Gattas chest and beyond sin feb 2013

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David Gattas is and Intensivist and clinical researcher from Royal Prince Alfred Hospital in Sydney. Known for his dry wit and calm composure under fire David is a rising power player for the ANZICS CTG and was heavily involved with the recent CHEST study. He's a mild mannered self effacing guy who would be embarrassed for me to say he does lots of genuinely good things, like absurdly long walks for Oxfam or cardiothoracic ICU camps in Fiji. He gave this talk at SIN evening in Sydney a couple of months ago when there was an insane amount of background noise, but the audio isn't too shabby. Go to www.intensivecarenetwork.com for the podcast and more.

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  • * Plus–minus values are means ±SD. There were no significant differences between the groups except for central venouspressure (P<0.001) and lactate level (P<0.05). To convert the values for creatinine to milligrams per deciliter, divide by88.4. HES denotes hydroxyethyl starch, and ICU intensive care unit.† Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 71, with higher scores indicatingan increased risk of death.‡ RIFLE (risk, injury, or failure) criteria for acute kidney injury at baseline were calculated from measures of availableurine output only in patients who satisfied the criteria for risk and injury. Changes in serum creatinine levels were notapplicable.
  • * Plus–minus values are means ±SD. There were no significant differences between the groups except for central venouspressure (P<0.001) and lactate level (P<0.05). To convert the values for creatinine to milligrams per deciliter, divide by88.4. HES denotes hydroxyethyl starch, and ICU intensive care unit.† Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 71, with higher scores indicatingan increased risk of death.‡ RIFLE (risk, injury, or failure) criteria for acute kidney injury at baseline were calculated from measures of availableurine output only in patients who satisfied the criteria for risk and injury. Changes in serum creatinine levels were notapplicable.APACHE II 17 corresponds to approx risk of death 20-25%
  • HES = 6% hydroxyethyl starch (130/0.4), Day 0 = day of randomization to the end of that day,which averaged 12 hours in both groups.During the first 4 days, the HES group receivedsignificantly less study fluid than the salinegroup (mean [±SD] daily average, 526±425 mlvs. 616±488 ml; P<0.001), with most of the volumeadministered in the first 24 hours (Fig. S1in the Supplementary Appendix).P values relate to comparisons over first four days after randomization.
  • HES = 6% hydroxyethyl starch (130/0.4), Day 0 = day of randomization to the end of that day,which averaged 12 hours in both groups.P values relate to comparisons over first four days after randomization.
  • Figure S2: Physiological effectsHES = 6% hydroxyethyl starch (130/0.4), Day 0 = day of randomization to the end of that day,which averaged 12 hours in both groups.P values relate to comparisons over first four days after randomization.During the first 4 days… central venous pressure was significantlyhigher in the HES group (11.3±4.8 mm Hg vs.10.4±4.4 mm Hg, P<0.001)
  • In the HES group, 597 of 3315 patients (18.0%)died within 90 days after randomization, as comparedwith 566 of 3336 patients (17.0%) in thesaline group (relative risk in the HES group, 1.06;95% confidence interval [CI], 0.96 to 1.18;P = 0.26)
  • There was no significant differencein the probability of survival betweenthe HES group and the saline group during the90 days after randomization (P = 0.27)
  • The diagnostic criteria for being at risk for various stages of renal injury were as follows: renal dysfunction (RIFLE-R), 1788 of 3309 pa-tients (54.0%) in the HES group and 1912 of 3335 patients (57.3%) in the saline group (relative risk, 0.94; 95% CI, 0.90 to 0.98; P = 0.007); injury to the kidney (RIFLE-I), 1130 of 3265 patients (34.6%) in the HES group and 1253 of 3300 patients (38.0%) in the saline group (relative risk, 0.91; 95% CI, 0.85 to 0.97; P = 0.005); and failure of kidney function (RIFLE-F), 336 of 3243 patients (10.4%) in the HES group and 301 of 3263 patients (9.2%) in the saline group (relative risk, 1.12; 95% CI, 0.97 to 1.30; P = 0.12).
