Publications
258 results found
Maitland K, Kiguli S, Opoka R, et al., 2018, Children’s Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia, Wellcome Open Research, Vol: 2, Pages: 1-36, ISSN: 2398-502X
Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia.Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 > or = 80% (permissive hypoxia); and High flow using AIrVO2TM compared with low flow delivery (routine care).Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%.Clinical trial registration: ISRCTN15622505
Hakim J, Maitland K, 2017, Oral abstracts of the 21st International AIDS Conference 18-22 July 2016, Durban, South Africa, Journal of the International AIDS Society, Vol: 19, ISSN: 1758-2652
Williams TN, Maitland K, 2017, The clinical epidemiology of sickle cell anemia in Africa, American Journal of Hematology, Vol: 93, Pages: 363-370, ISSN: 0361-8609
Sickle cell anemia (SCA) is the commonest severe monogenic disorders of humans. The disease has been highly characterized in high-income countries but not in sub-Saharan Africa where SCA is most prevalent. We conducted a retrospective cohort study of all children 0-13 years admitted from within a defined study area to Kilifi County Hospital in Kenya over a five-year period. Children were genotyped for SCA retrospectively and incidence rates calculated with reference to population data. Overall, 576 of 18,873 (3.1%) admissions had SCA of whom the majority (399; 69.3%) were previously undiagnosed. The incidence of all-cause hospital admission was 57.2/100 person years of observation (PYO; 95%CI 52.6-62.1) in children with SCA and 3.7/100 PYO (95%CI 3.7-3.8) in those without SCA (IRR 15.3; 95%CI 14.1-16.6). Rates were higher for the majority of syndromic diagnoses at all ages beyond the neonatal period, being especially high for severe anemia (hemoglobin <50g/L) (IRR 58.8; 95%CI 50.3-68.7), stroke (IRR 486; 95%CI 68.4-3,450), bacteremia (IRR 23.4; 95%CI 17.4-31.4), and for bone (IRR 607; 95%CI 284-1,300) and joint (IRR 80.9; 95%CI 18.1-362) infections. The use of an algorithm based on just five clinical features would have identified approximately half of all SCA cases among hospital-admitted children with a number needed to test to identify each affected patient of fourteen. Our study illustrates the clinical epidemiology of SCA in a malaria-endemic environment without specific interventions. The targeted testing of hospital-admitted children using the Kilifi Algorithm provides a pragmatic approach to early-diagnosis in high-prevalence countries where newborn screening is unavailable.
Maitland K, Kiguli S, Opoka RO, et al., 2017, Children’s Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia, Wellcome Open Research, Vol: 2, Pages: 100-100, ISSN: 2398-502X
Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia.Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares:Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO2TM compared with low flow delivery (routine care).Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%.
Houston KA, Gibb JG, Maitland K, 2017, Oral rehydration of malnourished children with diarrhoea and dehydration: A systematic review, Wellcome Open Research, Vol: 2, Pages: 66-66, ISSN: 2398-502X
Background: Diarrhoea complicates over half of admissions to hospital with severe acute malnutrition (SAM). World Health Organization (WHO) guidelines for the management of dehydration recommend the use of oral rehydration with ReSoMal (an oral rehydration solution (ORS) for SAM), which has lower sodium (45mmols/l) and higher potassium (40mmols/l) content than old WHO ORS. The composition of ReSoMal was designed specifically to address theoretical risks of sodium overload and potential under-treatment of severe hypokalaemia with rehydration using standard ORS. In African children, severe hyponatraemia at admission is a major risk factor for poor outcome in children with SAM complicated by diarrhoea. We therefore reviewed the evidence for oral rehydration therapy in children with SAM. Methods: We conducted a systematic review of randomised controlled trials (RCTs) on 18 (th) July 2017 comparing different oral rehydration solutions in severely malnourished children with diarrhoea and dehydration, using standard search terms. The author assessed papers for inclusion. The primary endpoint was frequency of hyponatraemia during rehydration. Results: Six RCTs were identified, all published in English and conducted in low resource settings in Asia. A range of ORS were evaluated in these studies, including old WHO ORS, standard hypo-osmolar WHO ORS and ReSoMal. Hyponatraemia was observed in two trials evaluating ReSoMal, three children developed severe hyponatraemia with one experiencing convulsions. Hypo-osmolar ORS was found to have benefits in time to rehydration, reduction of stool output and duration of diarrhoea. No trials reported over-hydration or fatalities. Conclusions: Current WHO guidelines strongly recommend the use of ReSoMal based on low quality of evidence. Studies indicate a significant risk of hyponatraemia on ReSoMal in Asian children, none have been conducted in Africa, where SAM mortality remains high. Further research should be conducted in Africa to ev
