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HES or How to End Science

2018; Lippincott Williams & Wilkins; Volume: 127; Issue: 6 Linguagem: Inglês

10.1213/ane.0000000000003796

1526-7598

Raphael Weiß, Manuel Wenk, Hugo Van Aken, Bernhard Zwißler, Daniel Chappell, Alexander Zarbock,

Traumatic Brain Injury and Neurovascular Disturbances

Only a few topics in perioperative and intensive care medicine today are as controversially discussed as the clinical role of intravenous hydroxyethyl starch (HES) solutions. A variety of HES products are available on the market, differing in their molar substitution, mean molecular weight, and C2/C6 ratio. HESs are identified by 3 numbers, for example, 6% HES 130/0.4. The first number (6%) indicates the concentration of the solution, the second (130) represents the mean molecular weight expressed in kilodalton, and the third (0.4) and most significant one is their molar substitution (Table 1).Table 1.: Characteristics of Different HES SolutionHES products are traditionally used as volume replacement to treat intravascular volume depletion. The macromolecules in the solution do not easily cross the vascular barrier into the extravascular space but rather stay in the blood vessels for an extended period until they are enzymatically degraded or undergo phagocytosis, at least in patients where the glycocalyx is still intact. This draws one of the major distinctions to crystalloid solutions that can easily leave the intravascular space and cross over into the extravascular space so that after only a few minutes about 80% of these solutions have already left the vascular system. In contrast, HES “binds” fluid in the blood vessels or may even lead to a shift of fluid from the extracellular to the intravascular space in the hypooncotic patient. This, however, may induce hypovolemia in the extravascular space, which explains why HES functions well as a short- and medium-term volume replacement in dynamic situations such as the perioperative setting (acute blood loss/trauma) but is obviously not the right choice for fluid replacement in cases of dehydration or any long-term approach to intensive care unit (ICU) fluid replacement in patients with a capillary leakage. In clinical practice up until now, “acute volume replacement”—but not “fluid replacement”—has always been the “right” indication for giving the patient HES and has potentially saved many lives by providing hemodynamic stabilization in the most severe clinical scenarios, such as trauma or postpartum hemorrhage. However, to be fair, it is well known that HES has also been used too generously as a fluid replacement for patients in the past. Importantly, many (older) trials with large molecular, highly substituted HES products, such as penta- or hetastarches, have shown adverse renal effects and coagulation disorders. Unfortunately, hetastarches are still used in many countries today and should be replaced by more modern tetrastarches (such as 6% HES 130/0.4–0.42). The downsides of penta- and hetastarch solutions are frequently falsely projected onto tetrastarches, which have been shown to have a much better risk/benefit ratio.1 Several large studies have made attempts to further explore the role of HES, particularly in the intensive care setting. The most cited of those trials are Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study, Scandinavian Starch for Severe Sepsis/Septic Shock Trial (6S), and Crystalloid versus Hydroxyethyl Starch Trial (CHEST), all of which have shown an increase in the rate of adverse effects, such as an increased rate of acute kidney injury, an increase in renal replacement therapy requirements, and even an increase in mortality when HES was used.2–4 However, all those trials have come under scrutiny, and there are ongoing discussions regarding methodological shortcomings, contradictive results, use of different HES solutions, or extraordinary high doses of HES (eg, in the VISEP trial, 40% of patients received an HES overdose) in these studies.5,6 These trials question the reliability of the data, particularly after a prospective study from 65 German ICUs showed that both duration and amounts of colloids used in daily practice were dramatically lower than in the previously mentioned trials.7 The CHEST trial, in particular, is facing allegations of potential data manipulation, mostly due to lack of transparency by the authors.5 Several attempts to access the original trial data have been turned down.8 Additionally, a published “independent reanalysis” of the CHEST data does not really provide confidence in the data because it was published by the original CHEST authors.9–11 A risk/benefit analysis by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) in June 2013 already recommended that “HES solutions should only be used for treatment of acute blood loss when crystalloids alone are not considered sufficient,”12 leading to an observable reduced use of HES products, with both sepsis and “critically ill patients” as the main clearly defined contraindications. The British Medicines and Healthcare Products Regulatory Agency followed the EMA recommendations at the time.13 Interestingly, the UK Yellow Card Pharmacovigilance System never recorded >1 serious adverse event from a HES product compared to about 100 events for crystalloid products every year. Since the termination of HES sales in 2013, the adverse event rate for crystalloids in the United Kingdom has increased by 262%, clearly questioning the role of crystalloids as the better alternative to HES products. This observation is further supported by data from the effects of fluid resuscitation with colloids versus crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial, which randomized almost 3000 patients in hypovolemic shock to fluid resuscitation with either crystalloids or colloids.14 The authors used a more pragmatic approach, including the initial resuscitation phase and giving much less (study) fluids as the previously mentioned trials. Consequently, they showed a better outcome, including reduced mortality at 90 days in the colloid group as compared to the crystalloid group. Methodologically different from VISEP, 6S, or CHEST, patients in the CRISTAL trial were first randomized to a treatment group, and the group adherence was strong. A further subgroup analysis showed that a survival advantage at 90 days was only observable in the HES group and disappeared when alternative colloids were used. Additionally, these alternative products tend to be expensive (eg, albumin), be less effective