Concerns over use of hydroxyethyl starch solutions
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5981 (Published 10 November 2014) Cite this as: BMJ 2014;349:g5981All rapid responses
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Adverse effects of hydroxyethyl starch solutions in surgical patients
In 2013, both the European Medicines Agency (EMA) [1] and the US Food and Drug Administration (FDA) [2] decided that hydroxyethyl starch (HES) solutions should no longer be used in critically ill patients, including those with sepsis. HES will remain available for limited indications such as perioperative infusion. In their analysis, Hartog and colleagues [3] make the case that all clinical use of HES solutions should be discontinued. Part of that case rests on two meta-analyses of ours in surgical patients [4,5].
Priebe [6] critiques the analysis by Hartog and co-authors in general and our two meta-analyses in particular. However, the critique is not valid. EMA has specifically stated that the concerns raised about the VISEP [7], 6S [8] and CHEST [9] results"do not constitute major limitations of these studies, and do not alter the assessment of these data as robust evidence of increased renal dysfunction and mortality associated with the use of HES from large randomised clinical trials in septic and critically ill patients" [10]. Furthermore, acute kidney injury (AKI) and excess mortality attributable to HES have been confirmed in a series of meta-analyses [11-16].
One of our meta-analyses evaluated renal replacement therapy (RRT) in 15 randomized trials with 4,409 total surgical patients [5]. Importantly, this is the only meta-analysis thus far to include surgical subgroup data from CHEST. In the meta-analysis, HES solutions as a class increased RRT with a pooled relative risk (RR) of 1.44 and 95% confidence interval (CI) of 1.04-2.01. In a prespecified subgroup analysis, the increase in RRT by HES 130/0.4 compared with crystalloid (RR, 1.47; CI, 1.02-2.12) coincided closely with the overall pooled RR of 1.44. In a subgroup analysis of data from CHEST, there was no evidence that surgical patients were at lower risk for RRT necessitated by HES 130/0.4 exposure than their non-surgical counterparts (ratio of RR, 1.19; CI, 0.77-1.83; non-surgical patients as the reference category).
The other meta-analysis assessed postoperative blood loss in 18 randomized trials of 970 total patients undergoing cardiopulmonary bypass (CPB) surgery [4]. HES solutions increased postoperative blood loss by 33.3% of a pooled standard deviation (CI, 18.2-48.3%) and reoperation for bleeding (RR, 2.24; CI, 1.14-4.40). HES also increased blood product transfusion.
In the critique it is falsely stated that in our RRT meta-analysis "study fluids were administered intraoperatively in only four trials". Actually, patients received intraoperative study fluid in 11 of the included trials (73.3%). The "ratio of RR" in our CHEST subgroup analysis is mislabeled as simply "RR", thus wrongly suggesting the absence of a significant increase in RRT among surgical HES recipients. Of the 10 trials assessable for RR, the individual trials with a point estimate of RR > 1 totaled 5, not 4, and included CHEST.
It is misleadingly stated that in the RRT meta-analysis "only three of the 15 included trials had satisfactory trial quality". What we reported was that three trials were known to have simultaneously satisfied all our validated quality criteria, namely randomization method, allocation concealment and blinding [17].
With respect to our CPB meta-analysis, it is inaccurate to state that the FDA Safety Communication "merely refers to the meta-analysis by Navickis and colleagues". Citing our meta-analysis as reference number 15 of the Safety Communication, the FDA stated the following about the implications for the Prescribing Information (PI) of HES solutions [2]:
"In a meta-analysis of 18 RCTs in patients undergoing open heart surgery in association with cardiopulmonary bypass [15], use of different HES products, irrespective of molecular weight or degree of molar substitution, was associated with increased bleeding. FDA considers excess bleeding a class effect warranting addition of this new safety information to the Warning and Precautions Section of the PI."
It is untrue that the CPB meta-analysis included only older HES solutions. In reality, 4 trials comparing HES 130/0.4 and HES 200/0.5 head to head were included.
Then there are flaws of statistical inference. A chief purpose of a meta-analysis is to borrow strength from multiple studies, some or all of which, taken singly, may be underpowered. That individual included studies, taken singly, do not show a statistically significant effect is therefore by no means a limitation of the meta-analysis, as the critique suggests. Nor is it a limitation that the effects in some studies are less precise than in others, since precision is used to weight the studies.
Erroneous statistical inference is also applied to subgroup differences in a Cochrane meta-analysis [13]. The correct approach is test of interaction [18,19]. In the Cochrane meta-analysis, RRT was increased by HES solutions (RR, 1.31; CI, 1.16-1.49) with no difference between septic and non-septic patients (p = 0.25 by test of interaction). The Cochrane investigators concluded that "all HES products increase the risk in AKI and RRT in all patient populations and a safe volume of any HES solution has yet to be determined" [13].