Houston KA, Gibb JG, Maitland K, 2017, Intravenous rehydration of malnourished children with acute gastroenteritis and severe dehydration: A systematic review., Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: Rehydration strategies in children with severe acute malnutrition (SAM) and severe dehydration are extremely cautious. The World Health Organization (WHO) SAM guidelines advise strongly against intravenous fluids unless the child is shocked or severely dehydrated and unable to tolerate oral fluids. Otherwise, guidelines recommend oral or nasogastric rehydration using low sodium oral rehydration solutions. There is limited evidence to support these recommendations. Methods: We conducted a systematic review of randomised controlled trials (RCTs) and observational studies on 15 (th) June 2017 comparing different strategies of rehydration therapy in children with acute gastroenteritis and severe dehydration, specifically relating to intravenous rehydration, using standard search terms. Two authors assessed papers for inclusion. The primary endpoint was evidence of fluid overload. Results: Four studies were identified, all published in English, including 883 children, all of which were conducted in low resource settings. Two were randomised controlled trials and two observational cohort studies, one incorporated assessment of myocardial and haemodynamic function. There was no evidence of fluid overload or other fluid-related adverse events, including children managed on more liberal rehydration protocols. Mortality was high overall, and particularly in children with shock managed on WHO recommendations (day-28 mortality 82%). There was no difference in safety outcomes when different rates of intravenous rehydration were compared. Conclusions: The current 'strong recommendations' for conservative rehydration of children with SAM are not based on emerging evidence. We found no clinical trials providing a direct assessment of the current WHO guidelines, and those that were available suggested that these children have a high mortality and remain fluid depleted on current therapy. Recent studies have reported no evidence of fluid overload or heart failure with mor
Houston K, Gibb J, Maitland K, 2017, Oral rehydration of malnourished children with diarrhoea and dehydration: A systematic review [version 1; referees: 1 approved, 1 approved with reservations], Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: Diarrhoea complicates over half of admissions to hospital with severe acute malnutrition (SAM). World Health Organization (WHO) guidelines for the management of dehydration recommend the use of oral rehydration with ReSoMal (an oral rehydration solution (ORS) for SAM), which has lower sodium (45mmols/l) and higher potassium (20mmols/l) content than standard ORS. The composition of ReSoMal was designed specifically to address theoretical risks of sodium overload and potential under-treatment of severe hypokalaemia with rehydration using standard ORS. In African children, severe hyponatraemia at admission is a major risk factor for poor outcome in children with SAM complicated by diarrhoea. We therefore reviewed the evidence for oral rehydration therapy in children with SAM.Methods: We conducted a systematic review of randomised controlled trials (RCTs) on 18th July 2017 comparing different oral rehydration solutions in severely malnourished children with diarrhoea and dehydration, using standard search terms. The author assessed papers for inclusion. The primary endpoint was frequency of hyponatraemia during rehydration.Results: Six RCTs were identified, all published in English and conducted in low resource settings in Asia. A range of ORS were evaluated in these studies, including standard ORS, hypo-osmolar ORS and ReSoMal. Hyponatraemia was observed in two trials evaluating ReSoMal, three children developed severe hyponatraemia with one experiencing convulsions. Hypo-osmolar ORS was found to have benefits in time to rehydration, reduction of stool output and duration of diarrhoea. No trials reported over-hydration or fatalities.Conclusions: Current WHO guidelines strongly recommend the use of ReSoMal based on low quality of evidence. Studies indicate a significant risk of hyponatraemia on ReSoMal in Asian children, none have been conducted in Africa, where SAM mortality remains high. Further research should be conducted in Africa to evaluate optimal OR
