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John Myburgh on Fluid Therapy


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John Myburgh on Fluid Therapy

  1. 1. Fluid resuscitation: time for a new paradigm John A Myburgh MBBCh PhD FCICM UNSW Professor of Critical Care Medicine The George Institute for Global Health University of New South Wales St George Hospitals, Sydney
  2. 2. Leith Infirmary 1831 Thomas Aitchinson Latta c1790-1833
  3. 3. “The most wonderful and satisfactory effect is the immediate consequence of the injection.” “The solution that was used consisted of two drachms of muriate, and two scruples of carbonate of soda to sixty ounces of water. It was at the temperature of 108 or 110o” “The quantity necessary to be injected will probably be found to Lewins: London Medical Gazette 1832 depend upon the quantity
  4. 4. “Verily sir, this is an astonishing method of medication, and I predict will lead to wonderful changes and improvements in the practice of medicine ” Lewins: London Medical Gazette 1832
  5. 5. Sydney Ringer 1834-1910 Alexis Hartmann 1898-1964
  6. 6. Ernst Starling 1866-1927 “Das Blut ist ein ganz besonder Saft” Faust (Goethe) Edwin Cohn 1892-1953
  7. 7. “I don’t care if you use dog’s piss, as long as you use it carefully.” Malcolm Fisher AO
  8. 8. Hypovolaemia 24/30 studies n=1104/1419 RRD 1.68 (1.25 – 2.23) Burns Overall excess mortality of 6% (95% C.I. 3 - 9%) Hypoalbuminaemia TOTAL Favours albumin Favours control Roberts: BMJ 1998
  9. 9. “…I would attempt to sue anyone who gave me an albumin infusion. And, as for any attempt to secure my informed consent to take part in a randomised trial . . . forget it !” Chalmers BMJ:1998
  10. 10. SAFE Study Investigators: NEJM 2004
  11. 11. SAFE Study Investigators: NEJM 2004
  12. 12. Should you change practice?
  13. 13. Mortality at 28 days Mortality at 2 years SAFE Study Investigators: NEJM 2007
  14. 14. Sepsis P=0.059 (Test for common relative risk) MVLR adjusting for baseline covariates in patients with complete data: 919/1218 (75.5%) 0.71 (0.52 – 0.97) p=0.03. SAFE Study Investigators: Int Care Med 2011
  15. 15. Lesson from SAFE Do not change your practice on the basis of a meta-analysis Large-scale trials are feasible and will answer a question Randomised behaviour vs random behaviour Challenge the dogma
  16. 16. Albumin in malaria 150 Children with severe malaria and metabolic acidosis Assigned to 4.5% albumin or normal saline or control No difference in resolution of base deficit Reduced mortality: 2/56 (3.6%) vs. 11/61 (18.0%); p=0.013 Maitland: Clinical Inf Dis 2005
  17. 17. Albumin in malaria Akech: PLoS Clinical Trials 2006
  18. 18. Maitland: New Eng J Med 2011
  19. 19. 2009-2011 Multicentred open-label RCT Albumin vs saline bolus vs no bolus in febrile hypotensive children n=3141/3600 Primary outcome: Mortality at 48h Mortality at 4 hours Mortality at 4 weeks Maitland: New Eng J Med 2011
  20. 20. T H Huxley 1825 - 1895 “That the great tragedy of Science is the slaying of a m beautiful hypothesis with an ugly fact”
  21. 21. What about synthetic colloids?
