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Safety of Modern Starches Used During Surgery: Misleading Conclusions

Takala, Jukka MD, PhD; Hartog, Christiane MD; Reinhart, Konrad MD

doi: 10.1213/ANE.0b013e318296913f
Letters to the Editor: Letter to the Editor
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Department of Intensive Care Medicine, University Hospital Bern (Inselspital), Bern, Switzerland

Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany. konrad.reinhart@med.uni-jena.de

Conflicts of Interest: The Department of Intensive Care Medicine, University Hospital of Bern has, or has had in the past, research contracts with Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, and Orion Pharma; and research and development/consulting contracts with Edwards Lifesciences SA, Maquet Critical Care AB, and Néstle. The money is/was paid into a departmental fund; Dr. Takala has not received any personal financial gain. The department has received unrestricted educational grants from the following organizations for organizing a quarterly postgraduate educational symposium, the Berner Forum for Intensive Care: Fresenius Kabi; gsk; MSD; Lilly; Baxter; astellas; AstraZeneca; B. Braun; CSL Behring; Maquet; Novartis; Covidien; Mycomed; and RobaPharma. Dr. Reinhart has had or has relationships with Eli Lilly, Eisai, Brahms, SIRS-Lab Jena, Biotest, Braun Melsungen, Edwards Lifesciences, and he is unpaid chairman of the Board of Directors of the Global Sepsis Alliance and of the International Sepsis Forum.

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To the Editor

The recent review by Van Der Linden et al.1 concludes “that data in the peer reviewed literature do not suggest an adverse safety signal” when tetrastarch is used perioperatively. The review as acknowledged by the authors was commissioned by a tetrastarch manufacturer. However, the unfortunate timing of publication immediately after publication of the Crystalloid Versus Hydroxyethyl Starch Trial2 may lead readers to underestimate safety concerns related to use of hydroxyethyl starches (HESs) in surgical patients. Major trials purely in the surgical setting are still lacking.3–5

The Crystalloid Versus Hydroxyethyl Starch Trial included 7000 intensive care unit patients,2 2829 of them after surgery. It showed that tetrastarch—like pentastarch—is not beneficial but harmful. Patients receiving tetrastarch received significantly more renal replacement therapy (RRT) (7.0% vs 5.8%), blood products (78 ± 250 mL vs 60 ± 190 mL) and had more pruritus (4.0% vs 2.2%). Earlier this year, another high-quality randomized control trial showed that tetrastarch significantly increased the need for RRT and 90-day mortality in sepsis.6 Indeed, all prospective studies assessing 90-day survival status after tetra- or pentastarch found significantly or slightly increased mortality rates.2,6–10

Studies in the surgical setting were not designed to assess patient-relevant safety outcomes. Most studies use other starches or synthetic colloids with similar risks11 as comparator and observation periods of <24 hours5 are too short to evaluate safety. Given these limitations, cumulative data analysis of survival, renal outcomes, or blood loss is meaningless.

The Van Der Linden et al.1 review lacks important elements of systematic reviews, e.g., the assessment of risk of bias in identified studies, additional information requested from study authors, a forest plot with results from individual studies or a funnel plot to assess risk of bias across studies, which would have helped authors and readers critically appraise the cumulative data.12 The authors perform some meta-analyses which find that tetrastarch is beneficial in surgical patients. The odds ratio of mortality at any time is 0.51 (0.24-1.05) with a favorable trend for HES from 21 studies with 1918 patients and 11 deaths after tetrastarch.1 Furthermore, we find the use of a fixed effects model problematic in this context since it can result in inaccurate confidence intervals. More importantly, however, the authors omitted 18 deaths (12/56 patients in the HES 130/0.4 group vs 6/53 in the saline group) from the Fluids in Resuscitation of Severe Trauma study with trauma patients.9 These figures were only published in reply to a letter,13 but should be known to the authors since the first author of the trauma study is a coauthor of the present paper. Recently, the first study to assess 90-day mortality in the surgical setting found 5 of 24 patients died after tetrastarch compared with 0 of 24 patients in the crystalloid group (P = 0.051).10