  • Figure 3. Serum Creatinine Levels and Urine Output through Day 6.Day 0 was defined as the day of randomization to the end of that day, whichaveraged 12 hours in the two study groups. P values are for the between groupcomparisons of means of the individual daily averages for 7 days, includingday 0. To convert the values for creatinine to milligrams per deciliter,divide by 88.4.
  • Figure 3. Serum Creatinine Levels and Urine Output through Day 6.Day 0 was defined as the day of randomization to the end of that day, whichaveraged 12 hours in the two study groups. P values are for the between groupcomparisons of means of the individual daily averages for 7 days, includingday 0. To convert the values for creatinine to milligrams per deciliter,divide by 88.4.
  • Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloidor albumin did not affect the relative risk of death (1.04, 95% confidenceinterval 0.89 to 1.22, 3414 patients, eight trials),
  • Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloidor albumin did not affect the relative risk of death (1.04, 95% confidenceinterval 0.89 to 1.22, 3414 patients, eight trials),
  • Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloidor albumin did not affect the relative risk of death (1.04, 95% confidenceinterval 0.89 to 1.22, 3414 patients, eight trials),
  • Gattas chest and beyond sin feb 2013

    1. 1. CHEST and BeyondHydroxyethyl starches in critical careDavid GattasFeb 2013
    2. 2. Hydroxyethyl Starch (HES) is..• A synthetic colloid• Modified natural polysaccharide– Amylopectin derived from waxy maize or potato– hydroxyethyl substitution slows hydrolysis by amylase– molecular weight and molar substitution influenceelimination• in a saline or plasma-adapted carrier solution
    3. 3. HES in critical careThis topic has it all• Science– transformation of the evidence– scale of trial design in critical care• History– shock and resuscitation– evidence-based medicine• Drama and Politics– scientific misconduct– clinical guideline development
    4. 4. HES in critical carepre-2010• Clinical paradigm– “modern rapidly degradable HES”• Actual usage– highly variable– based on geography, availability, local habits• Best evidence– Cochrane reviews– other reviews
    5. 5. 2009: “Modern Rapidly Degradable HES”Boldt Anesth Analg 2009;108:1574-82.
    6. 6. SAFE TRIPS Finfer Crit Care 2010;14:R185• Every day in ICU, about 1 in 3 patientsreceive an episode of fluid resuscitation• About half of this is colloid• About half of this colloid is HES2007: Actual use of HES
    7. 7. SAFE TRIPS Finfer Crit Care 2010;14:R1856%HES130 is the most frequently usedcolloid in ICU globally2007: Actual use of HES
    8. 8. 2007: Colloids2010: Renal Safety of HESPerel Cochrane Database Syst Rev 2007:CD000567.Dart Cochrane Database Syst Rev 2010:CD007594.“There is no evidence from RCTs thatresuscitation with colloids reduces the risk ofdeath, compared to resuscitation withcrystalloids, in patients with trauma, burns orfollowing surgery”“Large studies with adequate follow-up are required toevaluate the renal safety of HES products … There isinadequate clinical data to address the claim that safetydifferences exist between different HES products.
    9. 9. Schortgen 2001• N=129• Sepsis• 6%HES200/0.6Schortgen Lancet 2001;357:911-6
    10. 10. Brunkhorst 2008 (VISEP)• N=537• Sepsis• 10%HES200/0.5• StoppedearlyBrunkhorst N Engl J Med 2008;358:125-39
    11. 11. Published HES Reviews 1960-2010• 223 HES reviews– 165 made a recommendation• 124 favourable to HES, 41 unfavourable• Associated with favourable recommendation– reviews with lower methodological quality– reviews with no meta-analysis– reviews with potential COI among authorsHartog Intensive Care Medicine 2012;38:1258-71
    12. 12. Published HES Reviews 1960-2010Hartog Intensive Care Medicine 2012;38:1258-71
    13. 13. Starch Use in Australia• 6% HES 130/0.4 is the first starch approved bythe TGA late 2006.• Marketed from 2008• December 2008– over >40 hospitals in Australia used HES– > 200,000 units distributed• > 30% of synthetic colloid market
    14. 14. Myburgh N Engl J Med. 2013 Feb 21;368(8):775. doi: 10.1056/NEJMc1215977
    15. 15. Anesth Analg 2009; 109(6): 1752-62
    16. 16. “Shortly after…”Shafer Anesth Analg 2011; 112(3): 498-500.
