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 doi: https://doi.org/10.1136/bmj.f839 (Published 15 February 2013) Cite this as: BMJ 2013;346:f839All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
We thank professor Kranke and co-authors for their comment on our systematic review[1] where they suggest that systematic reviews should be more focused in terms of patients, indication for drugs, doses, mode of administration and length of intervention to prevent comparisons of ‘apples with oranges’. As an example they emphasize the inclusion of the Dolecek trial[2] in our systematic review, but correctly state that the exclusion of this trial does not affect the overall results and conclusions.
Should we have used more specific criteria for inclusion? Probably not. The rationale for restricting a systematic review to trials of certain subgroups of patients and certain modes of drug use is the hypothesis that the drug effect varies fundamentally among different trial designs. By excluding certain trials such hypothesis will never be tested, but just taken for granted. In addition, very specific criteria for inclusion may be defined according to the authors’ pre-existing knowledge of trials with certain outcomes, and thus increase the risk of subjective selection of trials and verification of desired hypotheses.[3] When we protocolized our systematic review, hydroxyethyl starch (HES) 130/0.38-45 was widely used despite results from randomised clinical trials demonstrating adverse effects with former starch solutions in patients with sepsis.[4,5] In such fields where patient safety is likely compromised, we believe that broad identification and inclusion of trials followed by pre-defined sensitivity and subgroup analyses are much more appropriate approaches to assess the association between drug effect and trial design. From that point of view, others would probably question our exclusion of trials investigating former HES solutions and trials of patients without sepsis. This, however, was based on our anticipation that former HES solutions were no longer used in daily clinical practice and that the relevant clinical question should focus on whether the effects of the use of HES 130/0.38-45 were beneficial or harmful in septic patients.
Several other systematic reviews of HES have recently been published by authors with no financial relationship with the manufactures of HES.[6-9] Criteria for in- and exclusion of trials as well as utilised HES preparations vary considerably among these reviews, but they consistently show no benefit with HES and clear indications of harm. The similarity of findings in these reviews indicates that the effects of HES are unlikely to be strongly dependent on type of HES solution, patient selection and mode of administration.
References
1 Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, et al. 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.
2 Dolecek M, Svoboda P, Kantorová I, Scheer P, Sas I, Bíbrová J, et al. Therapeutic influence of 20 % albumin versus 6% hydroxyethylstarch on extravascular lung water in septic patients: a randomized controlled trial. Hepato-gastroenterol 2009;56:1622–8.
3 Higgins J, Green S. Cochrane handbook for systematic reviews of interventions, version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org; 2012.
4 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.
5 Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911–6.
6 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
7 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 2013;39:558-68
8 Zarychanski R, Abou-Setta AM, Turgeon AF, Houston B, McIntyre L, Marshall J, et al. 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.
9 Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2013;2:CD000567.
Competing interests: Anders Perner was principal investigator for the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial and Nicolai Haase and Jørn Wetterslev were members of the steering committee. The 6S trial was funded by the Danish Research Council, the Rigshospitalet Research Council, and the Scandinavian Society ofAnaesthesiology and Intensive Care Medicine (the ACTA foundation). B Braun Melsungen delivered trial fluid to all sites free of charge. Neither the funders nor B Braun Melsungen had an influence on the protocol, trial conduct, data analyses, or reporting of the 6S trial. Anders Perner is head of research in his intensive care unit, which receives research funds from Fresenius Kabi and BioPorto. B Braun Melsungen has covered his travel expenses for presenting 6S data at the German Anaesthetic Congress 2012. Martin Siegemund was principal investigator for the Basel starch evaluation in sepsis (BaSES) trial. The BaSES trial was funded by the Department of Anaesthesia and Intensive Care of the University Hospital Basel. Fresenius Kabi delivered study fluids for free and paid for the packaging and blinding process. A signed contract between Fresenius Kabi and Martin Siegemund stated the Martin Siegemund was free to publish all data without influence from Fresenius Kabi. Fresenius Kabi covered travel expenses for his participation in meetings about fluid resuscitation.
