Skip to main content

Archived Comments for: Debate on HES safety is important, but must be based on facts

Back to article

  1. Twisting and ignoring facts on hydroxyethyl starch is not very helpful

    Matthias Jacob, University Hospital Munich

    3 October 2013

    Twisting and ignoring facts on hydroxyethyl starch is not very helpful

    Daniel Chappell and Matthias Jacob

    Department of Anesthesiology, University Hospital of Munich, Nussbaumstrasse 20, 80336 Munich, Germany

    Correspondence to: Matthias Jacob, MD, PhD
    Department of Anesthesiology,
    University Hospital of Munich,
    Nussbaumstrasse 20
    80336 Munich, Germany

    Keywords: colloids, crystalloids, fluid therapy, hydroxyethyl starch, sepsis

    "Facts do not cease to exist because they are ignored." Aldous Huxley

    We are grateful to Nicolai Haase and colleagues for their interest in our thoughts and happy that we agree in one major point: discussions on HES are important, but have to be based on facts.1 Unfortunately, their reply might arouse the suspicion to the reader that our comment was not accurate. This is certainly not the case, all numbers and statements2 were correct. We are happy to provide some help concerning the facts in this discussion.

    First, Haase et al. ignore the fact that fresh frozen plasma (FFP) contains albumin and other macromolecules and, therefore, is a colloid. Taking this into account, in 6S3 the majority of the patients in the crystalloid group received in fact up to 1 litre of colloids (HES, albumin and/or FFP) for initial stabilisation before the trial started. After that, 1/3 of these crystalloid group additionally received a colloid. Therefore, 6S is in fact not a trial purely comparing crystalloid vs. colloid but colloid in a usual vs. colloid in an unusual way. As to be expected, the usual way - to infuse 1 l of colloid in the first 24 hours of severe sepsis before switching to a crystalloidal maintenance protocol and treating a few patients with a colloid if required - led to a significantly better survival. We (and many others worldwide) cannot understand how this can lead to the conclusion that one of these applied colloids should be withdrawn from the market. The conclusion of Haase et al. does not reflect their results as over 75% of all patients received HES.

    Haase et al. state that neither they nor we could know what the doctors were doing in detail during the trial, especially what their decision was to infuse the study fluid or not based on in the individual case. We are afraid this is insufficient to serve as a reliable reference for worldwide future behavior. How should anybody recapture what happened to the patients if the authors cannot? How can the authors draw their incomprehensible conclusions without knowing what exactly happened? From studies which want to change our behavior around hemodynamic optimization a protocol including basic and extended hemodynamical monitoring and vasopressor/inotrops need is absolutely necessary.
    Nevertheless, we agree that 6S indicates how well the participating doctors are trained: They infused a colloid during the crucial initial resuscitation phase.
    The next point our comment criticized was the fact that the duration of ICU stay was not reported. According to the opinion of Haase et al. the aspect, alive and out of hospital, was chosen instead as it provides more infomation, as it is: less affected by survival bias. However, a fact is that the trial lasted over the entire ICU stay. Therefore, length of ICU stay is the only number which can tell us how long patients were treated according to the protocol. Despite being a nice additional information, the provided alternative is no scientifically adequate replacement.

    It is an interesting explanation for the fact that patients, in part, received a contraindicated drug, that the steering committee, scientific adivisors and Medicines Agencies approved the protocol. Approval does not release from medical responsibility and, therefore, does not justify to ignore the fact that renal failure was a contraindication for HES (stated e.g. by the American FDA4) before initiating 6S. Even if the authors believe this inclusion to be ethical, we would at least expect a subgroup analysis excluding these patients.

    We agree with Haase et al. that it takes time to define severe sepsis, and that an early inclusion of those patients is extremely difficult. However, that does not justify ignoring the fact that the majority of patients received HES, despite supposed to being a crystalloid group. Moreover, it is important to discuss the amount of colloids and infused during that vital initial stabilization phase (and discuss why they were infused during the trial). A point quite interesting in this setting is that CRISTAL, a randomized open label trial on over 3,000 patients, included these early 6 hours and shows an improved survival in the colloid group5 - the contrary of 6S. We cannot understand why the authors here ignore these results and why the European Medical Agency (EMA) won't postpone their decision until this trial is published.

    Last but not least Haase et al. declare that: safer ways of using HES in critically ill patients have not yet been identified. This is astonishing. First, their own trial showed that early hemodynamical stabilization with HES and other colloids is the basis of outcome success even in the septic patient. The authors recommend treating their patients as in the 'crystalloid' group, so why don't they recommend giving colloids to most patients in the initial stabilization phase? Beyond that, there are clear hints in literature showing a perioperative goal-directed therapy using HES to improve patient outcome and to reduce complication rates, hospital stay and morbidity.
    Nevertheless, we agree with Haase et al. that in 2013 no patient should be treated with HES following initial stabilization. As a fact, this is what 6S actually shows.

    It is not our main intention to criticize large RCTs such as 6S. But twisting facts, ignoring contraindications, hiding vital information and over-interpreting results is not helpful to advance the scientific discussions Haase et al. claim for. Even if the official authorities should extend the list of contraindications for HES towards the critically ill in general or withdraw this drug from the market, until today there are no high quality data supporting that.


    1. Haase N, Muller R, Perner A: Debate on HES safety is important but must be based on facts. Scand J Trauma Resusc Emerg Med. 2013, 21:66.
    2. Chappell D, Jacob M: Hydroxyethyl starch - the importance of being earnest. Scand J Trauma Resusc Emerg Med. 2013, 21:61.
    3. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH, Elkjaer JM, Poulsen LM, et al: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-134.
    5. Annane, D. Oral presentation at the Great World Fluid Debate London 2013.

    Competing interests

    The authors have held lectures for and received research grants from Baxter (Unterschleissheim, Germany), B Braun, Melsungen (Melsungen, Germany), Fresenius Kabi (Bad Homburg, Germany), Grifols (Barcelona, Spain) and Serumwerk Bernburg (Bernburg, Germany). MJ is member of the Albumin Advisory Board of Grifols (Barcelona, Spain).