Free
Correspondence  |   September 2013
Hydroxyethyl Starch 130/0.4: Safe for the Kidney in Surgical Patients?
Author Affiliations & Notes
  • (Accepted for publication May 24, 2013.)
    (Accepted for publication May 24, 2013.)×
  • Dr. Wiedermann has received fees for speaking and travel cost reimbursement from producers of plasma protein-derived therapies CSL Behring (Marburg, Germany), Baxter Schweiz (Zürich, Switzerland), Kedrion (Castelvecchio Pascoli, Italy), and PPTA Netherlands (Amsterdam, The Netherlands).
    Dr. Wiedermann has received fees for speaking and travel cost reimbursement from producers of plasma protein-derived therapies CSL Behring (Marburg, Germany), Baxter Schweiz (Zürich, Switzerland), Kedrion (Castelvecchio Pascoli, Italy), and PPTA Netherlands (Amsterdam, The Netherlands).×
Article Information
Correspondence
Correspondence   |   September 2013
Hydroxyethyl Starch 130/0.4: Safe for the Kidney in Surgical Patients?
Anesthesiology 09 2013, Vol.119, 735-736. doi:10.1097/ALN.0b013e31829ff30f
Anesthesiology 09 2013, Vol.119, 735-736. doi:10.1097/ALN.0b013e31829ff30f
To the Editor:
The safety of hydroxyethyl starch (HES), especially with regard to the kidney, has been on debate for many years.1  Newly reported meta-analyses of randomized controlled trials (RCTs), which included recent large trials of high quality, have moved the controversy much closer to consensus. HES solutions as a class have been shown to increase mortality, acute renal failure, renal replacement therapy (RRT), and erythrocyte transfusion in critically ill patients.2,3  Increased mortality and RRT have also been demonstrated specifically among critically ill patients receiving “modern” HES solutions that had been promoted as safer than their older counterparts.4,5  Among patients with sepsis, increases attributable to modern HES have been found in mortality, RRT, transfusion, and serious adverse events.6,7 
By far, the most extensively investigated modern solution is waxy maize-derived HES 130/0.4. However, similar renal effects have been observed in the 6S RCT of modern potato-derived HES 130/0.42 versus Ringer’s acetate in sepsis.8  Thus, in a meta-analysis combining the 6S trial with five RCTs of HES 130/0.4 versus saline (two in sepsis and one each in the intensive care unit, trauma, and cardiac surgery), the pooled relative risk for RRT was 1.27 with a 95% CI of 1.10–1.46.5  For the five RCTs of HES 130/0.4 alone with 6S excluded, the pooled relative risk (1.24; 95% CI, 1.05–1.47) is closely similar.
The accumulated evidence recently prompted an expert panel of the U.S. Food and Drug Administration to conclude that renal failure and bleeding are class effects of HES solutions.*0001  New randomized trial RRT data have been added to the Prescribing Information for HES 130/0.4 in the United States,†0002  and the U.S. Food and Drug Administration is considering further regulatory action.*0001  The European Medicines Agency is currently reevaluating the marketing approvals of HES solutions.‡0003  Avoidance of HES has been recommended in the latest Surviving Sepsis Campaign Guidelines.9 
Therefore, is there still a place for HES in any patient group? This is the question addressed by Martin et al. in a meta-analysis of 17 RCTs evaluating the perioperative infusion of HES 130/0.4 compared with various control fluids.10  Significant differences were not observed in the most extreme postoperative mean values of serum creatinine, the incidence of acute renal failure, or the need for RRT. One interpretation is that surgical patients are not susceptible to HES 130/0.4–mediated renal injury.
An alternative explanation is that renal injury was not detected due to limitations of the meta-analysis. In almost half the included studies, the control fluid was another HES solution or gelatin. Those artificial colloids exhibit their own deleterious renal effects1  and hence are inappropriate comparators that confound the conclusions of the meta-analysis. In the above-described meta-analysis of six RCTs, RRT was significantly increased by modern HES compared with crystalloid, whereas no such effect was seen in three additional included RCTs with other HES solutions or gelatin as the control fluid.5 
This was a meta-analysis of small trials exclusively, the majority at single centers. The median number of patients per trial was 65 (range, 11–140). Such trials are more vulnerable to bias. Significant publication bias favoring HES 130/0.4 has recently been shown in a meta-analysis of RCTs.4  Although Martin et al. could not detect publication bias by standard statistical tests, those tests are known to be insensitive in meta-analyses with only small trials.11  Moreover, many included trials in this meta-analysis showed risk of bias due to lack of blinding and inadequate or unclear randomization method and allocation concealment. The investigators neglected to present any assessment of quality of included trial or risk of bias.
