Hydroxyethyl starch - HES - Fluid resuscitation - Volume therapy - Shock - Safety - Meta-analyses

1. Where are we now?
Christian J. Wiedermann, MD
Central Hospital of Bolzano, Italy

2. A Watershed Year
• Large rigorous trials and meta-analyses finally bring new
clarity to long-standing debates.
– Are hydroxyethyl starch (HES) solutions safe?
– Are some HES solutions safer? Some HES doses?
– Does albumin confer any benefit?
• Clinical guidelines already incorporate the new evidence.
• Regulatory actions in the EU and US could accelerate
change in clinical practice.

3. Where were we then?
Wiedermann, 2004:
“The complications of HES appear to be
generic and may be more closely related to
the chemical entity HES than to the
molecular weight and substitution of the HES
solution.”
“It is by no means clear that dose limitations
can be safely relaxed for HES 130/0.4 or
other HES solutions.”
“Although numerous investigations of HES
solutions have been conducted, few of these
studies have been adequately powered to
assess safety. Such studies are needed
before safety claims can be accepted.”
Wiedermann. Wien Klin Wochenschr 116:583-94, 2004.

4. New Meta-Analyses of HES Randomized
Controlled Trials (RCTs)
Zarychanski et al 38 10978 All Critical Illness
Perel et al 25 9633 All Critical Illness
Wiedermann and Joannidis 15 8580 HES 130/0.4-0.42 Critical Illness
Gattas et al 35 10391 HES 130/0.4-0.42 Critical Illness
Haase et al 9 3456 HES 130/0.4-0.42 Sepsis
Patel et al 6 3033 HES 130/0.4-0.42 Severe Sepsis
Martin et al 17 1230 HES 130/0.4 Surgery
Navickis et al 18 970 All Cardiac Surgery
Authors RCTs Patients HES Tested Indication
Zarychanski et al. JAMA 309:678-88, 2013.
Perel et al. Cochrane Database Syst Rev 2, 2013.
Wiedermann and Joannidis. Swiss Med Wkly 143:w13747, 2013.
Gattas et al. Intensive Care Med DOI 10.1007/s00134-013-2840-0, 2013.
Haase et al. BMJ 346:f839 doi: 10.1136/bmj.f839, 2013.
Patel et al. Intensive Care Med DOI 10.1007/s00134-013-2863-6 2013.
Martin et al. Anesthesiology 118:387-94, 2013.
Navickis et al. J Thorac Cardiovasc Surg 144:223-30, 2012.
101 unique RCTs with 14675 unique patients included in the 8 meta-analyses.

5. Meta-Analyses of HES As a
Class in Critical Illness
1. Zarychanski et al. JAMA 309:678-88, 2013.
2. Perel et al. Cochrane Database Syst Rev 2, 2013.
Increased mortality vs. crystalloid or colloid with relative risk (RR) 1.09 and 95% confidence
interval (CI) 1.02-1.171 and vs. crystalloid (RR, 1.10; CI 1.02-1.19).2
Increases also demonstrated in renal replacement therapy (RRT), acute renal failure (ARF)
and red blood cell transfusion with RR (CI) 1.32 (1.15-1.50), 1.27 (1.09-1.47) and 1.42
(1.15-1.75), respectively.1

6. Boldt Did Matter
1. Ioannidis et al. J Clin Epidemiol 59:1023-32, 2006.
2. Zarychanski et al. JAMA 309:678-88, 2013.
Boldt trials identified in 2006 meta-analysis as exhibiting extreme homogeneity consistent
with fraud.1
Increased mortality demonstrable by Zarychanski et al.2 only after excluding unretracted.
Extreme
Homogeneity

7. Meta-Analyses of HES 130/0.4-0.42
in Critical Illness
1. Wiedermann and Joannidis. Swiss Med Wkly 143:w13747, 2013.
2. Gattas et al. Intensive Care Med DOI 10.1007/s00134-013-2840-0, 2013.
Increased mortality (RR, 1.08; CI; 1.00-1.17; p = 0.046) and RRT (1.25, CI, 1.08-1.44).2