Priebe cites a systematic review, in which the authors explicitly declined to perform a meta-analysis [20]. Hence, quantitative safety conclusions cannot be drawn. Also cited was a meta-analysis of renal function in 17 randomized trials evaluating HES 130/0.4 among 1,230 total surgical patients [21]. Numerous limitations of that meta-analysis have been identified [22,23], such as small included trial size (11-140 patients per trial), lack of statistical power (only 14 total RRT events), short follow-up (24 hours or less in more than one-third of the included trials) and heavy use of comparator fluids known to cause AKI (other HES solutions or gelatin in nearly half the trials). In another cited meta-analysis of 19 randomized trials with 1,567 total surgical patients, the investigators concluded that "we are unable to recommend the use of 6% HES solution in surgical patients" [24]. A cited pooled analysis was restricted to randomized trials sponsored by the manufacturer of HES 130/0.4 and thus did not include the totality of relevant evidence [25].
The best current evidence indicates that HES solutions as a class increase the risk of AKI and bleeding in surgical patients. Rigorously designed future studies would be required to establish whether HES can be safely used in the perioperative setting.
References
1. European Medicines Agency: Hydroxyethyl-starch solutions (HES) no longer to be used in patients with sepsis or burn injuries or in critically ill patients. HES will be available in restricted patient populations. 2013, www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Solutio... accessed 2014-12-04.
2. Food and Drug Administration: FDA Safety Communication: Boxed Warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. 2013, www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm; accessed 2014-12-04.
3. Hartog CS, Natanson C, Sun J, Klein HG, Reinhart K: Concerns over use of hydroxyethyl starch solutions. BMJ 349:g5981, 2014.
4. Navickis RJ, Haynes GR, Wilkes MM: Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: A meta-analysis of randomized trials. J Thorac Cardiovasc Surg 144:223-230, 2012.
5. Wilkes MM, Navickis RJ: Postoperative renal replacement therapy after hydroxyethyl starch infusion: a meta-analysis of randomized trials. Neth J Crit Care 18:4-9, 2014.
6. Priebe H-J: Re: Concerns over use of hydroxyethyl starch solutions. BMJ www.bmj.com/content/349/bmj.g5981/rr/780331, 2014.
7. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125-139, 2008.
8. 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 367:124-134, 2012.
9. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:1901-1911, 2012.
10. European Medicines Agency: Assessment report for solutions for infusion containing hydroxyethyl starch. 2013, www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hydroxy..., accessed 2014-12-04.
11. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S: 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 39:558-568, 2013.
12. 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 346:f839, 2013.
13. Mutter TC, Ruth CA, Dart AB: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev 7:CD007594, 2013.
14. 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 39:811-822, 2013.
15. Wiedermann C, Joannidis M: Increased mortality after infusion of "modern" hydroxyethyl starch. Swiss Med Wkly 143:w13747, 2013.
16. 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 309:678-688, 2013.
17. Jüni P, Altman DG, Egger M: Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 323:42-46, 2001.
18. Matthews JN, Altman DG: Statistics notes. Interaction 2: Compare effect sizes not P values. BMJ 313:808, 1996.
19. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM: Statistics in medicine — reporting of subgroup analyses in clinical trials. N Engl J Med 357:2189-2194, 2007.
20. van der Linden P, James M, Mythen M, Weiskopf RB: Safety of modern starches used during surgery. Anesth Analg 116:35-48, 2013.
21. 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 118:387-394, 2013.
22. Groeneveld AB, Navickis RJ, Wilkes MM: Hydroxyethyl starch 130/0.4 and postoperative acute kidney injury. Anesthesiology 119:733-735, 2013.
23. Wiedermann CJ: Hydroxyethyl starch 130/0.4: safe for the kidney in surgical patients? Anesthesiology 119:735-736, 2013.
24. Gillies MA, Habicher M, Jhanji S, Sander M, Mythen M, Hamilton M, Pearse RM: Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth 112:25-34, 2014.
25. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, van der Linden P: The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesth Analg 107:382-390, 2008.
Competing interests: Drs. Navickis and Wilkes have received previous unrestricted research grant support from Baxter, CSL Behring and Grifols.
Hartog and colleagues argue (1) against the decision of the European Medicines Agency (EMA) (2) to allow the continued use of hydroxyethyl starch (HES), and advise physicians to avoid HES solutions altogether. They base their advice primarily on three large multicentre randomised trials (3-5) which in their opinion are the only ones of sufficient methodological rigour and adequate control fluids to allow evaluation of HES safety. I disagree with several of their statements.