Maitland K, Houston KA, Gibb JG, et al., 2017, Gastroenteritis Aggressive Versus Slow Treatment For Rehydration (GASTRO): A Pilot rehydration study for severe dehydration: WHO plan C versus slower rehydration, Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children’s responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes. Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate (WHO plan ‘C’ – 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae. Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. D
Hakim J, Musiime V, Szubert AJ, et al., 2017, Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa, New England Journal of Medicine, Vol: 377, Pages: 233-245, ISSN: 0028-4793
BACKGROUNDIn sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV)infection, the rate of death from infection (including tuberculosis and cryptococcus) shortlyafter the initiation of antiretroviral therapy (ART) is approximately 10%.METHODSIn this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, weenrolled HIV-infected adults and children 5 years of age or older who had not received previousART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter.They underwent simultaneous randomization to receive enhanced antimicrobialprophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementaryfood or no supplementary food. Here, we report on the effects of enhanced antimicrobialprophylaxis, which consisted of continuous trimethoprim–sulfamethoxazole plus atleast 12 weeks of isoniazid–pyridoxine (coformulated with trimethoprim–sulfamethoxazolein a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin,and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim–sulfamethoxazole alone). The primary end point was 24-week mortality.RESULTSA total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomizationto receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients)and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic ormildly symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of death with enhancedprophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108[12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients(11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58to 0.99; P=0.04). Patients in the
Byrne L, Obonyo NG, Diab S, et al., 2017, An ovine model of hyperdynamic endotoxemia and vital organ metabolism, Shock, Vol: 49, Pages: 99-107, ISSN: 1540-0514
BACKGROUND: Animal models of endotoxemia are frequently used to understand the pathophysiology of sepsis and test new therapies. However, important differences exist between commonly used experimental models of endotoxemia and clinical sepsis. Animal models of endotoxemia frequently produce hypodynamic shock in contrast to clinical hyperdynamic shock. This difference may exaggerate the importance of hypoperfusion as a causative factor in organ dysfunction. This study sought to develop an ovine model of hyperdynamic endotoxemia and assess if there is evidence of impaired oxidative metabolism in the vital organs. METHODS: Eight sheep had microdialysis catheters implanted into the brain, heart, liver, kidney and arterial circulation. Shock was induced with a 4hr escalating dose infusion of endotoxin. After 3hrs vasopressor support was initiated with noradrenaline and vasopressin. Animals were monitored for 12hrs after endotoxemia. Blood samples were recovered for haemoglobin, white blood cell count, creatinine and proinflammatory cytokines (IL-1Beta, IL-6 & IL-8). RESULTS: The endotoxin infusion was successful in producing distributive shock with the mean arterial pressure decreasing from 84.5 ± 12.8 mmHg to 49 ± 8.03 mmHg (p < 0.001). Cardiac index remained within the normal range decreasing from 3.33 ± 0.56 l/min/m to 2.89l ± 0.36 l/min/m (p = 0.0845). Lactate/pyruvate ratios were not significantly abnormal in the heart, brain, kidney or arterial circulation. Liver microdialysis samples demonstrated persistently high lactate/pyruvate ratios (mean 37.9 ± 3.3). CONCLUSIONS: An escalating dose endotoxin infusion was successful in producing hyperdynamic shock. There was evidence of impaired oxidative metabolism in the liver suggesting impaired splanchnic perfusion. This may be a modifiable factor in the progression to multiple organ dysfunction and death.