8. Meta-Analyses of HES
130/0.4-0.42 in Sepsis
1. Haase et al. BMJ 346:f839 doi: 10.1136/bmj.f839, 2013.
2. Patel et al. Intensive Care Med DOI 10.1007/s00134-013-2863-6 2013.
3. Dellinger et al. Crit Care Med 41:580-637, 2013.
In severe sepsis, increased mortality (RR, 1.13; CI 1.02-1.25), RRT (RR, 1.41; CI, 1.08-
1.84), transfusion (RR, 1.21; CI, 1.08-1.36) and pruritus (RR, 1.81; CI, 1.37-2.38).1
In severe or non-severe sepsis, increased RRT (RR, 1.36; CI, 1.08-1.72), transfusion
(RR, 1.29; CI, 1.13-1.48,) and serious adverse events (RR, 1.30; CI, 1.02-1.67).2
Avoidance of HES recommended in new Surviving Sepsis Guidelines.3

9. Meta-Analysis of HES 130/0.4 in Surgery
Martin et al. Anesthesiology 118:387-94, 2013.
• No difference in creatinine at mean 2 days after surgery.
• No difference in RRT among 43% of patients with available
data (531/1230).
• Bleeding not assessed.

10. Why Adequate Follow-Up Is Key in
Assessing Renal Endpoints
Schortgen et al. Lancet 357:911-6, 2001.

11. US Food and Drug Administration
(FDA) Workshop
Transcript of the 104th Meeting of the Blood Products Advisory
Committee, Food and Drug Administration, Center for Biologics
Evaluation and Research, September 21, 2012.
“So the conclusions of the
panel were, and the majority
of the panel has concluded
actually that the toxic effects
on bleeding and the renal
failure constitute a class
effect of HES solutions…It
could lead to a warning in the
package insert if we consider
that to rise to that level.”
—Nisha Jain, MD, Chief Clinical Review
Branch, Division of Hematology, Office of
Blood Research & Review, Ctr. of
Biologics Evaluation & Research, FDA

12. European Medicines Agency (EMA) Review
“The European Medicines Agency will evaluate the benefit-risk balance
of HES-containing solutions for infusion and issue an opinion on
whether their marketing authorisations should be maintained, varied,
suspended or withdrawn across the EU.”

13. Albumin in Sepsis
• Effective volume expander in sepsis
• Antioxidant activity
• May lessen risk of hypoalbuminemia in sepsis
• RCTs show improved survival in patients with sepsis
receiving albumin
• New Surviving Sepsis Guidelines recommend albumin
Dellinger et al. Crit Care Med 41:580-637, 2013.

14. SAFE Study Subgroup: Mortality Reduced
by Albumin in Severe Sepsis
SAFE Study Investigators: N Engl J Med 350:2247-56, 2004.
Guidet et al: J Crit Care 22:197-203, 2007.
SAFE Study Investigators: Intensive Care Med 37:86-96, 2011.
SAFE Study RCT subgroup of ICU patients with severe sepsis.
4% albumin vs. saline.
Adjusted odds of death reduced 29% by albumin.
Serum albumin level increased by albumin infusion (p < 0.001).
No evidence of impairment in kidney function due to 4% albumin.
Albumin cost-effective in severe sepsis based on SAFE Study data.
Yes No Yes No
183 418 217 398 0.71 (0.52-0.97)* 0.03
Mortality Odds Ratio (CI) p
Albumin Control
* Adjusted for baseline risk factors
in subgroup of 919 patients (75.5%)
Favours
control
Favours
albumin

15. Meta-Analysis of RCTs in Sepsis
Yes No Yes No
Subgroup* 228 586 297 572 0.76 (0.62-0.95) 0.015
All 279 682 343 673 0.82 (0.67-1.00) 0.047
Trials Mortality Odds Ratio (CI) p
Albumin Control
Delaney et al: Crit Care Med 39:386-91, 2011.
* 6 trials of Boldt et al excluded
Meta-analysis of 17 RCTs with 1977 patients.
Albumin vs. crystalloid or artificial colloids.
Odds of death reduced 24% by albumin with trials of Boldt et al. excluded.
Favours
control
Favours
albumin

16. Conclusions
• HES solutions as a class - and HES 130/0.4-0.42 in
particular - increase mortality and RRT in critically ill
patients.
• HES also increases red blood cell transfusion.
• Adverse effects of HES 130/0.4-0.42 occur at doses far
lower than the approved daily maximum of 50 mL/kg body
weight.
• New Surviving Sepsis Guidelines recommend the use of
albumin and avoidance of HES.
• Regulatory actions in light of recent HES studies are under
consideration by both the FDA and EMA.