FEAST Trial Research Articles

Genesis of Antibiotic Resistance (AR) LVIII: Discordant Antibiotic Stewardship contort Early Goal Directed Fluid Resuscitation therapy (EGDT) with higher incidence of Mortality in severe Sepsis: A global melee

A retrospective analysis of EGDT trials from 2000 to 2018 registered in national clinical trials is presented here: (PRISM‐U) Study group attributed that the sepsis cohort with Mycobacterium tuberculosis (MTB) bacteremia for higher rate of in‐hospital mortality. FEAST (ISRCTN69856593) trial observed that fluid resuscitation in children with sepsis significantly increased mortality (48‐hour) possibly due to impaired perfusion. SSSP trail (NCT01449916) showed that though hypoxemic respiratory failure as contributing factor for mortality in addition to tissue hypoperfusion as inclusion criteria of patients with hypovolemia but excluding the patients with severe respiratory distress when ventilator support is not readily available could have potentially improved the survival rate. ARISE (NCT00975793) presented their report on the effectiveness of EGDT compare to that of usual sepsis care had similar (~18%) mortality rate concluding that EGDT did not reduce all‐cause mortality at 90 days. PRISM (NCT02030158) reported that, EGDT miss the mark to relieve mortality rate compare to that of usual care cohort. ProCESS (NCT00510835) reported that among 1341 patients, of whom 439 were randomly assigned to protocol‐based EGDT, 446 to protocol‐based standard therapy, and 456 to usual care in which protocol‐based resuscitation of patients in whom septic shock was diagnosed in the ER did not improve outcomes. ProMISe (ISRCTN36307479) concluded that septic shock cohort identified early and treated with intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol showed that no difference in mortality rate by 90 days. The IMPreSS study group found that compliance with “all of the evidence‐based bundle metrics” had a 40 % reduction in the odds of dying in hospital with the 3‐h bundle and 36 % for the 6‐h bundle. ProCESS Investigators (NCT00793442, NCT00510835 ) showed that increase in leucocyte rolling and adhering to dysfunctional endothelial surface in the cohort of septic shock compare to that of control, attributed to an increase in endothelial permeability‐hemostasis as cause for mortality. SSSP‐2 (NCT01663701) reported that cohort with sepsis and hypotension, most of whom were positive for HIV, in a resource‐limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in‐hospital mortality compared with usual care. MOSAICS Study Group attributed the high mortality rate in severe sepsis treatment for the variation in adhering to the “all of the evidence‐based bundle metrics” for sepsis treatment. GENESIS project comparing 6‐hour resuscitation bundle (RB) for severe sepsis cohort showed decreased mortality rate compare to that of no RB bundle. Taken together it is suggested that lack coherent antibiotic stewardship practices across the globe warrant immediate review during EGDT and implementation of such guidelines would likely improve the survival rate in both low and high resource setting.Support or Funding InformationSupported by the professional development funds by SWTJC to Subburaj Kannan

Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial

SummaryBackgroundFluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry.MethodsWe developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593.FindingsIncreasing respiratory (odds ratio 1·09, 95% CI 1·07–1·11), neurological (1·26, 1·21–1·31), and cardiovascular scores (1·09, 1·05–1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20–0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76–2·06; p=0·0002) in mean base excess and increase of 1·65 mmol/L (0·47–2·8; p=0·0070) in mean chloride, and a decrease of 0·96 mmol/L (0·45 to 1·47; p=0·0003) in bicarbonate. There were similar effects of fluid bolus in three patient subgroups, identified on the basis of their baseline characteristics. Hyperchloraemic acidosis and respiratory and neurological dysfunction induced by saline or albumin bolus explained the excess mortality due to bolus in Cox survival models.InterpretationIn the resuscitation of febrile children, albumin and saline boluses can cause respiratory and neurological dysfunction, hyperchloraemic acidosis, and reduction in haemoglobin concentration. The findings support the notion that fluid resuscitation with unbuffered electrolyte solutions may cause harm and their use should be cautioned. The effects of lower volumes of buffered solutions should be evaluated further.FundingMedical Research Council, Department for International Development, National Institute for Health Research, Imperial College Biomedical Research Centre.

