Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial
Kathryn Maitland, Elizabeth C George, Jennifer A Evans, Sarah Kiguli, Peter Olupot-Olupot, Samuel O Akech, Robert O Opoka, Charles Engoru, Richard Nyeko, George Mtove, Hugh Reyburn, Bernadette Brent, Julius Nteziyaremye, Ayub Mpoya, Natalie Prevatt, Cornelius M Dambisya, Daniel Semakula, Ahmed Ddungu, Vicent Okuuny, Ronald Wokulira, Molline Timbwa, Benedict Otii, Michael Levin, Jane Crawley, Abdel G Babiker, Diana M Gibb, FEAST trial group, Kathryn Maitland, Mukami J Mbogo, Gilbert Ogetii, James Tibenderana, Lilian Akello, Moses Waweru, Naomi Waithira, Trudie Lang, Roma Chilengi, Greg Fegan, Abdel Babiker, Elizabeth Russell, Margaret Thomason, Diana Gibb, Michael Levin, Sarah Kiguli, Robert O Opoka, Mariam Namutebi, Daniel Semakula, Ahmed Ddungu, Jalia Serwadda, Charles Engoru, Denis Amorut, Vincent Okuuny, Ronald Wokulira, Moses Okiror, Steven Okwi, Peter Olupot-Olupot, Paul Ongodia, Julius Nteziyaremye, Martin Chebet, Connelius Mbulalina, Tony Ssenyondo, Anna Mabonga, Emmanuela Atimango, Richard Nyeko, Benedict Otii, Sarah Achen, Paska Lanyero, Ketty Abalo, Paul Kinyera, Samuel O Akech, Molline Timbwa, Ayub Mpoya, Mohammed Abubakar, Mwanamvua Boga, Michael Kazungu, George Mtove, Hugh Reyburn, Regina Malugu, Ilse C E Hendriksen, Jacqueline Deen, Selemani Mtunguja, Hans-Jorg Lang, Mwanamvua Boga, Natalie Prevatt, Mohammed Shebe, Jackson Chakaya, Japheth Karisa, Jennifer Evans, Diana Gibb, Jane Crawley, Natalie Young, Bernadette Brent, Ayub Mpoya, Kathryn Maitland, Elizabeth C George, Jennifer A Evans, Sarah Kiguli, Peter Olupot-Olupot, Samuel O Akech, Robert O Opoka, Charles Engoru, Richard Nyeko, George Mtove, Hugh Reyburn, Bernadette Brent, Julius Nteziyaremye, Ayub Mpoya, Natalie Prevatt, Cornelius M Dambisya, Daniel Semakula, Ahmed Ddungu, Vicent Okuuny, Ronald Wokulira, Molline Timbwa, Benedict Otii, Michael Levin, Jane Crawley, Abdel G Babiker, Diana M Gibb, FEAST trial group, Kathryn Maitland, Mukami J Mbogo, Gilbert Ogetii, James Tibenderana, Lilian Akello, Moses Waweru, Naomi Waithira, Trudie Lang, Roma Chilengi, Greg Fegan, Abdel Babiker, Elizabeth Russell, Margaret Thomason, Diana Gibb, Michael Levin, Sarah Kiguli, Robert O Opoka, Mariam Namutebi, Daniel Semakula, Ahmed Ddungu, Jalia Serwadda, Charles Engoru, Denis Amorut, Vincent Okuuny, Ronald Wokulira, Moses Okiror, Steven Okwi, Peter Olupot-Olupot, Paul Ongodia, Julius Nteziyaremye, Martin Chebet, Connelius Mbulalina, Tony Ssenyondo, Anna Mabonga, Emmanuela Atimango, Richard Nyeko, Benedict Otii, Sarah Achen, Paska Lanyero, Ketty Abalo, Paul Kinyera, Samuel O Akech, Molline Timbwa, Ayub Mpoya, Mohammed Abubakar, Mwanamvua Boga, Michael Kazungu, George Mtove, Hugh Reyburn, Regina Malugu, Ilse C E Hendriksen, Jacqueline Deen, Selemani Mtunguja, Hans-Jorg Lang, Mwanamvua Boga, Natalie Prevatt, Mohammed Shebe, Jackson Chakaya, Japheth Karisa, Jennifer Evans, Diana Gibb, Jane Crawley, Natalie Young, Bernadette Brent, Ayub Mpoya
Abstract
Background: 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 all-cause 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 'non-responders' (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 re-appraisal of the rate, composition and volume of resuscitation fluids.
Trial registration: ISRCTN69856593.
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