Obonyo N, Brent B, Olupot-Olupot P, et al., 2017, Myocardial and haemodynamic responses to two fluid regimens in African children with severe malnutrition and hypovolaemic shock (AFRIM study), Critical Care, Vol: 21, ISSN: 1364-8535
BackgroundFluid therapy in severely malnourished children is hypothesized to be deleterious owing to compromised cardiac function. We evaluated World Health Organization (WHO) fluid resuscitation guidelines for hypovolaemic shock using myocardial and haemodynamic function and safety endpoints.MethodsA prospective observational study of two sequential fluid management strategies was conducted at two East African hospitals. Eligible participants were severely malnourished children, aged 6–60 months, with hypovolaemic shock secondary to gastroenteritis. Group 1 received up to two boluses of 15 ml/kg/h of Ringer’s lactate (RL) prior to rehydration as per WHO guidelines. Group 2 received rehydration only (10 ml/kg/h of RL) up to a maximum of 5 h. Comprehensive clinical, haemodynamic and echocardiographic data were collected from admission to day 28.ResultsTwenty children were enrolled (11 in group 1 and 9 in group 2), including 15 children (75%) with kwashiorkor, 8 (40%) with elevated brain natriuretic peptide >300 pg/ml, and 9 (45%) with markedly elevated median systemic vascular resistance index (SVRI) >1600 dscm-5/m2 indicative of severe hypovolaemia. Echocardiographic evidence of fluid-responsiveness (FR) was heterogeneous in group 1, with both increased and decreased stroke volume and myocardial fractional shortening. In group 2, these variables were more homogenous and typical of FR. Median SVRI marginally decreased post fluid administration (both groups) but remained high at 24 h. Mortality at 48 h and to day 28, respectively, was 36% (4 deaths) and 81.8% (9 deaths) in group 1 and 44% (4 deaths) and 55.6% (5 deaths) in group 2. We observed no pulmonary oedema or congestive cardiac failure on or during admission; most deaths were unrelated to fluid interventions or echocardiographic findings of response to fluids.ConclusionBaseline and cardiac response to fluid resuscitation do not indicate an effect of compromised cardiac function on response to
Mehta S, Burns KEA, Machado FR, et al., 2017, Gender parity in critical care medicine, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 425-429, ISSN: 1073-449X
Clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. These documents inform and shape patient care around the world. In this Perspective we discuss the importance of diversity on guideline panels, the disproportionately low representation of women on critical care guideline panels, and existing initiatives to increase the representation of women in corporations, universities, and government. We propose five strategies to ensure gender parity within critical care medicine.
Olupot-Olupot P, Engoru CE, Uyoga S, et al., 2017, High frequency of blackwater fever among children presenting to hospital with severe febrile illnesses in Eastern Uganda, Clinical Infectious Diseases, Vol: 64, Pages: 939-946, ISSN: 1537-6591
Background In the Fluid-Expansion-as-a-Supportive-Treatment (FEAST) trial an unexpectedly-high proportion of participants from Eastern Uganda presented with blackwater fever (BWF).Methods We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of three malaria-protective red blood cell polymorphisms in BWF-cases versus both trial (non-BWF) and population-controls. FindingsOf 3,170 trial participants 394 (12.4%) had BWF. The majority (318; 81.0%) presented in Eastern Uganda: the subjects of further analysis. BWF cases typically presented with both clinical jaundice 254/318 (80%) and severe-anaemia (Hb <5g/dl) 238/310 (77%). Plasmodium falciparum parasitaemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum Histidine Rich Protein-2 [192/246 (78.0%) versus 811/1154 (70.3%); p=0.014], suggesting recent anti-malarial treatment. Overall, 282/318 (88.7%) received transfusions, with 94/282 (33.3%) and 9/282 (3.4%) receiving 2 or 3 transfusions respectively. By day-28, 39/318 (12.3%) BWF cases and 154/1554 (9.9%) non-BWF controls had died (P=0.21) and 7/255 (3.0%) versus 13/1212 (1%; p=0.036) had severe anaemia. We found no association with G6PD deficiency. The prevalence of both the sickle cell trait [10/218 (4.6%)] and homozygous +thalassaemia [8/216 (3.7%)] were significantly lower among cases than population controls [334/2123 (15.7%) and 141/2114 (6.6%), respectively], providing further support for the role of malaria. InterpretationWe report the emergence of BWF in Eastern Uganda, a condition that according to local investigators was rare until the last 5 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.
