Journal ClubThe FEAST Trial: Mortality after Fluid Bolus in African Children with Severe Infection

Farooq Khan MDCMPGY-4 FRCP-EMMcGill University

August 22nd 2012

Salvatore Mottillo MDPGY-1 FRCP-EMMcGill University

Objectives

• To critically appraise a high quality, high impact article conducted in a low-income country on a controversial topic in Emergency Medicine internationally

• To understand the importance of research and evidence-based medicine in low and middle income countries, in particular with respect to EM

• To appreciate the challenges of conducting research under austere conditions and how they can be overcome

Outline

• Lecture on research in resource-poor settings• 1st half of FEAST trial video• Overview of the article• Appraisal• EBM topic: Subgroup analysis• 2nd half of video• Concluding remarks

Research in International EMScope, Impact, and Challenges

Farooq Khan PGY4 FRCP-EM

Outline

• Global Health Research on the WHO agenda– Why it is important– Challenges and how to overcome them– Example of its impact – TDR

• International EM research– Why it is important– Challenges and how to overcome them– Example of high-quality IEM research and its impact

No Health Without Research

“It seems astonishing that in the 21st century decisions on health care can still be made without a solid grounding in research evidence. This is true even in clinical research, whether for simple or complex interventions1, where systematic reviews time and time again conclude that the evidence base is inadequate.2

It is even more true in the areas of health policy and health systems, where quality research is hampered further by a lack of shared definitions, a lack of consensus on guiding principles, poor capacity (especially in low-resource regions), and methodological challenges.3,4”

Pang T, Terry RF, The PLoS Medicine Editors (2011) WHO/PLoS Collection ‘‘No Health WithoutResearch’’: A Call for Papers. PLoS Med 8(1): e1001008. doi:10.1371/journal.pmed.1001008

WHO – World Health Report 2013

• To show that research is important for meeting health needs and improving health outcomes

• To encourage countries to therefore invest more resources in developing and strengthening their national health research systems

• To argue that countries should not see research as an expense or as an afterthought, but as an investment for a better, healthier future

WHO Research Policy

• Capacity• Priorities • Standards• Translation • Organization

WHO Research for Health Strategy - 63rd World Health Assembly May 2010

TDR – At a glance - Video

• http://video.who.int/streaming/tdr/TDR_Gates_Award_video.wmv

TDR – An example of the impact of global health research

• Take home messages– Ownership of research by communities

leads to faster translation into action in those countries

– Empowering countries to develop own priorities, own research capacities and own citizens to support healthcare systems leads to sustainable development

TDR at a glance: Fostering an effective global research effort on diseases of povertyWHO 2010

EM Research in LMIC

“Emergency medical systems are part of the 10/90 gap in health research whereby less than 10% of global research investment is spent on problems affecting 90% of the world’s population”

Global Forum for Health Research. 10/90 report on health research 2002. Geneva: Global Forum for Health Research; 2002.

EM Research in LMIC

• EM research from developed countries– May not be relevant to patients LMIC

• Variation in genetics, lifestyle and environment– May not be applicable to LMIC

• Variation in social, economic and political pressures– May not be easily translated into practice in LMIC

• Lack of resources for implementation, cultural barriers

V. Anantharaman. Scope of Emergency Medicine research in Low and Middle income CountriesEuSEM, AAEM, IV Mediterranean EM Congress 2007

Emergency Care in LMIC

Challenges– Lack of pre-hospital care in

general– Scarcity of trained personnel at

all levels– Difficulty utilizing specialized

equipment– Weak telecommunications

infrastructure– Barriers in transportation– Health facilities lacking expertise – System lacking organization– Low levels of knowledge

translation

Interventions– Recruitment of lay responders– Training programs for nurses,

doctors and first responders– Equipment matched to level of

training– Harnessing cellular phone

technology and radio receiver sets

– Use of existing private motorized vehicles and bicycle transport

– Implementation of proper triage guidelines

– Organizing and financing system development

Challenges faced by IEM researchers

• Time– High service demand

• Personnel– Lack of dedicated, trained researchers – Brain drain

• Finances– EDs are not profitable business units– Not prioritised by Pharma – Lack of government funding– High levels of indirect costs

– V. Anantharaman. Scope of Emergency Medicine research in Low and Middle income CountriesEuSEM, AAEM, IV Mediterranean EM Congress 2007

Challenges faced by IEM researchers

• Infrastructure– Unreliable documentation – Basic data collection systems may be absent or

poorly implemented• Credibility

– Negative publication bias in HIC journals– Paucity of local journals in LMICs

Challenges faced by IEM researchers

• Ethical issues– Lack of valid oversight bodies – Confidentiality– Informed consent– Cultural differences (researcher vs participants)– Double standards and exploitation of subjects

• Fly-in, fly-out research

Iserson et al Challenges in International Medicine:Ethical Dilemmas, Unanticipated Consequences, and Accepting Limitations, SAEM Journal 2012

Ford et al, Ethics of conducting research in conflict settings, Conflict and Health 2009, 3:7

Strategies to circumvent challenges

• Capacity building on National/regional level– WHO, TDR, CIDA, etc.