    17. 17. Disclosure: no IRB approval1st retraction28 Oct 2010 http://www.aaeditor.org/NoticeofRetraction.pdf
    18. 18. Editors-in-Chief Statement #1Acta Anaesth Scand AnaesthesiaAnästh und Intensivmedizin Anästh Intensziv Notfall SchmerztherapieAnesth Analg AnesthesiologyBJA Can J AnesthesiaDer Anästh Eur J AnaesthIntensive Care Medicine• Regarding IRB approval:– If the IRB investigation demonstrates no approval we will retract• Regarding scientific fraud:– If the separate hospital investigation demonstratesany wrongdoing we will retract4 Feb 2011 http://www.aaeditor.org/EICJointStatement.pdf
    19. 19. Editors-in-Chief Statement #266 new retractions (total 88)prev + Crit Care Med, J Cran-Max-Facial Surg, Med Sci Mon, Minerva Anestesiol• No IRB approval for 88 reports4 Mar 2011 http://www.aaeditor.org/EIC.Joint.Statement.on.Retractions.pdf9 Aug 2012 press release http://www.klilu.de/Hospital Inquiry• False data in at least 10 of 91 studies
    20. 20. Gattas Anesth Analg 2012;114(1):159-69• 6% HES 130/0.4 RCTs only• Acutely ill adults• Date of search 24 Dec 2010• 36 studies including 11 retracted• 2149 participants including 541 retracted
    21. 21. MortalityGattas Anesth Analg 2012;114(1):159-69
    22. 22. AimTo evaluate the safety and efficacy of 6% hydroxyethylstarch (130/0.4) in 0.9% sodium chloride solution ascompared to 0.9% sodium chloride alone for fluidresuscitation in adult patients treated in the IntensiveCare Unit.
    23. 23. Design and oversight• Investigator-initiated, multicenter, prospective,blinded, parallel-group, randomised-controlled trial• 32 adult medical-surgical ICUs in Australia and NewZealand• Endorsed by the ANZICS Clinical Trials Group• N=7000• Powered to detect ARR 3.5% from baselinemortality of 26%• Powered to detect ARR 1.5% from baseline renalfailure of 6%
    24. 24. PRIMARY: All-cause mortality at 90 daysIncidence of acute kidney injury (RIFLE)Use of renal replacement therapyNew organ failures (resp, cardiovasc, coag, hepatic)Duration of ventilationDuration of renal replacement therapyCause-specific mortality within 90 daysICU and hospital mortality ratesService utilisation (ICU, hospital LOS, mechanical ventilation, RRT)Quality of life and functional outcome assessments (6 months)Cost-effectiveness analysisOutcomes
    25. 25. Study was conducted at maximum daily dose of 50mL/kg/dayStudy treatment
    26. 26. Final recruitment
    27. 27. Study FluidsMean [ SD] daily averageHES: 526 425 mlvsControl: 616 488 ml(P<0.001)
    28. 28. Net Fluid BalanceMean [ SD] dailyaverageHES: 921 1069 mlvsControl: 982 1161 ml(P=0.03)
    29. 29. CVPMean [ SD] daily averageHES: 11.3 4.8 mlvsControl: 10.4 4.4 ml(P<0.001)
    30. 30. Primary outcome: death at day 90
    31. 31. Probability of death at day 90
    32. 32. Renal Outcomes
    33. 33. Serum creatinine
    34. 34. Urine output
    35. 35. Adverse reactions
    36. 36. HES is associated with:• Effects which are– visible at thebedside– superficially„positive‟– minor• Effects which are– invisible at thebedside– negative– major
    37. 37. So what else is happening?