Maitland K, 2016, Severe malaria in African children — The need for continuing investment, New England Journal of Medicine, Vol: 375, Pages: 2416-2417, ISSN: 0028-4793
Obonyo NG, Fanning JP, Ng ASY, et al., 2016, Effects of volume resuscitation on the microcirculation in animal models of lipopolysaccharide sepsis: a systematic review., Intensive Care Medicine Experimental, Vol: 4, Pages: 1-16, ISSN: 2197-425X
BACKGROUND: Recent research has identified an increased rate of mortality associated with fluid bolus therapy for severe sepsis and septic shock, but the mechanisms are still not well understood. Fluid resuscitation therapy administered for sepsis and septic shock targets restoration of the macro-circulation, but the pathogenesis of sepsis is complex and includes microcirculatory dysfunction. OBJECTIVE: The objective of the study is to systematically review data comparing the effects of different types of fluid resuscitation on the microcirculation in clinically relevant animal models of lipopolysaccharide-induced sepsis. METHODS: A structured search of PubMed/MEDLINE and EMBASE for relevant publications from 1 January 1990 to 31 December 2015 was performed, in accordance with PRISMA guidelines. RESULTS: The number of published papers on sepsis and the microcirculation has increased steadily over the last 25 years. We identified 11 experimental animal studies comparing the effects of different fluid resuscitation regimens on the microcirculation. Heterogeneity precluded any meta-analysis. CONCLUSIONS: Few animal model studies have been published comparing the microcirculatory effects of different types of fluid resuscitation for sepsis and septic shock. Biologically relevant animal model studies remain necessary to enhance understanding regarding the mechanisms by which fluid resuscitation affects the microcirculation and to facilitate the transfer of basic science discoveries to clinical applications.
Nabwera HM, Fegan G, Shavadia J, et al., 2016, Pediatric blood transfusion practices at a regional referral hospital in Kenya, Transfusion, Vol: 56, Pages: 2732-2738, ISSN: 0041-1132
BACKGROUNDSevere anemia in children is a major public health problem in sub-Saharan Africa. In this study we describe clinical and operational aspects of blood transfusion in children admitted to Coast Provincial General Hospital, Kenya.STUDY DESIGN AND METHODSThis was an observational study where over a 2-year period, demographic and laboratory data were collected on all children for whom the hospital blood bank received a transfusion request. Clinical data were obtained by retrospective review of case notes over the first year.RESULTSThere were 2789 requests for blood for children (median age, 1.8 years; interquartile range [IQR], 0.6-6.6 years); 70% (1950) of the samples were crossmatched with 85% (1663/1950) issued. Ninety percent (1505/1663) were presumed transfused. Median time from laboratory receipt of request to collection of blood was 3.6 hours (IQR, 1.4-12.8 hr). Case notes of 590 children were reviewed and median pretransfusion hemoglobin level was 6.0 g/dL (IQR, 4.2-9.1 g/dL). Ninety-four percent (186) were transfused “appropriately” while 52% (120) were transfused “inappropriately.” There was significant disagreement between the clinical and laboratory diagnosis of severe anemia (exact McNemar's test; p < 0.0001). Antimalarials were prescribed for 65% (259) of children who received blood transfusions but only 41% (106) of these had a positive blood film.CONCLUSIONIn this setting, clinicians often order blood based on the clinical impression of “severe anemia.” This has implications for laboratory workload and the blood supply itself. However, the majority of children with severe anemia were appropriately transfused. The use of antimalarials with blood transfusions irrespective of blood film results is common practice.
