolus fluid resuscitation—short-term benefit but long-term harm
Authors: John Myburgh
Journal: The Lancet Respiratory Medicine (2019)

The results of the Fluid Expansion as Supportive Therapy (FEAST) trial1Maitland K Kiguli S Opoka RO et al.Mortality after fluid bolus in African children with severe infection.N Engl J Med. 2011; 364: 2483-2495Crossref PubMed Scopus (1094) Google Scholar provide compelling evidence about the safety and efficacy of bolus fluid resuscitation in certain patient populations. FEAST, which was done in children with compensated febrile hypotension in resource-poor conditions, involved the administration of boluses of 0·9% sodium chloride (saline) or 5% albumin, which significantly increased 48 h mortality when compared with patients who did not receive fluid boluses. FEAST was pragmatic and had high indices of internal validity, and challenged established clinical practice. The findings generated substantial debate, particularly about the generalisability of the results to adult patient populations and those treated in high-income countries.2Myburgh JA Fluid resuscitation in acute illness—time to reappraise the basics.N Engl J Med. 2011; 364: 2543-2544Crossref PubMed Scopus (43) Google Scholar Central to this debate are the putative mechanisms of increased mortality and whether increased mortality could be mitigated by the application of early monitoring and interventions, such as mechanical ventilation and vasoactive therapy. A post-hoc analysis of the FEAST data3Maitland K George EC Evans JA et al.Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.BMC Med. 2013; 11: 68Crossref PubMed Scopus (184) Google Scholar that characterised study patients according to the presenting syndrome and the nature of the terminal clinical event showed that the highest mortality occurred in patients with severe shock and acidosis. Despite resolution of shock within 1 h in patients who received boluses, this did not translate into improved survival. The greatest difference in mortality occurred in patients who received boluses, and this outcome was attributed to cardiovascular causes, specifically terminal arrhythmias and refractory hypotension, and not to respiratory or neurological causes. This analysis suggested that fluid bolus-specific cardiotoxicity, potentially dose-related, was the principal mechanism of death rather than fluid overload.4Myburgh J Finfer S Causes of death after fluid bolus resuscitation: new insights from FEAST.BMC Med. 2013; 11: 67Crossref PubMed Scopus (30) Google Scholar In The Lancet Respiratory Medicine, Michael Levin and colleagues5Levin M Cunnington AJ Wilson C et al.Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial.Lancet Respir Med. 2019; (published online June 10.)http://dx.doi.org/10.1016/S2213-2600(19)30114-6Scopus (43) Google Scholar re-analysed the FEAST trial using the hypothesis that the increased mortality associated with boluses resulted from a measurable adverse effect on specific organ function. The authors designed a novel scoring system using physiological and biochemical data from the FEAST database and datasets from four cohorts of paediatric patients, characterised by different pathological phenotypes. Composite scores for respiratory, cardiovascular, neurological function, and haematological and metabolic parameters were derived. Associations between physiological and metabolic scores and outcomes, changes associated with fluid bolus and volumes, and identification of phenotype subgroups within FEAST dataset were determined. The key findings were that fluid boluses were temporally associated with significant deteriorations in respiratory and neurological function, particularly at early time intervals and in patients who received greater volumes of fluid. Consistent with the previous post-hoc analysis, fluid boluses were associated with early improvements in cardiovascular function. However, later deaths were primarily attributed to deteriorations in neurological and respiratory function, which are surrogates for cerebral and pulmonary oedema. Additionally, fluid boluses were associated in dose-dependent haemodilution and the generation of a hyperchloraemic metabolic acidosis. These findings were observed in all FEAST phenotype subgroups that were defined by severity of illness. There was little association between the severity of lactic acidosis and the severity of shock and adverse outcome. This re-analysis5Levin M Cunnington AJ Wilson C et al.Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial.Lancet Respir Med. 2019; (published online June 10.)http://dx.doi.org/10.1016/S2213-2600(19)30114-6Scopus (43) Google Scholar had a definable hypothesis based on the results of a high-fidelity randomised controlled trial. The principal findings of FEAST—that fluid boluses were associated with increased mortality and adverse patient-centred outcomes—informed the design and interpretation of these exploratory analyses. The results are internally consistent with the main trial and post-hoc analysis, and provide granular information about putative mechanisms. Of these mechanisms, the findings suggest that administration of fluid boluses will transiently improve short-term cardiovascular function, but that this outcome is achieved at the expense of neurological and respiratory function, both in the short and longer term, resulting in increased mortality. Whether these effects are mitigated by prompt respiratory support remains undetermined. In the context of the FEAST patient population, of which a substantial proportion had acute brain pathology (ie, cerebral malaria), some caution is warranted although these observations are consistent with increased mortality associated with albumin in adult intensive care patients, although specific biochemical and osmotic effects associated with 4% albumin might be confounders.6Cooper DJ Myburgh J Heritier S et al.Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality?.J Neurotrauma. 2013; 30: 512-518Crossref PubMed Scopus (99) Google Scholar, 7Myburgh J Cooper DJ Finfer S et al.Saline or albumin for fluid resuscitation in patients with traumatic brain injury.N Engl J Med. 2007; 357: 874-884Crossref PubMed Scopus (584) Google Scholar The relative importance of the generation of a dose-dependent hyperchloraemic metabolic acidosis associated with boluses is highlighted by Levin and colleagues,5Levin M Cunnington AJ Wilson C et al.Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial.Lancet Respir Med. 2019; (published online June 10.)http://dx.doi.org/10.1016/S2213-2600(19)30114-6Scopus (43) Google Scholar and adds further weight to the body of emerging observational and registry studies8Raghunathan K Bonavia A Nathanson BH et al.Association between initial fluid choice and subsequent in-hospital mortality during the resuscitation of adults with septic shock.Anesthesiology. 2015; 123: 1385-1393Crossref PubMed Scopus (52) Google Scholar, 9Semler MW Self WH Wanderer JP et al.Balanced crystalloids versus saline in critically ill adults.N Engl J Med. 2018; 378: 1951Crossref PubMed Scopus (622) Google Scholar and data from currently recruiting, blinded, randomised controlled trials.10Hammond NE Bellomo R Gallagher M et al.The Plasma-Lyte 148 v Saline (PLUS) study protocol: a multicentre, randomised controlled trial of the effect of intensive care fluid therapy on mortality.Crit Care Resusc. 2017; 19: 239-246PubMed Google Scholar This re-analysis is an important contribution to the knowledge about the safety and efficacy of fluid resuscitation. Although many strongly held beliefs in this area remain largely based on physiologically based paradigms, clinical anecdotes, and pharmaceutical marketing, results from high-quality randomised controlled trials must remain the basis of informing clinical practice. I declare no competing interests. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trialIn the resuscitation of febrile children, albumin and saline boluses can cause respiratory and neurological dysfunction, hyperchloraemic acidosis, and reduction in haemoglobin concentration. The findings support the notion that fluid resuscitation with unbuffered electrolyte solutions may cause harm and their use should be cautioned. The effects of lower volumes of buffered solutions should be evaluated further. Full-Text PDF Open Access