1.Fluid resuscitation: time for a new paradigm John A Myburgh MBBCh PhD FCICMUNSWProfessor of Critical Care Medicine The George Institute for Global Health University of New South Wales St George Hospitals, Sydney

2. Leith Infirmary 1831Thomas Aitchinson Latta c1790-1833 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. 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. Sydney Ringer 1834-1910Alexis Hartmann 1898-1964 6. Ernst Starling 1866-1927Das Blut ist ein ganz besonder Saft Faust (Goethe)Edwin Cohn 1892-1953 7. I dont care if you use dogs piss, as long as you use it carefully. Malcolm Fisher AO 8. Hypovolaemia24/30 studies n=1104/1419RRD 1.68 (1.25 2.23) BurnsOverall excess mortality of 6% (95% C.I. 3 - 9%)HypoalbuminaemiaTOTAL Favours albuminFavours controlRoberts: BMJ 1998 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. SAFE Study Investigators: NEJM 2004 11. SAFE Study Investigators: NEJM 2004 12. Should you change practice? 13. Mortality at 28 daysMortality at 2 years SAFE Study Investigators: NEJM 2007 14. SepsisP=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. 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. Albumin in malaria150 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. Albumin in malariaAkech: PLoS Clinical Trials 2006 18. Maitland: New Eng J Med 2011 19. 2009-2011Multicentred open-label RCT Albumin vs saline bolus vs no bolus in febrile hypotensive children n=3141/3600 Primary outcome: Mortality at 48hMortality at 4 hoursMortality at 4 weeks Maitland: New Eng J Med 2011 20. T H Huxley 1825 - 1895That the great tragedy of Science is the slaying of a m beautiful hypothesis with an ugly fact 21. What about synthetic colloids? 22. Capital cost 500mLCost (AUD)Normal Saline Hartmanns Solution Plasmalyte Hypertonic Saline0.61 0.61 1.54 2.54Gelatins Dextrans Hetastarch Albumin Albumin (Australia)14.99 38.34 53.00 42.75 0.00* 23. Colloids vs crystalloids ColloidTrialsnRR95%CIAlbumin2377541.010.92 to 1.10HES166371.050.63 to 1.75Gelatin115060.910.49 to 1.72Dextran98341.240.94 to 1.65Perel: Cochrane Collaboration 2007 24. Colloids for fluid resuscitationColloidTrialsnRR95%CIAlbumin v HES2512341.140.91 to 1.43Albumin v gelatin76360.970.68 to 1.39Albumin v dextran43603.750.42 to 33.09Gelatin v HES1813371.000.80 to 1.25Bunn: Cochrane Collaboration 2009 25. Fluid volumes delivered SAFE TRIPS Investigators: Crit Care 2010 26. Colloid use in severe sepsis Choice Choice of Colloid: Severe sepsis sepsis of Colloid: Severe AlbuminStarchGelatinDextran450400350mL per person300250200150100500OCEANIAAMERICASASIANORTHERN EUROPESOUTHERN EUROPEWESTERN EUROPEAllSAFE TRIPS Investigators: Crit Care 2010 27. Renal replacement therapy: 31.0 v 18.8% p=0.001Brunkhorst: New Engl J Med 2008 28. HES: effects on renal function OutcomeTrialsnRR95%CIRenal replacement therapy3412361.380.89 to 2.16RRT : sepsis37021.591.2 to 2.1Author-defined ARF3411991.501.12 to 1.87Author-defined ARF: sepsis48321.551.22 to 1.96Dart: Cochrane Collaboration 2010 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. ANZICS Clinical Trials Group 31. Design and outcomes Power N=7000 To detection ARR 3.5% from baseline mortality of 21% (=0.05; 0.9) 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. Joachim Boldt 33. Gattas: Anes Analg 2012 34. n=7000 ANZICS Clinical Trials Group 35. Scandinavian Starch for Severe Sepsis/Septic Shock TrialMC 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% ( 0.05, =0.8)n=800Perner A: with permission 36. Scandinavian Starch for Severe Sepsis/Septic Shock Trial Inclusion criteria fulfilled 1211Exclusions 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 consent804 randomised patients Post-randomisation exclusions 4 deleted from database during the trial (Violation of in-/exclusion criteria AND no trial fluid given)798 patients analysed2 consent withdrawn after end of trial both in the HES group100% follow-up Perner A: with permission 37. Scandinavian Starch for Severe Sepsis/Septic Shock TrialPerner A: with permission 38. Scandinavian Starch for Severe Sepsis/Septic Shock Trial Kaplan Meier curves of survival censored at 90 days Survival Distribution FunctionDay 90 composite endpoint1.00.80.60.40.20.0 020406080DaysPerner A: with permission 39. Round Table 2012: Types of intravenous fluids John A MyburghMonty MythenMBBCh PhD FCICMMBBS FRCA MD FFICMProfessor of Critical Care Medicine The George Institute for Global Health University of New South Wales St George Hospitals, SydneyProfessor of Anaesthesia and Critical Care University College, London 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. 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. What about crystalloids?Abnormal saline vs Balanced salt solutions 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. 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. 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. Ringers 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. 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. 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 crystalloidsSSSSSS and CHEST will change the landscape 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. 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. 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. 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