Nightingale H, Walsh KJ, Olupot-Olupot P, et al., 2016, Validation of triple pass 24-hour dietary recall in Ugandan children by simultaneous weighed food assessment., BMC Nutr, Vol: 2, ISSN: 2055-0928
BACKGROUND: Undernutrition remains highly prevalent in African children, highlighting the need for accurately assessing dietary intake. In order to do so, the assessment method must be validated in the target population. A triple pass 24 hour dietary recall with volumetric portion size estimation has been described but not previously validated in African children. This study aimed to establish the relative validity of 24-hour dietary recalls of daily food consumption in healthy African children living in Mbale and Soroti, eastern Uganda compared to simultaneous weighed food records. METHODS: Quantitative assessment of daily food consumption by weighed food records followed by two independent assessments using triple pass 24-hour dietary recall on the following day. In conjunction with household measures and standard food sizes, volumes of liquid, dry rice, or play dough were used to aid portion size estimation. Inter-assessor agreement, and agreement with weighed food records was conducted primarily by Bland-Altman analysis and secondly by intraclass correlation coefficients and quartile cross-classification. RESULTS: 19 healthy children aged 6 months to 12 years were included in the study. Bland-Altman analysis showed 24-hour recall only marginally under-estimated energy (mean difference of 149kJ or 2.8%; limits of agreement -1618 to 1321kJ), protein (2.9g or 9.4%; -12.6 to 6.7g), and iron (0.43mg or 8.3%; -3.1 to 2.3mg). Quartile cross-classification was correct in 79% of cases for energy intake, and 89% for both protein and iron. The intraclass correlation coefficient between the separate dietary recalls for energy was 0.801 (95% CI, 0.429-0.933), indicating acceptable inter-observer agreement. CONCLUSIONS: Dietary assessment using 24-hour dietary recall with volumetric portion size estimation resulted in similar and acceptable estimates of dietary intake compared with weighed food records and thus is considered a valid method for daily dietary intake assessment
Church JA, Nyamako L, Olupot-Olupot P, et al., 2016, Increased adhesion of Plasmodium falciparum infected erythrocytes to ICAM-1 in children with acute intestinal injury, Malaria Journal, Vol: 15, ISSN: 1475-2875
Background: Children with severe malaria are at increased risk of invasive bacterial disease particularly infectionwith enteric gram-negative organisms. These organisms are likely to originate from the gut, however, how andwhy they breach the intestinal interface in the context of malaria infection remains unclear. One explanation is thataccumulation of infected red blood cells (iRBCs) in the intestinal microvasculature contributes to tissue damage andsubsequent microbial translocation which can be addressed through investigation of the impact of cytoadhesion inpatients with malaria and intestinal damage.Methods: Using a static adhesion assay, cytoadhesion of iRBCs was quantified in 48 children with malaria to recom‑binant proteins constitutively expressed on endothelial cell surfaces. Cytoadhesive phenotypes between childrenwith and without biochemical evidence of intestinal damage [defined as endotoxemia or elevated plasma intestinalfatty acid binding protein (I-FABP)] was compared.Results: The majority of parasites demonstrated binding to the endothelial receptors CD36 and to a lesser extent toICAM-1. Reduced adhesion to CD36 but not adhesion to ICAM-1 or rosetting was associated with malarial anaemia(p = 0.004). Increased adhesion of iRBCs to ICAM-1 in children who had evidence of elevated I-FABP (p = 0.022), amarker of intestinal ischaemia was observed. There was no correlation between the presence of endotoxemia andincreased adhesion to any of the recombinant proteins.Conclusion: Increased parasite adhesion to ICAM-1 in children with evidence of intestinal ischaemia lends furtherevidence to a link between the cytoadherence of iRBCs in gut microvasculature and intestinal damage.
Maitland K, 2015, Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomized controlled trial, Trials, Vol: 16, ISSN: 1745-6215
BackgroundIn sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9–10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.Methods/DesignTRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children.The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4–6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity
Maitland K, 2015, Management of severe paediatric malaria in resource-limited settings., BMC Medicine, Vol: 13, Pages: 263-263, ISSN: 1741-7015
Over 90% of the world's severe and fatal Plasmodium falciparum malaria is estimated to affect young children in sub-Sahara Africa, where it remains a common cause of hospital admission and inpatient mortality. Few children will ever be managed on high dependency or intensive care units and, therefore, rely on simple supportive treatments and parenteral anti-malarials. There has been some progress on defining best practice for antimalarial treatment with the publication of the AQUAMAT trial in 2010, involving 5,425 children at 11 centres across 9 African countries, showing that in artesunate-treated children, the relative risk of death was 22.5% (95% confidence interval (CI) 8.1 to 36.9) lower than in those receiving quinine. Human trials of supportive therapies carried out on the basis of pathophysiology studies, have so far made little progress on reducing mortality; despite appearing to reduce morbidity endpoints, more often than not they have led to an excess of adverse outcomes. This review highlights the spectrum of complications in African children with severe malaria, the therapeutic challenges of managing these in resource-poor settings and examines in-depth the results from clinical trials with a view to identifying the treatment priorities and a future research agenda.