• Capacity building on a local level– NGOs, University partnerships, leading by example

• Cost-saving endeavors– Better accountability, better prediction of direct

and indirect costs, recycling of costs saved, funding application strategies

Strategies to circumvent challenges

• Ethical principles to follow– Independent external DSMB/IRB– Collaborative partnerships– Community engagement– Social value– Scientific validity– Fair selection of participants– Harm-benefit ratio– Respect for participants and consent

Ford et al, Ethics of conducting research in conflict settings, Conflict and Health 2009, 3:7

Priority areas of research in LMIC

• Epidemiology of conditions that need to be addressed by emergency systems in these countries (e.g. trauma, infectious diseases)

• Economic analysis and cost-effectiveness in areas of low funding (e.g prehospital care, injury prevention)

• Well designed, locally appropriate intervention trials that establish effectiveness

The FEAST Trial - Video

• http://www.youtube.com/watch?v=hK9VUkL-DqU

The FEAST Trial

Overview

Background

• Malaria, sepsis, & other infections associated with early mortality in African children

• Guidelines recommend fluid resuscitation for shock

• P.I.C.O. Question– In children presenting with severe febrile illness and

impaired perfusion, does administration of 20 ml boluses of 5% albumin solution or 0.9% saline solution per kg of body weight diminish mortality at 48 hours?

Methods

• Article type– Sub-Saharan Africa, multicenter, open-treatment, RCT

• 2 stratum– Stratum A: children without severe hypotension (n=3,141)

• Group 1: saline-bolus group• Group 2: albumin-bolus group• Group 3: control group

– Stratum B: children with severe hypotension (n=29)• Same groups as A

 

• Initial boluses: 20 ml/kg

• Primary end-point– mortality at 48hrs

Results

• Total patients: 3,170– Median age: 24mo.– Malaria: 57% of patients– Other parameters

• Mortality at 48hrs– Saline-bolus group: 10.5%– Albumin-bolus group: 10.6%– Control group: 7.3%

Results

Mortality at 48 hours

The FEAST Trial

Critical Appraisal

Critical Appraisal

• Worksheet for a critical review of an article on therapy+

+Guyatt G, Rennie D, Meade M, Cook D. Users' Guides to the Medical Literature: essentials of Evidence-Based Clinical Practice. 2nd edition (Jama & Archives Journals). McGraw-Hill. Professional, 2008.

Critical Appraisal

GROUP 1

• I. Are the results valid?

– 1. Were patients randomized?– 2. Was randomization concealed?– 3. Were patients in the study groups similar with respect

to known prognostic factors?– 4. To what extent was the study blinded?

Critical Appraisal

GROUP 2

• I. Are the results valid? (continued)

– 5. Was follow-up complete?– 6. Were patients analyzed in the groups to which they

were randomized?– 7. Was the trial stopped early?

Critical Appraisal

GROUP 3

• II. What are the results?

– 1. How large was the treatment effect?– 2. How precise was the treatment effect?– 3. Secondary endpoints studied?

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?

– 1. Were all patient-important outcomes considered?– 2. Were the study patients similar to my patients?

Critical Appraisal

Will the FEAST trial change your practice?

Critical Appraisal - Answers

GROUP 1

• I. Are the results valid?– 1. Were patients randomized?

• Yes, Block randomization, stratified

– 2. Was randomization concealed?• Yes, Sealed envelopes, opened in numerical order

– 3. Were patients in the study groups similar with

respect to known prognostic factors?• Yes, large number of patients recruited (n=3,170)• Similar baseline characteristics between groups.

Critical Appraisal - Answers

GROUP 1

Critical Appraisal - Answers

GROUP 1

Critical Appraisal - Answers

GROUP 1

Critical Appraisal - Answers

GROUP 1

• I. Are the results valid?– 4. To what extent was the study blinded?

• Open-treatment trial

• Blinded end-point review committee

Critical Appraisal

GROUP 2

• I. Are the results valid? (continued)– 5. Was follow-up complete?

• Few pts lost to f-u, and losses similar between groups– Saline-bolus group: 8/1047 pts lost to f-u by 48hrs– Albumin-bolus group: 7/1050 pts lost to f-u by 48hrs– Control group: 2/1044 pts lost to f-u by 48hrs

Critical Appraisal

GROUP 2

• I. Are the results valid? (continued)– 6. Were patients analyzed in the groups to which they

were randomized?

• Almost all patients received intervention they were assigned to.– Saline-bolus group: 1041/1047 patients– Albumin-bolus group: 1045/1050 patients– Control group: 1043/1044 patients

• ITT analysis

Critical Appraisal

GROUP 2

• I. Are the results valid? (continued)– 7. Was the trial stopped early?

