CHEST and BeyondHydroxyethyl starches in critical care

David GattasFeb 2013

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 influence

elimination

• in a saline or plasma-adapted carrier solution

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

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

2009: “Modern Rapidly Degradable HES”

Boldt Anesth Analg 2009;108:1574-82.

SAFE TRIPS Finfer Crit Care 2010;14:R185

• Every day in ICU, about 1 in 3 patients receive an episode of fluid resuscitation

• About half of this is colloid• About half of this colloid is HES

2007: Actual use of HES

SAFE TRIPS Finfer Crit Care 2010;14:R185

6%HES130 is the most frequently used colloid in ICU globally

2007: Actual use of HES

2007: Colloids

2010: Renal Safety of HES

Perel Cochrane Database Syst Rev 2007:CD000567.Dart Cochrane Database Syst Rev 2010:CD007594.

“There is no evidence from RCTs that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery”

“Large studies with adequate follow-up are required to evaluate the renal safety of HES products … There is inadequate clinical data to address the claim that safety differences exist between different HES products.

Schortgen 2001

• N=129• Sepsis• 6%HES

200/0.6

Schortgen Lancet 2001;357:911-6

Brunkhorst 2008 (VISEP)

• N=537• Sepsis• 10%HES

200/0.5• Stopped

early

Brunkhorst N Engl J Med 2008;358:125-39

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 authors

Hartog Intensive Care Medicine 2012;38:1258-71

Published HES Reviews 1960-2010

Hartog Intensive Care Medicine 2012;38:1258-71

Starch Use in Australia

• 6% HES 130/0.4 is the first starch approved by the TGA late 2006.

• Marketed from 2008• December 2008

– over >40 hospitals in Australia used HES– > 200,000 units distributed

• > 30% of synthetic colloid market

Myburgh N Engl J Med. 2013 Feb 21;368(8):775. doi: 10.1056/NEJMc1215977

Anesth Analg 2009; 109(6): 1752-62

“Shortly after…”

Shafer Anesth Analg 2011; 112(3): 498-500.

Disclosure: no IRB approval1st retraction

28 Oct 2010 http://www.aaeditor.org/NoticeofRetraction.pdf

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 demonstrates

any wrongdoing we will retract

4 Feb 2011 http://www.aaeditor.org/EICJointStatement.pdf

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 reports

4 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

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

Mortality

Gattas Anesth Analg 2012;114(1):159-69

Aim

To evaluate the safety and efficacy of 6% hydroxyethyl starch (130/0.4) in 0.9% sodium chloride solution as compared to 0.9% sodium chloride alone for fluid resuscitation in adult patients treated in the Intensive Care Unit.

Design and oversight

• Investigator-initiated, multicenter, prospective, blinded, parallel-group, randomised-controlled trial

• 32 adult medical-surgical ICUs in Australia and New Zealand

• Endorsed by the ANZICS Clinical Trials Group• N=7000

• Powered to detect ARR 3.5% from baseline mortality of 26%

• Powered to detect ARR 1.5% from baseline renal failure of 6%

PRIMARY: All-cause mortality at 90 days

Incidence of acute kidney injury (RIFLE)Use of renal replacement therapy New organ failures (resp, cardiovasc, coag, hepatic)Duration of ventilationDuration of renal replacement therapy Cause-specific mortality within 90 days

ICU and hospital mortality ratesService utilisation (ICU, hospital LOS, mechanical ventilation, RRT)

Quality of life and functional outcome assessments (6 months)Cost-effectiveness analysis

Outcomes

Study was conducted at maximum daily dose of 50mL/kg/day

Study treatment

Final recruitment

Study Fluids

Mean [±SD] daily average

HES: 526±425 mlvs

Control: 616±488 ml

(P<0.001)

Net Fluid Balance

Mean [±SD] daily average

HES: 921±1069 mlvs

Control: 982±1161 ml

(P=0.03)

CVP

Mean [±SD] daily average

HES: 11.3±4.8 mlvs

Control: 10.4±4.4 ml

(P<0.001)

Primary outcome: death at day 90

Probability of death at day 90

Renal Outcomes

Serum creatinine

Urine output

Adverse reactions

HES is associated with:

• Effects which are– visible at the

bedside– superficially

‘positive’– minor

• Effects which are– invisible at the

bedside– negative– major

So what else is happening?

6S: Perner 2012

• N=804• Severe sepsis• 6% HES 130/0.42 vs Ringer’s acetate

Perner N Engl J Med 2012;367(2):124-34.

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

CRYSTMAS: Guidet 2012

• N=196• Severe sepsis• Lower volume of 6% HES 130 to achieve

haemodynamic 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.

Evidence transformation 2011-2013

• BASELINE approx 2100 subjects

• ADDED– At least 8400 new subjects (~ 10 new RCTs)

• SUBTRACTED– 541 subjects (11 RCTs)

Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0

Haase BMJ 2013;346:f839

Zarychanski JAMA 2013;309(7):678-88

Patients Randomised into 6% HES 130 Trials

Gattas Anesth Analg 2012;114(1):159-69Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0

Patients Randomised into 6% HES 130 Trials

Gattas Anesth Analg 2012;114(1):159-69Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0

GattasMyburghICM

HaasePernerBMJ

ZarychanskiMcIntyreJAMA

Published online 14 February 15 February 20 February

Population Critically ill Sepsis Critically ill

Intervention 6%HES130/0.4 6%HES130/0.4 All HES

Included trials 35 9 38

Included subjects 10391 3456 10880

Mortality

Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0

Mortality

Haase BMJ 2013;346:f839

Mortality

Zarychanski JAMA 2013;309(7):678-88

RR for death1.07 (95% CI, 1.00-1.14)

AR for death1.20%(95% CI 0.26-2.66%).

I2, 0%

Need for RRT

Gattas Intens Care Med 2013 DOI 10.1007/s00134-013-2840-0

Need for RRT

Haase BMJ 2013;346:f839

Need for RRT

Zarychanski JAMA 2013;309(7):678-88

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

High vslow riskof bias

Haase BMJ 2013;346:f839

Long-term vs short-term follow up

Haase BMJ 2013;346:f839 suppl.

Boldt

Zarychanski JAMA 2013;309(7):678-88

Excluding 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)

So now what?

“recommendations reflect the high value we place on the suggestion of harm in the setting of available alternatives”

Published pre-CHEST, pre-6S

Reinhart Intens Care Med 2012;38:368-83.

ESICM task force – early 2012

• 1B: avoid HES with MW>200 in severe sepsis

• 1C: avoid HES in patients at increased risk for AKI

• 2C: HES 130/0.4 should only be used in clinical trial context in these patient populations

Reinhart Intens Care Med 2012;38:368-83.

Includes CHEST and 6S

Dellinger Crit Care Med 2013;41:580-637

The End (?)

Dellinger Crit Care Med 2013;41:580-637

Discussion

• What is the safety and efficacy of administering low volumes of HES to low acuity (non-sepsis) patients?– in ICU?– in anaesthesia?

• How important is the volume sparing effect of colloids/HES?