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.
This study was a phase II safety and efficacy study.
The study was conducted at Kilifi District Hospital, Kenya.
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.
The interventions were volume resuscitation with either 4.5% human albumin solution or Gelofusine.
Primary endpoints were the resolution of shock and acidosis; secondary endpoints were in-hospital mortality and adverse events including neurological sequelae.
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).
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.
Background: In Africa, children admitted to hospital with severe malaria are at high risk of death even though effective malaria treatment is available. Death typically occurs during a narrow time window after admission and before antimalarial treatments can start working. Acidosis (excessive acidity of the blood) is thought to predict death, but it is not clear how acidosis arises. One possibility is that hypovolemia (lowered blood fluid volume) is important, which would normally require urgent resuscitation with fluids. However, there is little evidence on what type of fluid should be given. In the trial reported here, carried out in Kenya's Kilifi District Hospital between 2004 and 2006, 88 children admitted with severe malaria were assigned to receive either albumin solution (a colloid solution made from blood protein) or Gelofusine (a synthetic colloid). The primary outcomes that the researchers were interested in were correction of shock and acidosis in the blood after 8 h. However, the researchers also looked at death rate in hospital and adverse events after treatment.
What this trial shows: The investigators found no significant differences in the primary outcomes (correction of shock and acidosis in the blood 8 h after fluids were started) between children given Gelofusine and those given albumin. However, they did see a difference in death rates between children given Gelofusine and those given albumin. Death rates in hospital were lower in the group given albumin, and this was statistically significant. The researchers then combined the data on death rates from this trial with data from two other trials with an albumin arm. This combined analysis also supported the suggestion that death rates with albumin were lower than with other fluids, either Gelofusine or salt solution.
Strengths and limitations: There is currently very little evidence from trials to guide the initial management of fluids in children with severe malaria. The results from this trial indicate that further research is a priority. However, the actual findings from this trial must be tested in larger trials that recruit enough children to establish reliably whether there is a difference in death rate between albumin treatment and treatment with other fluids. This trial was not originally planned to find a clinically relevant difference in death rate, and therefore does not definitively answer that question. Further trials would also need to use a random method to assign participants to the different treatments, rather than alternate blocks (as in this trial). A random method ensures greater comparability of the two groups in the trial, and reduces the chance of selection bias (where assignment of patients to different treatments can be distorted during the enrollment process).
Contribution to the evidence: This study adds data suggesting that fluid resuscitation with albumin solution, as compared to Gelofusine, may reduce the chance of death in children with severe malaria. However, this finding is not definitive and would need to be examined in further carefully controlled trials. If the finding is supported by further research, then a solution to the problems of high cost and limited availability of albumin will need to be found.