• Yes, unlikely that superiority of the bolus strategy over the control strategy would be shown

Critical Appraisal

GROUP 3

• II. What are the results?– 1. How large was the treatment effect?– 2. How precise was the treatment effect?– Mortality at 48 hours

• Saline-bolus group: 110 deaths /1047 patients (10.5%)– RR vs control: 1.44 (95% CI, 1.09 to 1.90)– ARI vs control: 3.22%– NNH vs control: 31.06– OR vs control: 1.50

Critical Appraisal

GROUP 3

• II. What are the results?– Mortality at 48 hours

• Albumin-bolus group: 111/1050 (10.6%)– RR vs control: 1.45 (95% CI, 1.10 to 1.92)– ARI vs control: 3.29%– NNH vs control: 30.40– OR vs control: 1.51

Critical Appraisal

GROUP 3

• II. What are the results?

– Mortality at 48 hours• Bolus therapy (saline + albumin groups)

– RR vs control: 1.45 (95% CI, 1.13 to 1.86)– ARI vs control: 3.26%– NNH vs control: 30.67– OR vs control: 1.50

• No bolus (control group): 76/1044 (7.3%)

Critical Appraisal

GROUP 3

Mortality at 4 weeks

Critical Appraisal

GROUP 3

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– 1. Were all patient-important outcomes considered?

• Yes, mortality at 48 hours– Secondary endpoints

» Mortality at 4 weeks» Pulmonary edema» Severe hypotension» Increased ICP» Neurologic sequelae

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– 1. Were the study patients similar to my patients?

• Inclusion criteria– Children b/w 60d and 12y of age– ‘Severe febrile illness’

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– 1. Were the study patients similar to my patients?

• Exclusion criteria– Severe malnutrition– Gastroenteritis– Non-infectious shock

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– Differences between the study pop. and my patients?

• Severe malnourishment» Pts with acute severe malnutrition excluded

• 2% (n=70) mid-upper-arm circumference of <11.5 cm.

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– Differences between the study pop. and my patients?

• High prevalence (57%) malaria» Subgroup: bolus vs no bolus in pts without malaria (n=1,330)

• RR death at 48 hrs: 1.43 (1.01-2.04)• Adjusted RR: 1.51 (1.17-1.94)

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– Differences between the study pop. and my patients?

• Severe anemia» Subgroup: bolus vs no bolus in pts with less severe anemia or

>5g/dl (n=1,384)

• RR death at 48 hrs: 1.31 (0.93-1.84)• Adjusted RR: 1.47 (1.14-1.90)

Critical Appraisal

GROUP 4

• III. How can I apply the results to my patient care?– Differences between the study pop. and my patients?

• Pts did not fit WHO definition of shock» Subgroup: bolus vs no bolus in pts with WHO definition of

shock (n=65)

• ARI death at 48 hrs: 28.0 (3.4-52.5)

The FEAST Trial

EBM Topic: Subgroup Analysis

EBM topic: subgroup analysis

• Definition– Any evaluation of treatment effects for a specific endpoint

in subgroups of patients defined by baseline characteristics

• Why use subgroup analysis?– Differences in treatment effect between subpopulations– Consistency of trial conclusions for subpopulations

EBM topic: subgroup analysis

• Evaluating variability in subgroup analyses– Visual evaluation of variability

• How similar are the point estimates?• To what extent to the confidence intervals overlap?

• Statistical tests evaluating variability– Yes-or-no tests for heterogeneity that generate P-value– I2 test that quantifies the variability explained by

differences in the results

• Be careful for possible confounders– Can be adjusted in multivariate analysis

EBM topic: subgroup analysis

Subgroup analysis in the FEAST trial

EBM topic: subgroup analysis

• Guidelines for Deciding Whether Apparent Differences in Subgroup Response Are Real+

– Did the hypothesis precede rather than follow the analysis?

– Was the subgroup difference one of a small number of hypothesized effects tested?

– Is the subgroup difference suggested by comparisons within rather than between studies?

+Guyatt G, Rennie D, Meade M, Cook D. Users' Guides to the Medical Literature: essentials of Evidence-Based Clinical Practice. 2nd edition (Jama & Archives Journals). McGraw-Hill. Professional, 2008.

EBM topic: subgroup analysis

• Guidelines for Deciding Whether Apparent Differences in Subgroup Response Are Real

– Is the magnitude of the subgroup difference large?

– Is the subgroup difference consistent across studies?

– Was the subgroup difference statistically significant?

– Does external evidence support the

hypothesized subgroup difference?

The FEAST Trial

Discussion & Conclusion

Discussion

Will the FEAST trial change your practice?

Conclusion

• Fluid resuscitation increased the abs. risk of death at 48hrs by 3.3% in African hospitals

• Importance of fluid resuscitation as a lifesaving intervention in poor settings for children with shock?

• Questions raised regarding fluid-resuscitation guidelines in other settings as well

Thank You

farooq.khan@mail.mcgill.ca

salvatore.mottillo@mail.mcgill.ca