Implications for paediatric shock management in resource-limited settings: a perspective from the FEAST trial

BackgroundAlthough the African “Fluid Expansion as Supportive therapy” (FEAST) trial showed fluid resuscitation was harmful in children with severe febrile illness managed in resource-limited hospitals, the most recent evidence reviewed World Health Organization (WHO) guidelines continue to recommend fluid boluses in children with shock according to WHO criteria “WHO shock”, arguing that the numbers included in the FEAST trial were too small to provide reasonable certainty.MethodsWe re-analysed the FEAST trial results for all international definitions for paediatric shock including hypotensive (or decompensated shock) and the WHO criteria. In addition, we examined the clinical relevance of the WHO criteria to published and unpublished observational studies reporting shock in resource-limited settings.ResultsWe established that hypotension was rare in children with severe febrile illness complicating only 29/3170 trial participants (0.9%). We confirmed that fluid boluses were harmful irrespective of the definitions of shock including the very small number with WHO shock (n = 65). In this subgroup 48% of bolus recipients died at 48 h compared to 20% of the non-bolus control group, an increased absolute risk of 28%, but translating to an increased relative risk of 240% (p = 0.07 (two-sided Fisher’s exact test)). Examining studies describing the prevalence of the stringent WHO shock criteria in children presenting to hospital we found this was rare (~ 0.1%) and in these children mortality was very high (41.5–100%).ConclusionsThe updated WHO guidelines continue to recommend boluses for a very limited number of children presenting at hospital with the strict definition of WHO shock. Nevertheless, the 3% increased mortality from boluses seen across FEAST trial participants would also include this subgroup of children receiving boluses. Recommendations aiming to differentiate WHO shock from other definitions will invariably lead to “slippage” at the bedside, with the potential of exposing a wider group of children to the harm of fluid-bolus therapy.

Perspectives on aetiology, pathophysiology and management of shock in African children.

Paediatric shock is still a common emergency of public health importance with an estimated 400,000–500,000 reported cases annually. Mortality due to paediatric shock has varied over the years. Data in 1980s show that mortality rates due to septic shock in children were over 50%; but by the end of the year 2000 data indicated that though a marked decline in mortality rates had been achieved, it had stagnated at about 20%. Descriptions of paediatric shock reveal the lack of a common definition and there are important gaps in evidence-based management in different settings. In well-resourced healthcare systems with well-functioning intensive care facilities, the widespread implementation of shock management guidelines based on the Paediatric Advanced Life Support and European Paediatric Advanced Life Support courses have reduced mortality. In resource limited settings with diverse infectious causative agents, the Emergency Triage Assessment and Treatment (ETAT) approach is more pragmatic, but its impact remains circumscribed to centres where ETAT has been implemented and sustained. Advocacy for common management pathways irrespective of underlying cause have been suggested. However, in sub Saharan Africa, the diversity of underlying causative organisms and patient phenotypes may limit a single approach to shock management.Data from a large fluid trial (the FEAST trial) in East Africa have provided vital insight to shock management. In this trial febrile children with clinical features of impaired perfusion were studied. Rapid infusion of fluid boluses, irrespective of whether the fluid was colloid or crystalloid, when compared to maintenance fluids alone had an increased risk of mortality at 48 h. All study participants were promptly managed for underlying conditions and comorbidity such as malaria, bacteraemia, severe anaemia, meningitis, pneumonia, convulsions, hypoglycaemia and others. The overall low mortality in the trial suggests the potential contribution of ETAT, the improved standard of care and supportive treatment across the subgroups in the trial. Strengthening systems that enable rapid identification of shock, prompt treatment of children with correct antimicrobials and supportive care such as oxygen administration and blood transfusion may contribute to better survival outcomes in resources limited settings.

An unexpected finding in a randomised controlled trial

My favourite presentation at Evidence Live (www.evidencelive.org/)—the conference on evidence based medicine—was on the FEAST trial, which was a multicentre randomised controlled trial of fluid replacement in young children with severe febrile illness (most caused by malaria) in east Africa.1 This is an important topic because many young children die every day from dehydration secondary to febrile illnesses, particularly in developing countries. The interventions that were compared, namely intravenous infusion of fluids, were clinically applicable …

Mortality after Fluid Bolus in Children with Shock Due to Sepsis or Severe Infection: A Systematic Review and Meta-Analysis

