Secondary re-analysis of the FEAST trial

The article by Michael Levin and colleagues¹ rekindles the discussion about adverse effects of boluses in children with febrile illness and shock, as reported in the FEAST trial.² However, unfortunately, results of this re-analysis of FEAST data fall very short of providing mechanisms by which boluses increase mortality; differences in physiological scores and biochemistry results between groups by no means imply causality. Furthermore, some re-analyses and statements about our previous papers are erroneous and contradict work by the FEAST team aimed at understanding these mechanisms.

We firmly stand by our previous analyses of terminal clinical events (TCEs) in FEAST showing that the main reason for excess deaths with boluses was cardiovascular collapse, and not respiratory or neurological causes.³ Adverse events and deaths, possibly related to fluid overload, were actively solicited and reviewed throughout the trial by an endpoint review committee, masked to the group. The committee reviewed structured clinical narratives detailing clinical presentation, progression, and terminal events reported by trial clinicians trained on standardised proforma, together with serial bedside clinical observations and laboratory data. As reported in our previous study,² only about 2% of children had possible respiratory or neurological fluid overload events. Furthermore, based on pre-specified criteria, the endpoint review committee adjudicated TCE to cardiovascular, respiratory, or neurological causes without knowing the treatment. These data showed excess cardiovascular (collapse) TCEs in the bolus groups with no excess deaths in respiratory or neurological TCEs. We believe this evaluation is a much more robust analysis of mechanisms than equations that use surrogate risk scores. Levin¹ criticises this paper, indicating that lactate was included in the definition of cardiovascular TCE, which is incorrect.³

Furthermore the authors have 100% imputed base excess, chloride, bicarbonate and haemoglobin values 1 h after the randomisation; per design, none were actually measured at 1 h. The imputed values were derived from published literature of studies in individuals who had received larger 1 h fluid volumes and from data on the unselected (two centres) minority (32%) of FEAST survivors at 24 h, which anyway show normalised values (figure). Treating the imputed values as observed is misleading. Of note, the median bolus in FEAST was only 20 mL/kg (IQR 20–40), which was previously reported to normalise base excess⁴ and is modest compared with volumes recommended in current guidelines.

Figure. Measurements at baseline and at 24h in bolus (saline and albumin combined) and no bolus groups.

Box and whisker plots of median and IQR for a) base excess, b) bicarbonate, c) chloride, and d) haemoglobin concentrations.

Finally, we do agree that polarised views about FEAST results argue for further randomised trials on volume rate and type of fluid resuscitation, preferably in settings where intensive care is at a high premium.