George EC, Walker AS, Kiguli S, et al., 2015, Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score., BMC Medicine, Vol: 13, ISSN: 1741-7015
BACKGROUND: Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality. METHODS: Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors. RESULTS: A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score. CONCLUSIONS: Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency
Hassall OW, Thitiri J, Fegan G, et al., 2015, Safety and efficacy of allogeneic umbilical cord red blood cell transfusion for children with severe anaemia in a Kenyan hospital: an open-label single-arm trial, The Lancet Haematology, Vol: 2, Pages: e101-e107, ISSN: 2352-3026
BackgroundIn sub-Saharan Africa, children are frequently admitted with severe anaemia needing an urgent blood transfusion, but blood is often unavailable. When conventional blood supplies are inadequate, allogeneic umbilical cord blood could be a feasible alternative. The aim of this study was to assess the safety and efficacy of cord blood transfusion in children with severe anaemia.MethodsBetween June 26, 2007, and May 20, 2008, 413 children needing an urgent blood transfusion were admitted to Kilifi District Hospital in Kenya. Of these, 87 children were eligible for our study—ie, younger than 12 years, no signs of critical illness, and haemoglobin 100 g/L or lower (if aged 3 months or younger) or 40 g/L or lower (if older than 3 months). Cord blood was donated at Coast Provincial General Hospital, Mombasa, and screened for transfusion-transmitted infections and bacterial contamination. Red blood cells were stored vertically at 2–6°C to enable sedimentation. After transfusion, children were monitored closely for adverse events and followed up for 28 days. The primary outcome measure was the frequency and nature of adverse reactions associated with the transfusion. Secondary outcomes were the changes in haemoglobin concentrations 24 h and 28 days after transfusion, compared with pretransfusion levels. This trial is registered on ISRCTN.com, number ISRCTN66687527.FindingsOf the 87 children eligible for the study, cord blood was unavailable for 24, six caregivers declined consent, and two children were withdrawn before transfusion. Therefore, 55 children received umbilical cord red blood cells from 74 donations. Ten (18%) children had ten serious adverse events and 43 (78%) had 94 adverse events; the most frequent adverse events were anaemia (n=14), weight loss (n=12), and vomiting (n=10). An independent expert panel judged none of these adverse events to be probably or certainly caused by the cord blood transfusion (one-sided 97·5% CI 0–
Kiguli J, 2015, Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness, BMC Medicine, Vol: 13
Hoste AD, 2014, Four phases of intravenous fluid therapy: A conceptual model, British Journal of Anaesthesia, Vol: 113, Pages: 740-747, ISSN: 1471-6771
I.V. fluid therapy plays a fundamental role in the management of hospitalized patients. While the correct use of i.v. fluids can be lifesaving, recent literature demonstrates that fluid therapy is not without risks. Indeed, the use of certain types and volumes of fluid can increase the risk of harm, and even death, in some patient groups. Data from a recent audit show us that the inappropriate use of fluids may occur in up to 20% of patients receiving fluid therapy. The delegates of the 12th Acute Dialysis Quality Initiative (ADQI) Conference sought to obtain consensus on the use of i.v. fluids with the aim of producing guidance for their use. In this article, we review a recently proposed model for fluid therapy in severe sepsis and propose a framework by which it could be adopted for use in most situations where fluid management is required. Considering the dose–effect relationship and side-effects of fluids, fluid therapy should be regarded similar to other drug therapy with specific indications and tailored recommendations for the type and dose of fluid. By emphasizing the necessity to individualize fluid therapy, we hope to reduce the risk to our patients and improve their outcome.
