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The CHEST trial - HES in the ICU
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The CHEST trial - HES in the ICU


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  • 1. Colloids - The end of the end forstarches in the critically ill ??Dr Andrew FergusonConsultant in Anaesthetics and Intensive Care Medicine, Craigavon Area HospitalMyburgh JA, et al. Hydroxyethyl Starch or Saline for Fluid Resuscitation inIntensive Care. NEJM 2012; 367:1901-1911The CHEST Study
  • 2. Philosophical Disclosures• I’ve used HES, and I quite liked it• I like albumin• I believe all iv fluids are potentially harmful• No other conflicts to declare
  • 3. How this Piggy got to Market• Approval based on small clinical studies– Underpowered– Limited clinical settings– Limited follow-up duration– Limited comparators – better than ancestors• Approval based on what came before– Previously approved colloids/HES– Assumption of “a HES is a HES is a HES”
  • 4. What happened when Piggy got there?• Novelty• Marketing• Reinforcement by small positive trials• Usage outside original study settings• Impression of benefit => clinical bias• Increased usage• Positive poor-quality reviews
  • 5. The CHEST trial
  • 6. Who was in?• Consent obtained (pro-or retrospectively)• Fluid resuscitation required based on at least one of:• HR > 90 bpm• SBP <100 mmHg or MAP < 75 mmHg or 40% fall from baseline• CVP < 10 mmHg• PCWP < 12 mmHg• SPV/MAPV > 5 mmHg• Capillary refill time > 1 second• U/O < 0.5 ml/kg for 1 hour• Clinician content that HES and saline equally suited
  • 7. Who was out?
  • 8. Screening
  • 9. Fate of randomised patients
  • 10. Intervention• 6% HES 130/0.4/9:1 in 0.9% NaCl v 0.9% NaCl (saline)• Identical 500-ml Freeflex bags, composition checks• Staff blinded to allocation• Used for all fluid resuscitation in ICU during the first 90 daysfollowing randomisation or until death• Maximum daily dose 50 ml/kg/day• If upper limit exceeded during 24-hrs, open-label 0.9% NaClused until 24-h period lapsed, following which patient resumesallocated study fluid.
  • 11. Data collectionRIFLE up to day 7, SOFA to day 28, RRT in ICU
  • 12. Sample size (7000 patients)• Based on 90-day mortality of 26% in saline group– Actual 90-day mortality 17%• 90% power to detect absolute difference of > 3.5% inmortality with 5% loss to follow-up• 90% power to detect an increase in the RR for renalfailure by factor of 1.5 from expected 6% (saline group)– Actual incidence 9.2% of RIFLE-F– Actual incidence RRT 5.8%
  • 13. Statistical analysis• Binary outcomes– Relative risk (95% CI) & Chi-square• Continuous outcomes– Mean difference and unpaired t-tests• Adjusted analysis– Baseline covariates trauma, age, admission source,APACHE II, baseline creatinine– Binary outcomes - robust Poisson regression– Continuous outcomes - robust linear regression• Survival times– Log rank presented as Kaplan-Meier curves
  • 14. Primary Outcome – Death @ 90dNO significant difference
  • 15. Secondary OutcomesMore RRT, significantly less RIFLE-R and -ILower incidence of new CVS failureMore hyperbilirubinaemia
  • 16. The piggy goes “wee….wee….wee”
  • 17. Tertiary outcomesNo significant difference
  • 18. Treatment related adverse effectsEffectively all cutaneous
  • 19. Subgroup Analyses – Death @ 90dBased on urine output
  • 20. Fluid IntakeMorefluid inSalinegroupMoreblood inHESgroup
  • 21. Author’s conclusions• No difference in 90 day mortality overall or sub-groups• 21% relative increase in RRT• Less new CVS failure• No evidence of clinical benefit with HES
  • 22. Criticisms put forward• “All-comers” study - dilution of benefit and harm• Indications for administration of fluid• Use of a colloid in patients post-resuscitation phase• Lack of goal-directed approach• Lack of renal data past day 7 and no control of RRT• No assessment of harm effect of PRBC transfusion• No control of transfusion trigger
  • 23. The bottom line for the patientYou’ll be less likely to need pressors, BUTYou’re just as likely to dieYou won’t get off the vent or out of ICU quickerYour creatinine is more likely to go upYou’re more likely to need “dialysis”You’re more likely to get a blood transfusionYou’re more likely to go a bit yellowYou’re more likely to get a rashYou’re more likely to get an itch and it may not go away
  • 24. Where next?• Enough evidence to guide practice inside ICU• Calls for– focus on pre-ICU resuscitation phase– more perioperative trials– better crystalloids– ditch HES altogether outside RCT• Regulatory review
  • 25. “It is a mistake to think you can solve any majorproblems just with potatoes”Douglas Adams, Life, the Universe, and Everything
  • 26. Parting thoughts – ChallengeassumptionsIf you have never changed your mind about somefundamental tenet of your belief, if you have neverquestioned the basics, and if you have no wish to do so,then you are likely ignorant.Before it is too late, go out there and find someone who, inyour opinion, believes, assumes, or considers certain thingsvery strongly and very differently from you, and just have abasic honest conversation. It will do both of you good.”Vera Nazarian, The Perpetual Calendar of Inspiration
  • 27. Not everyone agrees about efficacy• It works if you select the right end-point– What should that be? Haemodynamics? Volume?Oedema?• It works in some conditions, not in others– Effects are disease-specific• It works in some patients, not in others– Effects are patient-specific (for unknown reasons)• It works if you don’t give too little or too much– Effects are dose-specific (dosing schedule unknown)• It works if you give it at the right time– Effects are time-specific (best time-point unknown)
  • 28. Not everyone agrees about safety• It is safe in some conditions, is harmful in others– Any harm is disease-specific• It is safe for some patients, is harmful to others– Any harm is patient-specific (but who?)• It’s benign, if you choose the right one– Any harm is molecule & structure-specific• It is benign, but the carrier is harmful– Any harm is formulation-specific (no evidence)• It is safe unless overdosed– Harm is dose-specific
  • 29. Complex questions about HES• Do we know when we should/shouldn’t use it?• Do we know what we want it to do?• Do we know how to measure/titrate its effect?• Does it do what we want it to do?– Even if it does, then:• Is it as good as the alternatives?• Is it as safe as the alternatives?• Is it as cost-effective as the alternatives?
  • 30. Fluid-related background signals…• Acid-base abnormalities• Impaired coagulation• Fluid overload• Osmolality and tonicity issues• Allergic reactions• Direct organ toxicity• Effects on inflammation
  • 31. Physiological effects
  • 32. Outcome adjusted for age, APACHE, baselinecreatinine trauma diagnosis
  • 33. Remaining questionsMechanism? Are the issues secondary toa) Inappropriate use?b) Cumulative exposure?c) Dosing rate?d) Impact of endothelial glycocalyx disruption?e) Impact of blood product use?Is HES still an option for EGDT in severe sepsis asa defined, time & volume limited therapy?