Browsing by Author "Maitland, Kathryn"
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Item Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness(BMC Medicine, 2015) Kiguli, Sarah; Maitland, Kathryn; George, Elizabeth C; Olupot-Olupot, Peter; Opoka, Robert O; Engoru, Charles; Akech, Samuel O; Nyeko, Richard; Mtove, George; Reyburn, Hugh; Levin, Michael; Babiker, Abdel G; Gibb, Diana M; Crawley, JaneBackground: Severe anaemia in children is a leading cause of hospital admission and a major cause of mortality in sub-Saharan Africa, yet there are limited published data on blood transfusion in this vulnerable group. Methods: We present data from a large controlled trial of fluid resuscitation (Fluid Expansion As Supportive Therapy (FEAST) trial) on the prevalence, clinical features, and transfusion management of anaemia in children presenting to hospitals in three East African countries with serious febrile illness (predominantly malaria and/or sepsis) and impaired peripheral perfusion. Results: Of 3,170 children in the FEAST trial, 3,082 (97%) had baseline haemoglobin (Hb) measurement, 2,346/3,082 (76%) were anaemic (Hb <10 g/dL), and 33% severely anaemic (Hb <5 g/dL). Prevalence of severe anaemia varied from 12% in Kenya to 41% in eastern Uganda. 1,387/3,082 (45%) children were transfused (81% within 8 hours). Adherence to WHO transfusion guidelines was poor. Among severely anaemic children who were not transfused, 52% (54/103) died within 8 hours, and 90% of these deaths occurred within 2.5 hours of randomisation. By 24 hours, 128/1,002 (13%) severely anaemic children had died, compared to 36/501 (7%) and 71/843 (8%) of those with moderate and mild anaemia, respectively. Among children without severe hypotension who were randomised to receive fluid boluses of 0.9% saline or albumin, mortality was increased (10.6% and 10.5%, respectively) compared to controls (7.2%), regardless of admission Hb level. Repeat transfusion varied from ≤2% in Kenya/Tanzania to 6 to 13% at the four Ugandan centres. Adverse reactions to blood were rare (0.4%). Conclusions: Severe anaemia complicates one third of childhood admissions with serious febrile illness to hospitals in East Africa, and is associated with increased mortality. A high proportion of deaths occurred within 2.5 hours of admission, emphasizing the need for rapid recognition and prompt blood transfusion. Adherence to current WHO transfusion guidelines was poor. The high rates of re-transfusion suggest that 20 mL/kg whole blood or 10 mL/kg packed cells may undertreat a significant proportion of anaemic children. Future evaluation of the impact of a larger volume of transfused blood and optimum transfusion management of children with Hb of <6 g/dL is warranted.Item Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial(2013) Maitland, Kathryn; George, Elizabeth C; Evans, Jennifer; Kiguli, Sarah; Olupot-Olupot, Peter; Akech, Samuel O; Opoka, Robert O; Engoru, Charles; Nyeko, Richard; Mtove, George; Reyburn, Hugh; Brent, Bernadette; Nteziyaremye, Julius; Mpoya, Ayub; Prevatt, Natalie; Dambisya, Cornelius M; Semakula, Daniel; Ddungu, Ahmed; Okuuny, Vicent; Wokulira, Ronald; Otii, Benedict; Levin, Michael; Crawley, Jane; Babiker, Abdel G; Gibb, Diana M; FEAST trial groupBackground: Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour allcause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload. Methods: Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events. Results: Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and ‘nonresponders’ (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events. Conclusions: Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a reappraisal of the rate, composition and volume of resuscitation fluids.Item High Frequency of Blackwater Fever Among Children Presenting to Hospital With Severe Febrile Illnesses in Eastern Uganda(Clinical Infectious Diseases, 2017) Olupot-Olupot, Peter; Engoru, Charles; Uyoga, Sophie; Muhindo, Rita; Macharia, Alex; Kiguli, Sarah; Opoka, Robert O; Akech, Samuel; Ndila, Carolyne; Nyeko, Richard; Mtove, George; Nteziyaremye, Julius; Chebet, Martin; George, Elizabeth C; Babiker, Abdel G; Gibb, Diana M; Williams, Thomas N.; Maitland, KathrynBackground. 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 3 malaria- protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. Results. Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia 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%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous α+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. Conclusions. We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.Item Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa(BMC Medicine, 2018) Aramburo, A; Todd, Jim; George, Elizabeth C.; Kiguli, Sarah; Olupot-Olupot, Peter; Opoka, Robert O; Engoru, Charles; Akech, Samuel O; Nyeko, Richard; Mtove, George; Gibb, Diana M; Babiker, Abdel G; Maitland, KathrynBackground: Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas. Methods: In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L). Results: Of 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4. 