In the VISEP study (3), an unphysiologically 10%, unbalanced, hyperchloraemic, second generation pentastarch solution was compared with that of a balanced, normochloraemic crystalloid solution. Thus, this was not only a comparison between HES and crystalloid, but also between different fluid tonicities and electrochemical properties. Chloride is a potent renal vasoconstrictor (6). In healthy individuals, the infusion of 2 L of 0.9% normal saline decreased renal perfusion by 40% (7). Implementation of a chloride-restrictive intravenous fluid administration strategy decreased the incidence of acute kidney injury and renal replacement therapy (RRT) in critically ill patients (8). Furthermore, the recommended daily dose of pentastarch was exceeded by ≥ 10% at least once in 38% of patients (3). Notably, in correctly dosed patients mortality was significantly lower than in those over-dosed, and it even tended to be lower than in those receiving Ringer’s lactate. These findings suggest that an overdose of hyperoncotic pentastarch solution contributed to the adverse renal effects.
Hartog et al. postulate that the three large trials (3-5) documented the detrimental effects of HES. In the VISEP study (3), the increase in 90-day mortality was not statistically significant. In the 6S study (4), 90-day mortality was significantly higher in the HES compared to the crystalloid group in the per-protocol population, but not in the appropriately modified intention-to-treat population. The statement that the CHEST study (5) showed HES-induced nephrotoxicity, is incorrect. The adjusted renal outcome variables RRT and RIFLE-F were not statistically different between groups, and HES was even associated with a significantly better adjusted outcome of RIFLE-R and RIFLE I.
Hartog et al. state that a recent meta-analysis (9) “confirmed an increased risk of requiring renal replacement therapy” in surgical patients. Although the authors emphasise the importance of methodological rigour, only three of the 15 included trials had satisfactory trial quality. In four of the 15 included trials, first and second generation HES solutions of higher molecular weight (450 and 200 kDa) and higher molecular substitution ratio (0.5-0.7) were used. Although this is a meta-analysis of trials in surgical patients, study fluids were administered intraoperatively in only four trials. Of the 10 trials included in the assessment of RRT, none had a 95% confidence interval (CI) > 1.0, and only four had a risk ratio (RR) > 1 with huge CIs reflecting high predictive uncertainty.
The authors of the meta-analysis conclude that “… there was no evidence from CHEST that surgical patients might be less susceptible to HES-induced renal failure prompting RRT than their non-surgical counterparts” (9). However, their presented data suggest the exact opposite. In surgical patients, the incidences of RRT in the HES and saline groups were 4.3% and 3.0%, respectively; in non-surgical patients, the respective incidences were 9.0% in the HES and 7.8% in the saline group (surgical vs. non-surgical patients; RR, 1.19; 95% CI, 0.77 to 1.83).
Hartog et al. mention the open letter to the EMA (10), signed by themselves and “by more than 80 clinicians and leaders of medical societies worldwide”, protesting against EMA’s revised decision. However, they lack to mention the counter statement (11) which was signed by a comparable number of clinicians and leaders of medical societies worldwide, clearly opposing the view expressed by the authors of the open letter.
Hartog et al. state that it is unjustified to replace acute blood loss in surgical and trauma patients with a product (i.e., HES) that induces coagulopathy. They support their statement with reference to a FDA Safety Communication (12), and two meta-analyses (13, 14). The meta-analysis by Mutter et al. (14) does not address the issue of coagulopathy at all. It rather showed that in non-septic patients, HES compared to other fluids was not associated with significantly increased risk of RRT, renal dysfunction or renal failure, and was even associated with decreased risk of RIFLE-R and RIFLE-I. The FDA Safety Communication (12) merely refers to the meta-analysis by Navickis and colleagues (13). This included only studies that had compared first and second generation high-molecular weight (450 and 200 kDa, respectively), higher molar substitution (0.7 and 0.5, respectively) HES solutions with albumin solutions of various concentrations on bleeding following cardiopulmonary bypass. However, such (mostly hyperoncotic, hyperchloraemic) HES solutions should no longer be used.
Numerous cardiac surgery studies suggest that the effects of HES 130/0.4 on blood loss and transfusion requirements are not different from that of other types of fluids (15-17). HES-induced abnormalities in ex vivo coagulation tests do not necessarily correlate with postoperative blood loss and blood product administration (18-20). A pooled analysis of randomized clinical trials found less blood loss and transfusion requirements in major surgery associated with a third generation waxy maize HES 130/0.4 compared to a second generation HES 200/0.5 solution (21). Several recent (non-cited) meta-analyses did not find any association between HES containing solutions and renal dysfunction (22-24), increased blood loss (24), and allogeneic erythrocyte transfusion (24). Furthermore, several recent experimental studies documented better outcome with HES 130/0.4 compared to crystalloids (25-27).
Fortunately, the revised recommendation of the EMA maintains the option of administering waxy maize balanced 6% HES 130/0.4 solution to patients with hypovolaemia and acute blood loss which might well save lives under certain circumstances. It is important to remain earnest (28), and not to twist and ignore facts on HES (29). “Ultimately, it should be in everyone’s interest to interpret the existing data on medical topics objectively and neutrally, without rushing to premature, far-reaching conclusions which could confuse physicians and even render future therapy with potentially life-saving drugs impossible” (11).
