Timing of Enteral Feeding in Cerebral Malaria in Resource-Poor Settings: A Randomized Trial

Maude, Richard J.; Hoque, Gofranul; Hasan, Mohammad Rashedul; Sayeed, Abu; Akter, Shahena; Samad, Rasheda; Alam, Badrul; Yunus, Emran Bin; Rahman, Ridwanur; Rahman, Waliur; Chowdhury, Romal; Seal, Tapan; Charunwatthana, Prakaykaew; Chang, Christina C.; White, Nicholas J.; Faiz, MA; Day, Nicholas P. J.; Dondorp, Arjen M.; Hossain, Amir

doi:10.1371/journal.pone.0027273

Cited by 40 publications

(31 citation statements)

References 24 publications

(28 reference statements)

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“…Serial GCS (assessed 6 hourly) and lactate (assessed 6 hourly) data from adult patients with severe malaria enrolled in studies at Chittagong Medical College Hospital (CMCH), Chittagong, Bangladesh between 2005 and 2012. The Bangladeshi patients were enrolled in observational and treatment studies including studies on levamisole, timing of enteral feeding, N-acetylcysteine and paracetamol [15, 18, 20, 22]. These randomized clinical trials were monitored internally as well as by an outside monitor.…”

Section: Methodsmentioning

confidence: 99%

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

et al. 2017

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BackgroundClinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria.MethodsThree datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures.ResultsImprovements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery.ConclusionsThe relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

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Section: Methodsmentioning

confidence: 99%

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

et al. 2017

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“…Given their low incidence, our trial was underpowered to demonstrate with certainty that implementation of the infection treatment bundle did not result in more adverse events. This conclusion is important because previous sepsis therapies supported by scientific evidence from high-income countries resulted in more complications and/or higher fatality rates when implemented in resource-limited settings [7][8][9]. For instance, three randomized controlled trials conducted in sub-Saharan Africa reported increased mortality associated with early fluid resuscitation in patients with sepsis and malaria in the absence of mechanical ventilation [8,9,19].…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 60% of the 7 million global deaths in neonates and infants annually are attributable to infection, with the majority of cases occurring in middle-and low-income countries [4]. Recommended intensive care interventions for the management of patients with sepsis [5] may be impractical, unaffordable, and possibly even harmful when implemented in middle-and low-income countries [6][7][8][9]. Consequently, early recognition and appropriate treatment of acute infection is essential.…”

Section: Introductionmentioning

confidence: 99%

Increasing evidence-based interventions in patients with acute infections in a resource-limited setting: a before-and-after feasibility trial in Gitwe, Rwanda

et al. 2018

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Objective: To evaluate whether a focused education program and implementation of a treatment bundle increases the rate of early evidence-based interventions in patients with acute infections.Design: Single-center, prospective, before-and-after feasibility trial.Setting: Emergency department of a sub-Saharan African district hospital. Patients:Patients > 28 days of life admitted to the study hospital for an acute infection. Interventions:The trial had three phases (each of 4 months). Interventions took place during the second (educational program followed by implementation of the treatment bundle) and third (provision of resources to implement treatment bundle) phases. Measurements and main results:Demographic, clinical, and laboratory data were collected at study enrollment; 24, 48, and 72 h after hospital admission; and at discharge. A total of 1594 patients were enrolled (pre-intervention, n = 661; intervention I, n = 531; intervention II, n = 402). The rate of early evidence-based interventions per patient during Intervention Phase I was greater than during the pre-intervention phase (74 ± 17 vs. 79 ± 15%, p < 0.001).No difference was detected when data were compared between Intervention Phases I and II (79 ± 15 vs. 80 ± 15%, p = 0.58). No differences in the incidence of blood transfusion (pre-intervention, 6%; intervention I, 7%; intervention II, 7%) or severe adverse events in the first 24 h (allergic reactions: pre-intervention, 0.2%; intervention I, 0%; intervention II, 0%; respiratory failure: pre-intervention, 2%; intervention I, 2%; intervention II, 2%; acute renal failure: pre-intervention, 2%; intervention I, 2%; intervention II, 1%) were observed.

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“…A recent clinical trial of children and adults with CM compared the effect of early and late commencement of enteral feeds in a setting where intubation was not available [68]. Early enteral feeding was started on the day of admission, while late enteral feeding was begun after 60 h in adults or 36 h in children [68]. The trial was stopped after 56 subjects were enrolled owing to a high rate of aspiration pneumonia in the early feeding group.…”

Section: Nutritional Supportmentioning

confidence: 99%

Pediatric Cerebral Malaria: A Scourge of Africa

et al. 2012

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Cerebral malaria, defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia, affects up to 1 million people per year, the vast majority of them being children living in sub-Saharan Africa. Despite optimal treatment, this condition kills 15% of those affected and leaves 30% of survivors with neurologic sequelae. The clinical diagnosis is hampered by its poor specificity, but the presence or absence of a malarial retinopathy in cerebral malaria has proven to be important in the differentiation of underlying coma etiology. Both antimalarials and intense supportive care are necessary for optimal treatment. As of yet, clinical trials of adjunctive therapies have not improved the high rates of mortality and morbidity. Survivors are at high risk of neurologic sequelae including epilepsy, neurodisabilities and cognitive–behavioral problems. The neuroanatomic and functional bases of these sequelae are being elucidated. Although adjunctive therapy trials continue, the best hope for African children may lie in disease prevention. Strategies include bednets, chemoprophylaxis and vaccine development.

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Timing of Enteral Feeding in Cerebral Malaria in Resource-Poor Settings: A Randomized Trial

Cited by 40 publications

References 24 publications

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

Increasing evidence-based interventions in patients with acute infections in a resource-limited setting: a before-and-after feasibility trial in Gitwe, Rwanda

Pediatric Cerebral Malaria: A Scourge of Africa

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