62; 95% CI 2.7, 8.0; p < 0.001). Conclusions: Independently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment.Item Mortality after Fluid Bolus in African Children with Severe Infection(New England Journal of Medicine, 2011) Maitland, Kathryn; Kiguli, Sarah; Opoka, Robert O.; Engoru, Charles; Olupot-Olupot, Peter; Akech, Samuel O.; Nyeko, Richard; Mtove, George; Reyburn, Hugh; Lang, Trudie; Brent, Bernadette; Evans, Jennifer A.; Tibenderana, James K.; Crawley, Jane; Russell, Elizabeth C.; Levin, Michael; Babiker, Abdel G.; Gibb, Diana M.Background The role of fluid resuscitation in the treatment of children with shock and lifethreatening 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). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. 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 albuminbolus 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. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.)Item Mortality risk over time after early fluid resuscitation in African children(Clinical care, 2019) George, Elizabeth C.; Kiguli, Sarah; Olupot Olupot, Peter; Opoka, Robert O.; Engoru, Charles; Akech, Samuel O.; Nyeko, Richard; Mtove, George; Mpoya, Ayub; Thomason, Margaret J.; Crawley, Jane; Evans, Jennifer A.; Gibb, Diana M.; Babiker, Abdel G.; Maitland, Kathryn; Walker, A. SarahBackground: African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear. Methods: In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20–40 ml/kg 5% albumin or 0.9% saline over 1–2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other). Results: Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death. Conclusions: The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration.Item Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score(BMC Medicine, 2015) George, Elizabeth C.; Walker, A. Sarah; Kiguli, Sarah; Olupot-Olupo, Peter; Opoka, Robert O.; Engoru, Charles; Akech, Samuel O.; Nyeko, Richard; Mtove, George; Reyburn, Hugh; Berkley, James A.; Mpoya, Ayub; Levin, Michael; Crawley, Jane; Gibb, Diana M.; Maitland, Kathryn; Babiker, Abdel G.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 Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.Item WHO guidelines on fluid resuscitation in children : Authors’ reply to Southall(BMJ Publishing Group Ltd, 2014) Kiguli, Sarah; Akech, Samuel O; Mtove, George; Opoka, Robert O; Engoru, Charles; Olupot-Olupot, Peter; Nyeko, Richard; Evans, Jennifer; Crawley, Jane; Prevatt, Natalie; Reyburn, Hugh; Levin, Michael; George, Elizabeth C; South, Annabelle; Babiker, Abdel G; Gibb, Diana M; Maitland, KathrynSouthall made several points about our recent article.1 2 He suggests that “lethal hyperchloraemia” secondary to use of normal saline in FEAST (for boluses or maintenance) resulted in excess mortality. However, he did not comment on the key finding of the trial—that the increased 48 hour mortality was identical in both normal saline bolus (10.6%) and albumin bolus (10.6%) arms compared with the no bolus control group (7.3%).3 Harm was shown for every age group, in every condition, at each of the six hospitals, regardless of degree of acidosis,4 and for all definitions of shock.5 Despite differences in physical properties of albumin and saline, the timing of excess mortality after administration was identical (Kaplan-Meier mortality curves),3 making his hypothesis improbable.Item WHO guidelines on fluid resuscitation in children: missing the FEAST data(Bmj, 2014) Kiguli, Sarah; Akech, Samuel O; Mtove, George; Opoka, Robert O; Engoru, Charles; Olupot-Olupot, Peter; Nyeko, Richard; Evans, Jennifer; Crawley, Jane; Prevatt, Natalie; Reyburn, Hugh; Levin, Michael; George, Elizabeth C; Babiker, Abdel G; Gibb, Diana M; Maitland, KathrynThe World Health Organization recommendations on management of common childhood illnesses affect the lives of millions of children admitted to hospital worldwide. Its latest guidelines,1 released in May 2013, continue to recommend rapid fluid resuscitation for septic shock, even though the only large controlled trial of this treatment (Fluid Expansion as a Supportive Treatment (FEAST) found that it increased the risk of death in African children.2 A subsequent systematic review of bolus resuscitation in children with shock resulting from severe infection also did not support its use.3 Failure to take this evidence into account is not consistent with WHO’s commitment to systematically and transparently assess evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) process when producing guidelines and could endanger the lives of children