Debate on aggressive vs restricted fluid resuscitation in childhood sepsis

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Prof Michael Levin & Dr David Inwald presentations at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

Prof Michael Levin & Dr David Inwald presentations at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

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  • 1. Meningococcal disease Fluid resuscitation in meningococcal sepsis :less or more Michael Levin Debate MRF conference 2013 © Imperial College London
  • 2. © Imperial College London
  • 3. © Imperial College London
  • 4. Where did this protocol come from? Is it evidence based ? Physiological basis vs Evidence from Randomised Trials
  • 5. © Imperial College London
  • 6. © Imperial College London
  • 7. What is the evidence for hypovolaemia? • CVP and echocardiography suggests volume depletion pre fluid resuscitation • Capillary leak
  • 8. Microvascular Events in Sepsis © Imperial College London
  • 9. Protein leak in meningococcal sepsis Controls Mild Moderate Severe Fatal Nephrotics Meningococcal Disease Orogui critical care med 1999 © Imperial College London © Imperial College London
  • 10. What are the consequences of volume replacemeent if there is a generalised capillary leak • • • • Pulmonary Oedema Cerebral Oedema Tissue oedema and ascites Compartment synbdrome
  • 11. © Imperial College London
  • 12. © Imperial College London
  • 13. A delicate balance: Fluids restore ventricular filling Capillary leak may lead to pulmonary oedema; tissue oedema Early elective ventilation Early dialysis / haemofiltration
  • 14. What is the role of cardiac failure • Impaired myocardial contractility • Inotrope unresponsiveness • Pulmonary oedema following volume resuscitation
  • 15. Capillary Leak Acidosis Reduced circulating volume Hypoxia Reduced preload Hypoglycaemia Hypocalcaemia Hypokalaemia Hypophosphataemia TNF, IL1 Nitric oxide complement Myocardial Failure Hypotension Reduced coronary perfusion Cardiodepressant factors Bacterial toxins Neutrophil products Energy depletion PAF Prostaglandins © Imperial College London
  • 16. © Imperial College London Role of IL6 in myocardial depression in meningococcal septic shock Pathan et al Lancet 2004
  • 17. © Imperial College London
  • 18. Admissions & mortality from severe meningococcal disease, St Mary’s PICU, 1992-97 100 predicted death rate (%) 80 30 20 60 observed death rate (%) 40 Admissions Death rate (%) 40 10 20 0 0 1992 1993 1994 1995 1996 1997 © Imperial College London
  • 19. If Fluid reuscitation improves outcome in sepsis in PICU, would it improve outcome of sepsis/Malaria in Africa ? Highest rates of child mortality are in Africa 1 in 8 children dies before age 5 (20-fold the mortality in industrialized countries) 15-30% mortality among children admitted to hospitals in sub-Saharan Africa despite being on antibiotics and quinine >50% deaths occur within 24 hours of admission supportive therapies often not considered/unavailable
  • 20. Fluid Expansion As a Supportive Therapy FEAST Trial Fluid Expansion As Supportive Therapy in critically ill African children FEAST Trial Team (PI Prof Kath Maitland) m a la r ia c o n s o r t iu m D is e a s e C o n t r o l, B e t t e r H e a lt h w w w .m a la riac o ns o rtiu m .o rg Fluid Expansion As a Supportive Therapy
  • 21. FEAST partners Support: Funded by MRC, UK Albumin and Saline donated by Baxter, UNITED KINGDOM MRC Clinical Trials Unit, London & Imperial College, London (Sponsor) UGANDA (4 centres) Mulago Hospial, Kampala Mbale Soroti Lacor Hospital, Gulu KENYA Kilifi TANZANIA Teule 21
  • 22. Trial Design: EARLY fluid resuscitation (FEAST A) Children with febrile illness Children with impaired and impaired perfusion consciousness and/or with impaired respiratory distress consciousness and impaired perfusion and/or respiratory distress Bolus 5% albumin 20 ml/Kg (40 ml/Kg after Aug 2010) over 1 hour Impaired perfusion Children with respiratory Any one of: distress and clinical secs, •Cap refill 3 or more •Severe tachycardia, evidence of impaired •temperature perfusion gradient •weak pulse Bolus 0.9% saline 20 ml/Kg (40 ml/Kg after Aug 2010) over 1 hour Control (No bolus) Maintenance fluids only Follow-up to 4 weeks (24 weeks if developed neurological sequelae by 4 weeks) Clinical assessments at 1, 4, 8, 24, 48 hours and at 4 weeks Excluded: Fluid loss due to gastroenteritis, burns or trauma. Severe malnutrition
  • 23. Hypotensive Shock (FEAST Stratum B) Children eligible for FEAST A that have hypotensive shock* on admission Bolus 5% albumin Bolus 0.9% saline 40mls/kg (60mls/kg after August 2010) per hour 40mls/kg (60mls/kg after August 2010) per hour Follow-up to 4 weeks (24 weeks if developed neurological sequelae by 4 weeks) Clinical assessments at 1, 4, 8, 24, 48 hours and at 4 weeks *Hypotensive shock defined as severe hypotension plus signs of impaired perfusion. Severe hypotension: <1yr sbp <50mmHg; 1-5 yrs sbp <60mmHg; >5yrs: sbp <70mmHg
  • 24. Typical setting of the trial
  • 25. FEAST(Fluid Expansion As Supportive Therapy) Trial
  • 26. FEAST: Survival in first 48 hours Percent survived 100% 95% 90% 85% No Bolus 92.7% Boluses 89.4% 3.3% excess mortality in bolus arms (10.6%) vs contro No difference in mortality between Albumin vs saline 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Hours from admission
  • 27. Response to the trial
  • 28. Should FEAST result in changes to UK meningococcal sepsis algorhythm ?? • Why did Fluids cause Harm in FEAST • Are the findings applicable to Developed countries • How does availability of ventilation;inotropes; PICU alter findings from FEAST • All subgroups showed harm in FEAST • Anemia/non anemic; acidosis/non acidosis; malaria/non malaria
  • 29. A personal perspective • FEAST should not be ignored by developed country PICUs • Fluids may have caused pulmonary deterioration or cerebral oedema • The broad inclusion criteria might have resulted in patients with pneumonia and heart failure being included. • The availability of ventilation and inotropes may mitigate the pulmonary / cardiac/ cerebral effects of fluids • BUT it is the only RCT of fluids with a control arm
  • 30. Fluid resuscitation in septic shock: between Sylla and Charybdis
  • 31. Protocolised management is good Butbolus may be life savingbe better BUT may thought may in severe shock Fluid be associated with pulmonary and cerebral oedema Fluids should be used with more thought; and continual re evaluation to detect adverse effects Less may be more- and we need further studiesIncluding further analysis of FEAST Data which should be open access
  • 32. © Imperial College London
  • 33. Thank you © Imperial College London