Anderson ST, Kaforou M, Brent AJ, et al., 2014, Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa, New England Journal of Medicine, Vol: 370, Pages: 1712-1723, ISSN: 1533-4406
Kotlyar S, Nteziyaremye J, Olupot-Olupot P, et al., 2014, Spleen volume and clinical disease manifestations of severe <i>Plasmodium falciparum</i> malaria in African children, TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, Vol: 108, Pages: 283-289, ISSN: 0035-9203
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Olupot-Olupot K, Engoru C, Thompson J, et al., 2014, Phase II trial of standard versus increased transfusion volume in Ugandan children with acute severe anemia, BMC Medicine, Vol: 12, ISSN: 1741-7015
Background: Severe anemia (SA, hemoglobin <6 g/dl) is a leading cause of pediatric hospital admission in Africa,with significant in-hospital mortality. The underlying etiology is often infectious, but specific pathogens are rarelyidentified. Guidelines developed to encourage rational blood use recommend a standard volume of whole blood(20 ml/kg) for transfusion, but this is commonly associated with a frequent need for repeat transfusion and pooroutcome. Evidence is lacking on what hemoglobin threshold criteria for intervention and volume are associatedwith the optimal survival outcomes.Methods: We evaluated the safety and efficacy of a higher volume of whole blood (30 ml/kg; Tx30: n = 78) againstthe standard volume (20 ml/kg; Tx20: n = 82) in Ugandan children (median age 36 months (interquartile range(IQR) 13 to 53)) for 24-hour anemia correction (hemoglobin >6 g/dl: primary outcome) and 28-day survival.Results: Median admission hemoglobin was 4.2 g/dl (IQR 3.1 to 4.9). Initial volume received followed therandomization strategy in 155 (97%) patients. By 24-hours, 70 (90%) children in the Tx30 arm had corrected SAcompared to 61 (74%) in the Tx20 arm; cause-specific hazard ratio = 1.54 (95% confidence interval 1.09 to 2.18, P = 0.01).From admission to day 28 there was a greater hemoglobin increase from enrollment in Tx30 (global P <0.0001).Serious adverse events included one non-fatal allergic reaction and one death in the Tx30 arm. There were sixdeaths in the Tx20 arm (P = 0.12); three deaths were adjudicated as possibly related to transfusion, but nonesecondary to volume overload.Conclusion: A higher initial transfusion volume prescribed at hospital admission was safe and resulted in anaccelerated hematological recovery in Ugandan children with SA. Future testing in a large, pragmatic clinicaltrial to establish the effect on short and longer-term survival is warranted.
Maitland K, 2014, New diagnostics for common childhood infections, New England Journal of Medicine, Vol: 370, Pages: 875-877, ISSN: 1533-4406
Kiguli S, Akech SO, Mtove G, et al., 2014, WHO GUIDELINES ON FLUID RESUSCITATION IN CHILDREN Concerns about intravenous fluids given to critically ill children Reply, BMJ-BRITISH MEDICAL JOURNAL, Vol: 348, ISSN: 1756-1833
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- Citations: 1
Madan NJ, Ades AE, Price M, et al., 2014, Strategies for efficient computation of the expected value of partial perfect information, Medical Decision Making, Vol: 34, Pages: 327-342, ISSN: 0272-989X
Expected value of information methods evaluate the potential health benefits that can be obtained from conducting new research to reduce uncertainty in the parameters of a cost-effectiveness analysis model, hence reducing decision uncertainty. Expected value of partial perfect information (EVPPI) provides an upper limit to the health gains that can be obtained from conducting a new study on a subset of parameters in the cost-effectiveness analysis and can therefore be used as a sensitivity analysis to identify parameters that most contribute to decision uncertainty and to help guide decisions around which types of study are of most value to prioritize for funding. A common general approach is to use nested Monte Carlo simulation to obtain an estimate of EVPPI. This approach is computationally intensive, can lead to significant sampling bias if an inadequate number of inner samples are obtained, and incorrect results can be obtained if correlations between parameters are not dealt with appropriately. In this article, we set out a range of methods for estimating EVPPI that avoid the need for nested simulation: reparameterization of the net benefit function, Taylor series approximations, and restricted cubic spline estimation of conditional expectations. For each method, we set out the generalized functional form that net benefit must take for the method to be valid. By specifying this functional form, our methods are able to focus on components of the model in which approximation is required, avoiding the complexities involved in developing statistical approximations for the model as a whole. Our methods also allow for any correlations that might exist between model parameters. We illustrate the methods using an example of fluid resuscitation in African children with severe malaria.
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