We read with interest the recent systematic review on “the effects of fluid therapy with hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin on mortality, kidney injury, bleeding, and serious adverse events in patients with sepsis”.[1]
For the purpose of this analysis the authors identified trials that “have one intervention group that received hydroxyethyl starch 130 with substitution ratios between 0.38 and 0.45 in any concentration and in any carrier solution, and have at least one other intervention group that received either crystalloid or human albumin.”[1]
In contrast to a simultaneously performed systematic review,[2] the authors did not explicitly mention a dedicated focus on acute volume resuscitation, but aimed “to assess the effects of fluid therapy with hydroxyethyl starch”. Therefore, in principle they cannot be criticized for having included a clinical trial in which a fixed dose of two different colloid solutions (6% HES 130/0.4, 250ml, every 6 h or 20% albumin, 100 ml, every 12 h) had been compared.[3]
However, the paper does not add valuable information to the body of evidence on “acute volume resuscitation”. It investigates whether the administration of one fluid administered on a regular basis and in a fixed dose for more than two days is favourable over the other. For clinicians mixing up acute volume resuscitation and chronic administration does not help gaining a picture of the beneficial or harmful effects of an intervention in a specific context.
Of note: The infused study drugs were not maintenance fluids but colloids usually administered to restore intravascular volume. This trial is difficult to align with initial volume resuscitation that even in these days remain a gap in evidence and further contrasts with recently completed pragmatic trials on “fluid resuscitation” in which fluid therapy was based on the treating physician´s judgment, mostly in accordance with one or more physiological variables, and for a long period of time.
The recurrent criticism of comparing apples with oranges in meta-analyses will inevitably arise, irrespective of the fact that the inclusion or exclusion of this specific trial has only marginal effects on the calculated pooled outcomes.
However, regarding the arbitrary terminology of sepsis related fluid resuscitation the authors are in good company with other analyses focusing on that topic. The paper we picked up to highlight the rather liberal inclusion criteria can be found in other systematic reviews as well.[4]
Similar inconsistencies can be found in the most recent recommendation of the surviving sepsis campaign.[5] In section G on “Fluid therapy of severe sepsis”, that mainly deals with acute fluid resuscitation, “a multicenter randomized trial (n = 794) in patients with septic shock [that] compared intravenous albumin (20 g, 20 %) every 8 h for 3 days to intravenous saline solution” is used as supporting evidence to justify the use of albumin.
In summary, being more precise with the therapy under investigation in meta-analyses, in terms of drug, dose, mode of administration and length of intervention may help to avoid enforcing common prejudices towards systematic reviews. It also enforces the perception that scientists performing meta-analyses not only care for a formal assessment of the “risk of bias” but also care about the content validity of the included trials and thus help to answer a well-framed question.
Thus, we would have the opportunity to learn the whole PICO-story (patient, intervention, comparator, outcome) and not only whether a substance is deemed to be “good” or “bad”. This would enable readers and clinicians to successfully walk along the long and winding road of evidence-based medicine.[6,7]
References:
1. Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, et al. 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
2. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, et al. 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
2. Dolecek M, Svoboda P, Kantorová I, Scheer P, Sas I, Bíbrová J, et al. Therapeutic influence of 20 % albumin versus 6% hydroxyethylstarch on extravascular lung water in septic patients: a randomized controlled trial. Hepatogastroenterology 2009;56:1622-8.
4. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567
5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
6. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ 1996;312:71-2
7. Heneghan C, Godlee F. Where next for evidence based healthcare? BMJ 2013 Feb 6;346:f766. doi: 10.1136/bmj.f766
Competing interests: PK (LKP) and CW (PI) are coordinators and investigators of an investigator initiated trial aiming to investigate acute volume resuscitation in severe sepsis and received funding from FreseniusKabi Germany.
The German professor Joachim Boldt had most of his published work retracted in 2011 due to failure of acquiring ethical approval for research and fabrication of study data [1,2]. In the above systematic review, the supplementary table of excluded studies lists three retracted papers (references 27 to 29) and six non-retracted papers authored by Dr. Boldt (references 22 to 26 and 39). At time of writing, the authors of the review were fully aware of the Boldt scandal. Thus, the findings, discussion and conclusion of the above systematic review is unaffected by any work of Dr. Boldt.
REFERENCES
1. Editors-in-Chief Statement Regarding irb approval of clinical trials by Joachim Boldt. 2011. http://www.aaeditor.org/EICJointStatement.pdf. Assessed 6th March 2013.