  22. 22. Capital cost 500mL Cost (AUD) Normal Saline Hartmann’s Solution Plasmalyte® Hypertonic Saline 0.61 0.61 1.54 2.54 Gelatins Dextrans Hetastarch Albumin Albumin (Australia) 14.99 38.34 53.00 42.75 0.00*
  23. 23. Colloids vs crystalloids Colloid Trials n RR 95%CI Albumin 23 7754 1.01 0.92 to 1.10 HES 16 637 1.05 0.63 to 1.75 Gelatin 11 506 0.91 0.49 to 1.72 Dextran 9 834 1.24 0.94 to 1.65 Perel: Cochrane Collaboration 2007
  24. 24. Colloids for fluid resuscitation Colloid Trials n RR 95%CI Albumin v HES 25 1234 1.14 0.91 to 1.43 Albumin v gelatin 7 636 0.97 0.68 to 1.39 Albumin v dextran 4 360 3.75 0.42 to 33.09 Gelatin v HES 18 1337 1.00 0.80 to 1.25 Bunn: Cochrane Collaboration 2009
  25. 25. Fluid volumes delivered SAFE TRIPS Investigators: Crit Care 2010
  26. 26. Colloid use in severe sepsis Choice Choice of Colloid: Severe sepsis sepsis of Colloid: Severe Albumin Starch Gelatin Dextran 450 400 350 mL per person 300 250 200 150 100 50 0 OCEANIA AMERICAS ASIA NORTHERN EUROPE SOUTHERN EUROPE WESTERN EUROPE All SAFE TRIPS Investigators: Crit Care 2010
  27. 27. Renal replacement therapy: 31.0 v 18.8% p=0.001 Brunkhorst: New Engl J Med 2008
  28. 28. HES: effects on renal function Outcome Trials n RR 95%CI Renal replacement therapy 34 1236 1.38 0.89 to 2.16 RRT : sepsis 3 702 1.59 1.2 to 2.1 Author-defined ARF 34 1199 1.50 1.12 to 1.87 Author-defined ARF: sepsis 4 832 1.55 1.22 to 1.96 Dart: Cochrane Collaboration 2010
  29. 29. Starch use in Australia…. 6% hydroxyethyl starch 130/0.4 is the first starch approved by the Therapeutic Goods Administration in November 2006. 2008 marketing of HES started December 2008 over >40 hospitals in Australia used HES: >200,000 units distributed 30% of semi-synthetic colloid market Australia was in a unique position to conduct a large-scale randomised controlled trial.
  30. 30. ANZICS Clinical Trials Group
  31. 31. Design and outcomes Power N=7000 To detection ARR 3.5% from baseline mortality of 21% (α=0.05; β0.9) To detect RRI in renal failure by 1.3 from baseline of 6%. Outcomes All-cause mortality at 90 days Incidence of acute renal injury/acute renal failure Interval mortality rates Organ failures (respiratory, cardiovascular, coagulation and hepatic) Incidence of pruritis (D90) Quality of life and functional outcome assessments (6 months) Cost-effectiveness analysis
  32. 32. Joachim Boldt
  33. 33. Gattas: Anes Analg 2012
  34. 34. n=7000 ANZICS Clinical Trials Group
  35. 35. Scandinavian Starch for Severe Sepsis/Septic Shock Trial MC DB RCT 6% HES (130/0.42) in Ringers acetate vs Ringers acetate (33mL/kg/d) Severe sepsis + fluid resuscitation Primary outcome: Death or RRT at day 90 10% ARR from incidence of 50% (α 0.05, β=0.8) n=800 Perner A: with permission
  36. 36. Scandinavian Starch for Severe Sepsis/Septic Shock Trial Inclusion criteria fulfilled 1211 Exclusions 6 Age < 18 years 0 Allergy towards IMP 138 Dialysis 1 Organ transplant 5 Burn injury >10% 9 Intracraniel bleeding 21 S-K+ >6 mM 25 Other trial 15 No active therapy 152 >1000 ml synthetic colloid 51 No informed consent 804 randomised patients Post-randomisation exclusions 4 deleted from database during the trial (Violation of in-/exclusion criteria AND no trial fluid given) 798 patients analysed 2 consent withdrawn after end of trial both in the HES group 100% follow-up Perner A: with permission
  37. 37. Scandinavian Starch for Severe Sepsis/Septic Shock Trial Perner A: with permission
  38. 38. Scandinavian Starch for Severe Sepsis/Septic Shock Trial Kaplan Meier curves of survival censored at 90 days Survival Distribution Function Day 90 composite endpoint 1.0 0.8 0.6 0.4 0.2 0.0 0 20 40 60 80 Days Perner A: with permission
  39. 39. Round Table 2012: Types of intravenous fluids John A Myburgh Monty Mythen MBBCh PhD FCICM MBBS FRCA MD FFICM Professor of Critical Care Medicine The George Institute for Global Health University of New South Wales St George Hospitals, Sydney Professor of Anaesthesia and Critical Care University College, London
