It has been widely suggested that a large, well powered randomized controlled trial comparing a conservative to liberal fluid strategy in sepsis needs to be performed. This study has already been conducted, namely the FEAST trial.

BACKGROUND

The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established.

METHODS

We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks.

RESULTS

The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90;

P = 0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P = 0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P = 0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P = 0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P = 0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P = 0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin bolus group and 56% (9 of 16) in the saline-bolus group died (P = 0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia.

CONCLUSIONS

Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa.

Commentary:

This study randomized children with sepsis and impaired perfusion in a 1:1:1 ratio, to rapid volume expansion over the course of 1 hour with 20 ml/kg intravenous 0.9% saline solution (saline-bolus group), 20 ml/kg of 5% human-albumin solution (albumin-bolus group) or no bolus (control group). In the saline-bolus and albumin-bolus groups, additional 20 ml/kg boluses were given at 1 hour if impaired perfusion persisted. Over the course of 8 hours, the median cumulative volume of fluid received was 40.0 ml/kg in the albumin-bolus group, 40.0 ml/kg in the saline-bolus group, and 10.1 ml/kg in the control group. The mortality at 48 hours is shown in the figure below. Sub-group analysis demonstrated HARM from fluid boluses in all sub-groups analyzed. There was no evidence supporting a benefit from bolus fluid infusion in any subgroup.

The FEAST study clearly demonstrated that in children with sepsis and evidence of imparted perfusion an aggressive approach to fluid management (ie. an initial fluid bolus of 20 ml/kg followed by additional boluses vs no bolus) resulted in a significant increase in mortality. It is noteworthy that the approach to fluid management in the bolus groups is very similar to that mandated by the Surviving Sepsis Campaign (initial bolus of 30ml/kg followed by additional boluses guided by vital signs). Defenders of the Surviving Sepsis Campaign have argued that the results of the FEAST study cannot be generalized to adults in both resource-rich and resource-poor settings. This is obviously “disingenuous”. The results of studies in mice (Cecal ligation and perforation model) are frequently extrapolated to adult humans; the defenders of the SSC are happy to extrapolate studies done in mice but not in small humans… that is absurd. Physiologically children are just small adults. Furthermore, they contend that African children are somehow different from humans in more developed countries; this is clearly unacceptable reasoning. In addition, they suggest that the results of the FEAST study are not generalizable as approximately half the children had malaria. This is likely to be untrue for two reasons; firstly, acute falciparum malaria is pathophysiologically similar to gram -ve sepsis; and secondly, fluids were harmful in the sub-group of patients without malaria.

The results of this study confirm what we already know; sepsis is primarily not a fluid responsive condition and that an aggressive approach to fluid management kills patients with sepsis. Clearly, a “few extra bags” of crystalloid make a difference.