2. Akademisches Lehrkrankenhaus der Johannes Gutenberg-Universität Mainz. Hospital Presents Results of Final Report: Committee Completes Investigation in the Case of Dr Boldt. 2012. http://www.klilu.de/content/veranstaltungen___presse/pressearchiv/2012/h.... Assessed 6th March 2013.
Competing interests: No competing interests
Re: Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis
Dear Editor
We read with interest that as of the 27th of June, intravenous (IV) fluids containing hydroxyethyl starch have been withdrawn from use in acutely unwell patients in the UK [1]. These recommendations by the MRHA were based on findings by Haase et al that hydroxyethyl starch preparations were associated with an increased incidence of adverse events, compared with crystalloids or albumin [2]. Using hydroxyethyl starch in patients with sepsis was associated with a greater need for renal replacement therapy and red cell transfusion. These findings support a Cochrane review by The London School of Hygiene and Tropical Medicine, which showed that colloid preparations may account for up to 250 deaths each year [3].
Although The British Consensus Guidelines on Intravenous Fluid therapy for Adult Surgical Patients (GIFTASUP) in 2008 advised balanced crystalloid solutions, saline is still widely prescribed [4]. We found that knowledge of fluid prescribing amongst the primary prescribers (Foundation Doctors) is poor, widespread, and that current education on this topic is failing [5].
For over a decade, inappropriate fluid prescribing, in particular excessive prescription of 0.9% sodium chloride, has been associated with adverse outcomes. Shaw et al found greater morbidity in patients receiving 0.9% sodium chloride (5.6%) compared with those receiving balanced crystalloid solutions (2.9%), in patients after open abdominal surgery. Major complications were more frequent in those given 0.9% sodium chloride (34%) compared with those who received balanced crystalloids (23%) [6]. Lobo et al found that 25% of junior doctors prescribed over 2 litres of 0.9% sodium chloride a day to patients. This may cause hyperosmolarity, and hyperchloraemic acidosis, reduced renal blood flow and glomerular filtration rate, and thus promote sodium retention [7]. Randomised blinded trials found greater side effects with 0.9% sodium chloride than with balanced crystalloid preparations [8-9]. Recently draft guidelines from NICE found no acceptable comparisons of the clinical efficacy of 0.9% sodium chloride and balanced solutions, and showed that there was little cost difference between them [10]. Modern approaches to acid-base balance, applying the concept of strong ions, although physiochemically more complex, support the advantages of balanced solutions [11].
With growing evidence that adverse outcomes result from excessive use of 0.9% sodium chloride, we suggest care is needed when alternatives are considered to the use of starch solutions. The remit of the MHRA needs to look into not only hydroxyethyl starch but also other non-isotonic crystalloid fluids.
Yours sincerely,
Mairi Cruickshanks
Gordon B Drummond
Simon Paterson-Brown
Arfon G M T Powell
References
1.) MHRA suspends use of hydroxyethyl starch (HES) drips. MHRA.
http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON287028 (Cited July 2013)
2.) Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M et al.
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.
3.) Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2013:2:CD000567.
4.) British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients. BAPEN. http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup.pdf (cited July 2013).
5.) Powell AGMT, Walker VC, Paterson-Brown L, Drummond GB, Paterson-Brown S. Intravenous fluid prescribing, knowledge and confidence in F1 doctors. Ann R Coll Surg Engl; (Suppl) 2013;95:1–6
6.) Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821-9.
7.) Lobo DN, Dube MG, Neal KR, Simpson J, Rowlands BJ, Allison SP. Problems with solutions: drowning in the brine of an inadequate knowledge base. Clin Nutr. 2001;20:125-30.
8.) O’Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. Anesth Analg 2005; 100:1518–1524.
9.) Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001;93:817–822.
10.) Intravenous fluid therapy: guideline consultation. NICE. http://www.nice.org.uk/nicemedia/live/13298/63879/63879.pdf (Cited July 2013)
11.) Kellum, JA and Elbers, PWG (2009). Stewart’s Textbook of Acid-Base. 2nd ed. Amsterdam: Lulu Enterprises.
Competing interests: No competing interests