The statistical power of this meta-analysis to detect an effect on RRT was limited by a very low event rate resulting both from incomplete data and inadequate follow-up. RRT data were not available for 57% of the patients in the meta-analysis, and follow-up was for 5 days or less in most included studies. The median reported time to HES-induced acute renal failure is 16 days,12  therefore, many events were undoubtedly missed. Consequently, only 14 total RRT events were observed in this meta-analysis corresponding to 2.6% of the patients with available RRT data. In contrast, there were 672 RRT events in the meta-analysis of six RCTs corresponding to 8.3% of the patients.5  Furthermore, that meta-analysis was devoid of heterogeneity (I2, 0%) indicating, contrary to the contention of the Martin et al., that RRT is not a highly variable endpoint in RCTs.
No mechanistic basis is suggested by the investigators for reduced renal risk in surgical patients. The nephrotoxicity of HES is associated with storage in renal tubular cells and osmotic nephrosis.13  It is unclear why surgical patients should be less susceptible to such renal storage of HES and consequent impairment of renal function.
This meta-analysis fails to provide convincing evidence that surgical patients are at low risk of HES 130/0.4–induced renal injury. Rather, it highlights the lack of high-quality data on the safety of perioperative HES 130/0.4 infusion. Such data would be needed before it can be determined whether HES 130/0.4 might have a role to play for fluid management in surgery.
References
Wiedermann, CJ Hydroxyethyl starch—Can the safety problems be ignored?. Wien Klin Wochenschr. (2004). 116 583–94 [Article] [PubMed]
Zarychanski, R, Abou-Setta, AM, Turgeon, AF, Houston, BL, McIntyre, L, Marshall, JC, Fergusson, DA Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: A systematic review and meta-analysis.. JAMA. (2013). 309 678–88 [Article] [PubMed]
Perel, P, Roberts, I, Ker, K Colloids versus crystalloids for fluid resuscitation in critically ill patients.. Cochrane Database Syst Rev. (2013). 2 CD000567 [PubMed]
Wiedermann, CJ, Joannidis, M Increased mortality after infusion of “modern” hydroxyethyl starch.. Swiss Med Wkly. (2013). 143 w13747 [PubMed]
Gattas, DJ, Dan, A, Myburgh, J, Billot, L, Lo, S, Finfer, S CHEST Management Committee, Fluid resuscitation with 6% hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: Systematic review of effects on mortality and treatment with renal replacement therapy.. Intensive Care Med. (2013). 39 558–68 [Article] [PubMed]
Haase, N, Perner, A, Hennings, LI, Siegemund, M, Lauridsen, B, Wetterslev, M, Wetterslev, J Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis.. BMJ. (2013). 346 f839 [Article] [PubMed]
Patel, A, Waheed, U, Brett, SJ Randomised trials of 6% tetrastarch (hydroxyethyl starch 130/0.4 or 0.42) for severe sepsis reporting mortality: Systematic review and meta-analysis.. Intensive Care Med. (2013). 39 811–22 [Article] [PubMed]
Perner, A, Haase, N, Guttormsen, AB, Tenhunen, J, Klemenzson, G, Åneman, A, Madsen, KR, Møller, MH, Elkjær, JM, Poulsen, LM, Bendtsen, A, Winding, R, Steensen, M, Berezowicz, P, Søe-Jensen, P, Bestle, M, Strand, K, Wiis, J, White, JO, Thornberg, KJ, Quist, L, Nielsen, J, Andersen, LH, Holst, LB, Thormar, K, Kjældgaard, A-L, Fabritius, ML, Mondrup, F, Pott, FC, Møller, TP, Winkel, P, Wetterslev, J Hydroxyethyl starch 130/0.4 versus Ringer’s acetate in severe sepsis.. N Engl J Med. (2012). 367 124–34 [Article] [PubMed]
Dellinger, RP, Levy, MM, Rhodes, A, Annane, D, Gerlach, H, Opal, SM, Sevransky, JE, Sprung, CL, Douglas, IS, Jaeschke, R, Osborn, TM, Nunnally, ME, Townsend, SR, Reinhart, K, Kleinpell, RM, Angus, DC, Deutschman, CS, Machado, FR, Rubenfeld, GD, Webb, SA, Beale, RJ, Vincent, JL, Moreno, R Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup, Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012.. Crit Care Med. (2013). 41 580–37 [Article] [PubMed]
Martin, C, Jacob, M, Vicaut, E, Guidet, B, Van Aken, H, Kurz, A Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients.. Anesthesiology. (2013). 118 387–94 [Article] [PubMed]
Wilkes, MM, Navickis, RJ Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials.. Ann Intern Med. (2001). 135 149–64 [Article] [PubMed]
Schortgen, F, Lacherade, JC, Bruneel, F, Cattaneo, I, Hemery, F, Lemaire, F, Brochard, L Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study.. Lancet. (2001). 357 911–6 [Article] [PubMed]
Cittanova, ML, Leblanc, I, Legendre, C, Mouquet, C, Riou, B, Coriat, P Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients.. Lancet. (1996). 348 1620–2 [Article] [PubMed]