The authors report a reduced risk for allogeneic blood transfusion after tetrastarch compared with comparator fluids (odds ratio, 0.73 [0.61–0.87]; P = 0.0004).1 Again, a forest plot with study references should have been provided. More importantly, most studies use unsuitable comparators, and the 2 largest studies used a hemoglobin-based oxygen carrier, which is not approved for clinical use on account of increased risk of death and myocardial infarction.14 After hemoglobin-based oxygen carrier, 10.5% more patients required allogeneic blood transfusions which may have shifted the signal considerably in favor of tetrastarch.15 The findings of the Mittermayr et al. study16 should be considered: more patients receiving tetrastarch than patients receiving Ringer’s lactate during orthopedic surgery required allogeneic blood products (3/19 vs 1/20), fibrinogen (6/19 vs 0/20), and more patients received red blood cell units (9 vs 2). Schramko et al.17 reported similar impairment in thromboelastometry after HES 130 and HES 200 compared with human albumin. A systematic review found that HES 130/0.4 administration results in a weaker and smaller clot in comparison with crystalloid or albumin control fluids.18 Finally, the authors found no signal for an increased risk for RRT based on 7 studies with 790 patients and various control fluids (mostly colloids). The number of patients appears small; e.g., to detect an increase in RRT in cardiac surgical patients, approximately 1000 patients need to be randomized into 2 groups with relevant control fluids.5

For the sake of further transparency, the affiliation of Dr. Edward Burdett (responsible for the literature search) and the role of the company representatives acknowledged for noninterference should be provided. Low-quality reviews overwhelm the results of well-performed meta-analyses on HESs;19 and the limitations described above do little to correct this imbalance in the literature.

Jukka Takala, MD, PhD

Department of Intensive Care Medicine

University Hospital Bern (Inselspital)

Bern, Switzerland

Christiane Hartog, MD

Konrad Reinhart, MD

Department of Anesthesiology and Intensive Care

Jena University Hospital

Jena, Germany

konrad.reinhart@med.uni-jena.de

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REFERENCES

1. Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg. 2013;116:35–48
2. 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 SACHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. . Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–11
3. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer SCHEST Management Committee. . Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis. Anesth Analg. 2012;114:159–69
4. Gattas D, Dan A, Myburgh J, Billot L, Lo S, Finfer S. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4): systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013;39:558–68
5. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg. 2011;112:635–45
6. 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 AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J6S Trial Group; Scandinavian Critical Care Trials Group. . Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34
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 KGerman Competence Network Sepsis (SepNet). . Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–39
8. Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, Forceville X, Feissel M, Hasselmann M, Heininger A, Van Aken H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16:R94
9. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth. 2011;107:693–702
10. Feldheiser A, Pavlova V, Bonomo T, Jones A, Fotopoulou C, Sehouli J, Wernecke KD, Spies C. Balanced crystalloid compared with balanced colloid solution using a goal-directed haemodynamic algorithm. Br J Anaesth. 2013;110:231–40
11. Groeneveld AB, Navickis RJ, Wilkes MM. Update on the comparative safety of colloids: a systematic review of clinical studies. Ann Surg. 2011;253:470–83
12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700
13. James MFM, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Reply from the authors. Br J Anaesth. 2012;108:322–4
14. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA. 2008;299:2304–12
15. Olofsson CI, Górecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, Levy HStudy 6084 Clinical Investigators. . Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology. 2011;114:1048–63
16. Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, Oswald E, Bach C, Schnapka-Koepf M, Innerhofer P. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg. 2007;105:905–17 table of contents
17. Schramko AA, Suojaranta-Ylinen RT, Kuitunen AH, Kukkonen SI, Niemi TT. Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Anesth Analg. 2009;108:30–6
18. Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review. Intensive Care Med. 2011;37:1725–37
19. Hartog CS, Skupin H, Natanson C, Sun J, Reinhart K. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses. Intensive Care Med. 2012;38:1258–71
© 2013 International Anesthesia Research Society