The document traces the evidence around the use of hydroxyethyl starch (HES) in critical care from early reviews showing potential benefits to large trials published in 2012-2013 that associated HES with increased mortality and renal failure risk in sepsis patients, leading major clinical guidelines to recommend avoiding HES in high-risk patients like those with severe sepsis. While early evidence suggested HES may be useful for volume resuscitation, later trials involving thousands more patients established the risks of HES outweigh any potential benefits in critically ill populations. Questions remain around the safety and efficacy of low-dose HES for low-acuity non-sepsis
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 influence
elimination
• in a saline or plasma-adapted carrier solution
3. HES in critical care
This 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. HES in critical care
pre-2010
• Clinical paradigm
– “modern rapidly degradable HES”
• Actual usage
– highly variable
– based on geography, availability, local habits
• Best evidence
– Cochrane reviews
– other reviews
6. 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
7. SAFE TRIPS Finfer Crit Care 2010;14:R185
6%HES130 is the most frequently used
colloid in ICU globally
2007: Actual use of HES
8. 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.
10. Brunkhorst 2008 (VISEP)
• N=537
• Sepsis
• 10%HES
200/0.5
• Stopped
early
Brunkhorst N Engl J Med 2008;358:125-39
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 authors
Hartog Intensive Care Medicine 2012;38:1258-71
13. 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
14. Myburgh N Engl J Med. 2013 Feb 21;368(8):775. doi: 10.1056/NEJMc1215977
17. Disclosure: no IRB approval
1st retraction
28 Oct 2010 http://www.aaeditor.org/NoticeofRetraction.pdf
18. Editors-in-Chief Statement #1
Acta Anaesth Scand Anaesthesia
Anästh und Intensivmedizin Anästh Intensziv Notfall Schmerztherapie
Anesth Analg Anesthesiology
BJA Can J Anesthesia
Der Anästh Eur J Anaesth
Intensive 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
19. Editors-in-Chief Statement #2
66 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.pdf
9 Aug 2012 press release http://www.klilu.de/
Hospital Inquiry
• False data in at least 10 of 91 studies
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
22. 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.
23. 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%
24. 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 ventilation
Duration of renal replacement therapy
Cause-specific mortality within 90 days
ICU and hospital mortality rates
Service utilisation (ICU, hospital LOS, mechanical ventilation, RRT)
Quality of life and functional outcome assessments (6 months)
Cost-effectiveness analysis
Outcomes
41. HES is associated with:
• Effects which are
– visible at the
bedside
– superficially
„positive‟
– minor
• Effects which are
– invisible at the
bedside
– negative
– major
59. 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
64. “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.
65. 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.
68. 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?
Notas do Editor
* 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),