  40. 40. Emerging issues in fluid resuscitation Ubiquitous intervention in acute medicine Selection and use is entirely dependent on geography Administered by relatively junior medical staff in random fashion Inconsistent haemodynamic and physiological endpoints Net association of fluid retention with consequent adverse clinical effects The place and rationale for “maintenance” fluids is questionable
  41. 41. Emerging issues in fluid resuscitation Consistent data on ratios of crystalloid:colloid ratio of 1:1.4 Overall, there is little evidence to support the use of colloids Paradigm shift to regard fluid resuscitation as same as a drug: Context specific in various patient populations Specific indications and contraindications Toxicity relating to the volume, rate of administration and type of fluid
  42. 42. What about crystalloids? “Abnormal” saline vs “Balanced” salt solutions
  43. 43. Crystalloids: normal saline The most commonly used resuscitation fluid globally. Normal saline is the most extensively studied crystalloid in highquality randomised-controlled trials. Established, although unproven, role in trauma resuscitation, particularly traumatic brain injury There is increasing evidence of potential iatrogenic harm: Hyperchloraemic acidosis Oedema Microcirculatory effects
  44. 44. Crystalloids: normal saline Increased mortality in febrile children with compensated shock in low-income countries when administered as bolus Emerging trials: association with acute kidney injury Observational data in peri-operative patients –comparisons with Ringers Lactate Observational data in critically ill patients – chloride restrictive vs chloride liberal fluid resuscitation An increasing imperative to conduct a large-scale high quality randomised-controlled trial to determine safety and efficacy comparing saline to a physiological solution
  45. 45. Crystalloids: balanced salt solutions Physicochemical properties of balanced salt solutions render none as “ideal” Relates to requirement of a solution with a SID of 24, using endogenous anions. Ringer’s lactate: hypotonicity Ringers acetate: cardiotoxicity Plasmalyte 148: alternative non-physiological anions New, non-propietary solutions not established Questions emerge in relation to developmental and regulatory requirements No major emerging trials at present
  46. 46. Colloids: albumin Equivalence to saline in terms of safety Cost effectiveness not established Increased mortality in traumatic brain injury Related to the development of intracranial hypertension Potential hypotonicity Potential beneficial effects for fluid resuscitation in sepsis Increased mortality in febrile children with compensated shock in low-income countries when administered as bolus Emerging trials Albumin as an infusion to maintain normoalbuminaemia post resuscitation Potential non-colligative properties
  47. 47. Colloids: hydroxyethyl starch Most commonly prescribed colloid globally. Cost effectiveness not established Evidence for nephrotoxcity with hyperoncotic, high MW preparations Evidence for adverse effects related to accumulation in RES Uncertainty about the purported increased safety profile associated with formulary changes No substantive evidence of safety or effectiveness over crystalloids SSSSSS and CHEST will change the landscape
  48. 48. Colloids: gelatins Second most commonly used synthetic colloid after hydroxyethyl starch Cost effectiveness not established Emerging evidence of potential nephrotoxcity No current or emerging trials at present
  49. 49. Publications from Round Table (i) The current status of fluid therapy in the ICU: Recognition of importance Emerging evidence that selection and use can have a direct impact on outcome We need a paradigm shift Recommendations for education, practice improvement , quality assurance and audit
  50. 50. Publications from Round Table (ii) Future directions for fluid therapy in ICU: Unmet needs (better fluids?) Research questions and priorities Evaluation for use (research methods: observation, RCT), meaningful outcomes
  51. 51. “A suitable clinical investigation is required to resolve between such conflicting authorities the mass of the profession is unable to decide; and thus, instead of any uniform mode of treatment, every town and village has its different system or systems, while the daily lists of mortality proclaim the general inefficiency of the whole.” Lancet 1832