Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial

Abstract

Background: Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload.

Methods: Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events.

Results: Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events.

Conclusions: Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids.

Trial registration: ISRCTN69856593.

Figure 1

Patient flow. ¹Inclusion criteria: Children aged >60 days and <12 years with severe febrile illness including impaired consciousness (prostration or coma) and/or respiratory distress (increased work of breathing) were screened for clinical evidence of impaired perfusion (shock) to be eligible for the trial. Impaired perfusion was defined as any one of the following: CRT 3 or more secs, lower limb temperature gradient, a weak radial pulse volume or severe tachycardia: (<12 months: >180 beats per minute (bpm); 12 months to 5 years: >160bpm; >5 years: >140 bpm). ²Exclusion criteria: Evidence of severe acute malnutrition (visible severe wasting or kwashiorkor); gastroenteritis; chronic renal failure, pulmonary edema or other conditions in which volume expansion is contraindicated; non-infectious causes of severe illness (68); if they already received an isotonic volume resuscitation. ³Other reasons for exclusion: child unable to return for follow-up (111), enrolled in a different study (65), no trial packs/fluid or blood (47), previously enrolled to FEAST (17), died (11), other (181), missing reason (26). ⁴Severe hypotension defined as systolic blood pressure <50mmHg if <12m; <60mmHg if 1-5years; <70mmHg if >5years- eligible children with severe hypotension were enrolled into FEAST B (see text) ⁵Child was not febrile (had no fever or history of fever). ⁶One child had severe hypotension and one child did not have impaired perfusion.

Figure 2

Mortality at 48 hours by presentation syndrome. (a) Complete information; n = 2,396. (b) Incomplete information; n = 745. 48-hour mortality by presentation syndrome and in bolus (albumin and saline) and control (no bolus) arms for those for which severe shock or acidosis (n = 633), or respiratory syndrome (n = 105) or neurological syndrome (n = 8) could not be ascertained. Areas are proportional to the size of subgroups. B: bolus arm; C: control arm.

Figure 3

Mortality risk at 48 hours for bolus compared to no bolus by presentation syndromes at baseline. Forest plots comparing effect of bolus versus no bolus for each baseline presentation syndrome (respiratory, neurological or severe shock or acidosis); children could be assigned to more than one syndrome.

Figure 4

Mortality risk at 48 hours for bolus compared to no bolus by individual respiratory symptoms/signs at baseline.

Figure 5

Mortality risk at 48 hours for bolus compared to no bolus by individual neurological signs/symptoms at baseline.

Figure 6

Mortality risk 48 hours for bolus compared to no bolus by shock-related or systemic signs at baseline.

Figure 7

Cumulative incidence of mortality for bolus combined and no bolus arms by terminal clinical events for 297 children who died within 48 hours.