Volume Expansion with Albumin Compared to Gelofusine in Children with Severe Malaria: Results of a Controlled Trial

Abstract

Objectives:Previous studies have shown that in children with severe malaria, resuscitation with albumin infusion results in a lower mortality than resuscitation with saline infusion. Whether the apparent benefit of albumin is due solely to its colloidal properties, and thus might also be achieved with other synthetic colloids, or due to the many other unique physiological properties of albumin is unknown. As albumin is costly and not readily available in Africa, examination of more affordable colloids is warranted. In order to inform the design of definitive phase III trials we compared volume expansion with Gelofusine (succinylated modified fluid gelatin 4% intravenous infusion) with albumin.Design:This study was a phase II safety and efficacy study.Setting:The study was conducted at Kilifi District Hospital, Kenya.Participants:The participants were children admitted with severe falciparum malaria (impaired consciousness or deep breathing), metabolic acidosis (base deficit > 8 mmol/l), and clinical features of shock.Interventions:The interventions were volume resuscitation with either 4.5% human albumin solution or Gelofusine.Outcome Measures:Primary endpoints were the resolution of shock and acidosis; secondary endpoints were in-hospital mortality and adverse events including neurological sequelae.Results:A total of 88 children were enrolled: 44 received Gelofusine and 44 received albumin. There was no significant difference in the resolution of shock or acidosis between the groups. Whilst no participant developed pulmonary oedema or fluid overload, fatal neurological events were more common in the group receiving gelatin-based intervention fluids. Mortality was lower in patients receiving albumin (1/44; 2.3%) than in those treated with Gelofusine (7/44; 16%) by intention to treat (Fisher's exact test, p = 0.06), or 1/40 (2.5%) and 4/40 (10%), respectively, for those treated per protocol (p = 0.36). Meta-analysis of published trials to provide a summary estimate of the effect of albumin on mortality showed a pooled relative risk of death with albumin administration of 0.19 (95% confidence interval 0.06–0.59; p = 0.004 compared to other fluid boluses).Conclusions:In children with severe malaria, we have shown a consistent survival benefit of receiving albumin infusion compared to other resuscitation fluids, despite comparable effects on the resolution of acidosis and shock. The lack of similar mortality benefit from Gelofusine suggests that the mechanism may involve a specific neuroprotective effect of albumin, rather than solely the effect of the administered colloid. Further exploration of the benefits of albumin is warranted in larger clinical trials.

Phase II trial on the use of Dextran 70 or starch for supportive therapy in Kenyan children with severe malaria*

“…The participants in the trial were therefore comparable to study cohorts enrolled in our previous fluid resuscitation trials [3,15,19], with one exception [16].…”

“…We aimed to recruit 80 children: 40 to receive Dextran and 40 to receive HES which would give sufficient data on the frequency of serious adverse events and clinical data on correction of hypovolaemic shock. Our previous experience suggested that this number was sufficient to provide information on these key endpoints [3,10,15,16]. Additional new data generated by the study included bolus volumes required of Dextran and HES to achieve satisfactory improvements in haemodynamic features of shock (primary endpoint).…”

“…Additional new data generated by the study included bolus volumes required of Dextran and HES to achieve satisfactory improvements in haemodynamic features of shock (primary endpoint). The trial had a similar design to previously published trials [3,10,15,16] but differed since children with decompensated shock (low systolic blood pressure) were excluded in the current trial since ethical approval to defer consent for these cases, permitted in the previous studies, was declined. The ethics committee raised concerns over the safety of the Dextrans -which in a previous trial had resulted in acute febrile reactions [23].…”

“…In a series of trials we have established that fluid resuscitation with 5% human albumin solution (HAS) results in a lower mortality than either 0.9% saline or Gelofusine ® (a gelatin polymer) [3,10,15,16]. The greatest benefit was seen in the high risk group with acidosis and coma [10].…”

What’s New in the Recognition and Management of Septic Shock in Children: Dos and Don'ts

“…Some of the factors that may be related to the outcome in that particular group of patients include: high rates of malaria; significant anemia; lack of identification of pathogens in the majority of the patients (only 12 % had positive blood cultures and there were no other tests for bacterial or viral pathogens); lack of availability of respiratory support (ventilation was not available, and in some cases access to oxygen was extremely limited). The result was particularly surprising in light of previous studies from that region demonstrating improvements in patients with severe malaria treated with fluid boluses [74,75]. It is relevant that although early antibiotic administration, vigorous volume resuscitation, and early use of inotropic support was associated with a dramatic improvement in outcomes from severe meningococcal disease in the UK [76], early endotracheal intubation and ventilation was provided for these patients.…”