with a high risk of inducing allergic reactions (eg, gelatin), or have a generally high risk/benefit ratio (eg, dextran). Nonetheless, these products are recommended as alternatives to HES by the EMA. In October 2017, a Swedish initiative led to an ad hoc expert meeting in London, with a scheduled reassessment of HES solutions by the PRAC of the EMA. Results from 2 retrospective drug utilization studies showed that HES products were continued to be used in critically ill and septic patients even after the 2013 recommendations and found that restrictions and contraindications of the use of HES particularly in the intensive care setting were often not adhered to. Again, there are some noticeable irregularities connected with the 2 drug utilization studies trials. First, both studies were based on the same questionnaire, which surprisingly did not allow coding for intravascular hypovolemia but only dehydration and hyperhydration—both being contraindications for the use of HES products and thus completely ignoring volume resuscitation as the proper indication for giving patients HES solutions. Furthermore, PRAC experts and marketing authorization holders were heard. Consequently, PRAC issued an official statement after the February 2018 meeting recommending a suspension of the marketing authorization for HES solutions so that all HES products should be withdrawn from the European market without even mentioning the various experts opinions from the ad hoc meeting and the meeting itself.15 All available clinical trials from 2013 onward amply demonstrate that HES products appear to be safe and effective in a defined perioperative setting. An overview of the most important clinical trial can be found in Table 2. Current high-quality guidelines consider HES solutions as safe as crystalloids in the perioperative period, with no evidence of renal insufficiency or increased mortality.24 A recently published study from 2018 investigating crystalloids versus colloids for intraoperative goal-directed fluid therapy even showed a significantly lower rate of postoperative complications,25 and particularly for major abdominal surgery, additional positive effects on improved intestinal blood flow and motility are discussed.26–28Table 2.: Overview of RCTs Investigating the Role of HES Solutions on Kidney InjuryConsidering the pros and cons and using the available scientific evidence as a foundation for decision making, this procedure has left large parts of the scientific community in astonishment. The recommendation to withdraw HES from the market was neither based on available scientific evidence nor did it reflect the opinion of the majority of the relevant medical societies. If a decision is pushed so hard that the regulating authority cannot wait for potentially important results of currently running trials, then this arouses the suspicion that possibly the results shall deliberately not form a part of the current decisions. Instead decisions appear to be somehow based on majority decisions by regulating authorities. The initial PRAC recommendation to withdraw all HES-containing products for any indication in every setting leaves a bad aftertaste. It is a far-reaching judgment without acknowledging the (soon) available scientific evidence from 2 trials (Prospective, randomized, controlled, double-blind, multi-centre, multinational study on the safety and efficacy of a 6% Hydroxyethyl starch [HES] sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery [PHOENICS] and PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch [HES] solution versus an electrolyte solution in trauma patients [TETHYS]) that were requested by the EMA in 2013 but rather base it on an apparently politically calculated decision. A few weeks ago, at the end of June 2018, the EMA issued a statement from the Coordination Group for Mutual Recognition and Decentralised Procedures - human (CMDh) (the medicines regulatory body representing the European Union [EU] Member States) informing that they “decided that hydroxyethyl starch (HES) solutions for infusion should remain on the market provided that a combination of additional measures to protect patients is implemented.”29 Further, “The CMDh agreed with the PRAC’s assessment of the serious risks in critically ill patients and patients with sepsis. However, the CMDh gave further consideration to the place of HES in the clinical practice of some countries, noted that previous risk minimization measures had some effect, and considered that a combination of new risk minimization measures would effectively ensure that HES solutions are not used in patients at risk.” The process was then forwarded to the European Commission, which has confirmed the CMDh recommendation to not suspend HES. In summary, the way the decisions were put forward by a Medical Authority was not as transparent as one would wish it to be. A scientific discourse that includes all available data and carefully differentiates for the various settings in perioperative medicine is required. Every drug can be used safely and effectively when it is used appropriately, according to its indication and in the right patient population. However, when a drug such as HES is used outside the approved indication, in excess amounts or for the wrong patient collective (which includes critically ill or septic patients), there is a risk for side effects. Results of several studies show that HES products can safely be used in the intraoperative period and in trauma patients to compensate for blood loss. This is not the case in the ICU setting. We must overcome this holy, pseudoscientific, and emotionally driven war that we have on this topic and finally conduct a reasonable, detailed scientific debate. As Galileo Galilei once said: By denying scientific principles, one may maintain any paradox. DISCLOSURES Name: Raphael Weiss, MD. Contribution: This author helped conduct literature review and prepare the manuscript. Name: Manuel Wenk, MD. Contribution: This author helped conduct literature review and prepare the manuscript. Name: Hugo Van Aken, MD. Contribution: This author helped conduct literature review and prepare the manuscript. Name: Bernhard Zwißler, MD. Contribution: This author helped conduct literature review and prepare the manuscript. Name: Daniel Chappell, MD. Contribution: This author helped conduct literature review and prepare the manuscript. Name: Alexander Zarbock, MD. Contribution: This author helped conduct literature review and prepare the manuscript. This manuscript was handled by: Jean-Francois Pittet, MD.