    38. 38. 6S: Perner 2012• N=804• Severe sepsis• 6% HES 130/0.42 vs Ringer‟s acetatePerner N Engl J Med 2012;367(2):124-34.
    39. 39. BaSES: Siegemund (unpublished)• N=241, single centre• Sepsis• 6% HES130/0.4 vs saline• Mortality RR 0.97 (0.65-1.45)• RRT RR 1.83 (0.93-3.59)Siegemund M. NCT00273728 BaSES,personal communication, 2012-09-12
    40. 40. CRYSTMAS: Guidet 2012• N=196• Severe sepsis• Lower volume of 6% HES 130 to achievehaemodynamic stability• Mortality RR 1.20 (0.8-1.74)• RRT RR 1.83 (0.93-3.59)Guidet B Crit Care 2012;16(3):R94.
    41. 41. Evidence transformation 2011-2013• BASELINE approx 2100 subjects• ADDED– At least 8400 new subjects (~ 10 new RCTs)• SUBTRACTED– 541 subjects (11 RCTs)
    42. 42. Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0
    43. 43. Haase BMJ 2013;346:f839
    44. 44. Zarychanski JAMA 2013;309(7):678-88
    45. 45. Patients Randomised into 6% HES 130 TrialsGattas Anesth Analg 2012;114(1):159-69Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0
    46. 46. Patients Randomised into 6% HES 130 TrialsGattas Anesth Analg 2012;114(1):159-69Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0
    47. 47. GattasMyburghICMHaasePernerBMJZarychanskiMcIntyreJAMAPublished online 14 February 15 February 20 FebruaryPopulation Critically ill Sepsis Critically illIntervention 6%HES130/0.4 6%HES130/0.4 All HESIncluded trials 35 9 38Included subjects 10391 3456 10880
    48. 48. MortalityGattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0
    49. 49. MortalityHaase BMJ 2013;346:f839
    50. 50. MortalityZarychanski JAMA 2013;309(7):678-88RR for death1.07(95% CI, 1.00-1.14)AR for death1.20%(95% CI 0.26-2.66%).I2, 0%
    51. 51. Need for RRTGattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0
    52. 52. Need for RRTHaase BMJ 2013;346:f839
    53. 53. Need for RRTZarychanski JAMA 2013;309(7):678-88
    54. 54. Further exploration of these data• Haase Perner– analysis of trials with low risk of bias– analysis of trials according to period of follow up• Zarychanski McIntyre– analysis of trials with and without Boldt
    55. 55. High vslow riskof biasHaase BMJ 2013;346:f839
    56. 56. Long-term vs short-term follow upHaase BMJ 2013;346:f839 suppl.
    57. 57. BoldtZarychanski JAMA 2013;309(7):678-88Excluding BoldtRR for death1.09(95% CI, 1.02-1.17)Boldt trialsRR for death0.94(95% CI 0.82-1.09).OverallRR for death1.06(1.00-1.13)
    58. 58. So now what?
    59. 59. “recommendations reflect the high value we placeon the suggestion of harm in the setting ofavailable alternatives”Published pre-CHEST, pre-6SReinhart Intens Care Med 2012;38:368-83.
    60. 60. ESICM task force – early 2012• 1B: avoid HES with MW>200 in severe sepsis• 1C: avoid HES in patients at increased risk forAKI• 2C: HES 130/0.4 should only be used in clinicaltrial context in these patient populationsReinhart Intens Care Med 2012;38:368-83.
    61. 61. Includes CHEST and 6SDellinger Crit Care Med 2013;41:580-637
    62. 62. The End (?)Dellinger Crit Care Med 2013;41:580-637
    63. 63. Discussion• What is the safety and efficacy ofadministering low volumes of HES to lowacuity (non-sepsis) patients?– in ICU?– in anaesthesia?• How important is the volume sparing effectof colloids/HES?

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