IntroductionSepsis is one of the leading causes of childhood mortality, yet controversy surrounds the current treatment approach. We conducted a systematic review to assess the evidence base for fluid resuscitation in the treatment of children with shock due to sepsis or severe infection.MethodsWe searched 3 databases for randomized trials, quasi-randomized trials, and controlled before-after studies assessing children with septic shock in which at least one group was treated with bolus fluids. The primary outcome was mortality at 48 hours. Assessment of methodological quality followed the GRADE criteria. Relative risks (RRs) and 95% confidence intervals (CI) were calculated and data pooled using fixed-effects method.Results13 studies met our inclusion criteria. No bolus has significantly better mortality outcomes at 48 hours for children with general septic shock (RR 0.69; 95%CI 0.54–0.89), and children with malaria (RR 0.64; 95%CI 0.45–0.91) when compared to giving any bolus. This result is largely driven by a single, high quality trial (the FEAST trial). There is no evidence investigating bolus vs no bolus in children with Dengue fever or severe malnutrition. Colloid and crystalloid boluses were found to have similar effects on mortality across all sub-groups (general septic shock, malaria, Dengue fever, and severe malnutrition).ConclusionsThe majority of all randomized evidence to date comes from the FEAST trial, which found that fluid boluses were harmful compared to no bolus. Simple algorithms are needed to support health-care providers in the triage of patients to determine who could potentially be harmed by the provision of bolus fluids, and who will benefit.

The FEAST trial of fluid bolus in African children with severe infection

We acknowledge that the assimilation of the FEAST trial results1 is challenging, since they question decades of practice in resource-rich countries and our understanding of the pathophysiology of shock in severe infection. This is precisely why carefully done randomised clinical trials are so important, since they generate robust data to guide and change clinical practice. We now welcome discussion of the possible explanations and interpretations of our findings.

The FEAST trial of fluid bolus in African children with severe infection – Authors' reply

I think the FEAST Trial Group might have misunderstood some of my comments. I did not say that the results could not be extrapolated to children with “shock” in their setting. I agree with Kathryn Maitland and colleagues that they can be. What I said was: “The main message—fluid boluses are dangerous in children with malaria, and in other common febrile illnesses in which ADH secretion is likely to be high—is important to disseminate clearly” and “This trial does not inform about the management of other shock conditions: dengue shock syndrome in Asia, or hypovolaemic shock from diarrhoea and vomiting.

The FEAST trial of fluid bolus in African children with severe infection

I applaud Trevor Duke's effort1 to cast clarity on the interpretation of the FEAST trial results,2 in which the benefits of the fluid bolus approach for severely ill African children are seriously questioned. The flaws and inaccuracies of the study are thoroughly underlined and explained. I agree with Duke's conclusions that the study results could be open to misinterpretation, and concur about the key exigency of better understanding the population studied, to fully appreciate the implications of the trial.

The FEAST trial of fluid bolus in African children with severe infection

The FEAST trial of fluid bolus in African children with severe infection

Association of Catalytic Iron With Cardiovascular Disease

The ability of iron to cycle reversibly between its ferrous and ferric oxidation states is essential for the biological functions of iron but may contribute to vascular injury through the generation of powerful oxidant species. We examined the association between chemical forms of iron that can participate in redox cycling, often referred to as "catalytic" or "labile" iron, and cardiovascular disease (CVD). In our cross-sectional study of 496 participants, 85 had CVD. Serum catalytic iron was measured using the bleomycin-detectable iron assay that detects biologically active iron. The odds of existing CVD for subjects in the upper third of catalytic iron were 10 times that of subjects with lower catalytic iron in unadjusted analyses. The association was decreased by 1/2 by age adjustment, but little additional attenuation occurred after adjusting for age, Framingham Risk Score, estimated glomerular filtration rate, hypertension status, high-density lipoprotein cholesterol, and systolic blood pressure, with the association remaining strong and significant (odds ratio 3.8, 95% confidence interval 1.4 to 10.1). In conclusion, we provide preliminary evidence for a strong detrimental association between high serum catalytic iron and CVD even after adjusting for several co-morbid conditions; however, broader prospective studies are needed to confirm these findings, which would support therapeutic trials to assess the beneficial effects of iron chelators on CVD.

Aspirin-associated iron loss as an anticancer mechanism

A consensus view has emerged favoring an anticancer effect of long-term aspirin use. Aspirin-induced loss of stored iron from chronic gastrointestinal bleeding is proposed as a mechanism underlying this beneficial effect. In iron depletion, less iron may be available for carcinogenesis through free-radical mediated mechanisms and for promotion of tumor growth. Low-dose aspirin increases gastrointestinal losses of transfused radiolabeled autologous red cells. Observational studies report lower serum ferritin values with regular aspirin use. A protective effect of induced iron reduction against cancer mortality has been confirmed in a recent trial (FeAST) with subjects randomized to iron reduction or observation. Serum ferritin reductions in the FeAST trial were within conventionally normal reference ranges and were quantitatively similar to ferritin reductions in observational studies in regular aspirin users. Delayed anticancer effects of aspirin are compatible with the proposed mechanism, as continual microbleeding has a gradual cumulative effect on stored iron.