References
1. Hartog CS, Natanson C, Sun J, Klein HG, Reinhart K. Concerns over use of hydroxyethyl starch solutions. BMJ 2014;349:g5981
2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2...
3. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-39.
4. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367:124-34.
5. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367:1901-11.
6. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983;71:726-35.
7. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012;256:18-24.
8. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566-72.
9. Wilkes MM, Navickis RJ. Postoperative renal replacement therapy after hydroxyethyl starch infusion: a meta-analysis of randomised trials. Neth J Crit Care 2014;18:1-9.
10. Bellomo R, Bion J, Finfer S, Myburgh J, Perner A, Reinhart K. Open letter to the Executive Director of the European Medicine Agency concerning the licensing of hydroxyethyl starch solutions for fluid resuscitation. Br J Anaesth 2014;112:595-600.
11. Coriat P, B. Guidet B, de Hert S, Kochs E, Kozek S, Van Aken H. Counter statement to open letter to the Executive Director of the European Medicines Agency concerning the licensing of hydroxyethyl starch solutions for fluid resuscitation. Br J Anaesth 2014;113:194-5.
12. FDA Safety Communication: boxed warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. Revised November 25, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.h...
13. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2012;144:223-30.
14. Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev 2013;7:CD007594
15. Van der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013;116:35-48.
16. Hanart C, Khalife M, De Ville A, Otte F, De Hert S, Van der Linden P. Perioperative volume replacement in children undergoing cardiac surgery: Albumin versus hydroxyethyl starch 130/0.4. Crit Care Med 2009;37:696-701.
17. Van der Linden P, de Ville A, Hofer A, Heschl M, Gombotz H. Six percent hydroxyethyl starch 130/0.4 (Voluven®) versus 5% human serum albumin for volume replacement therapy during elective open-heart surgery in pediatric patients. Anesthesiology 2013;119:1296-309.
18. Schramko AA, Suojaranta-Ylinen RT, Kuitunen AH. Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Anesth Analg 2009;108:30-6.
19. Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T. Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Br J Anaesth 2010;104:691-7.
20. Chong Sung K, Kum Suk P, Mi Ja Y, Kyoung Ok K. Effects of intravascular volume therapy using hydroxyethyl starch (130/0.4) on post-operative bleeding and transfusion requirements in children undergoing cardiac surgery: a randomized clinical trial. Acta Anaesthesiol Scand 2006;50:108-11.
21. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P. The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesth Analg 2008;107:382-90.
22. 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.
23. Gillies MA, Habicher M, Jhanji S, Sander M, Mythen M, Hamilton M, Pearse RM. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth 2014;112:25-34.
24. Van der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013;116:35-48.
25. Pape A, Kutschker S, Kertscho H, Stein P, Horn O, Lossen M, et al. The choice of the intravenous fluid influences the tolerance of acute normovolemic anemia in anesthetized domestic pigs. Crit Care 2012;16:R69
26. Silva PL, Güldner A, Uhlig C, Carvalho N, Beda A, Rentzsch I, et al. Effects of intravascular volume replacement on lung and kidney function and damage in nonseptic experimental lung injury. Anesthesiology 2013;118:395-408.
27. Konrad FM, Mik EG, Bodmer SIA, Ates NB, Willems HFEM, Klingel K, et al. Acute normovolemic hemodilution in the pig is associated with renal tissue edema, impaired renal microvascular oxygenation, and functional loss. Anesthesiology 2013;119:256-69.
28. Chappell D, Jacob M. Twisting and ignoring facts on hydroxyethyl starch is not helpful. Scand J Trauma Resusc Emerg Med 2013;21:85
29. Chappell D, Jacob M. Hydroxyethyl starch – the importance of being earnest. Scan J Trauma Resusc Emerg Med 2013;21:61
Competing interests: No competing interests
Re: Concerns over use of hydroxyethyl starch solutions
In his critisism of the analysis by Hartog and co-authors dr. Priebe [1] misquotes the results of the 6S trial [2] saying that the increased mortality with starch was not observed in the modified intention to treat population. This is incorrect. In the 6S trial the relative increased risk for 90-day mortality of starch vs. crystalloid was 1.17 (95% CI 1.01-1.36, P=0.03) in the modified intention to treat population [2].
Thus the conclusion of the NEJM paper was correctly that 'Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an
increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate.'
References
1. Priebe H-J: Re: Concerns over use of hydroxyethyl starch solutions. BMJ www.bmj.com/content/349/bmj.g5981/rr/780331, 2014.
2. 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 367:124-134, 2012.
Competing interests: My units receives research grants from CSL Behring and Fresenius Kabi