Volume Therapy with Hydroxyethyl Starches

The year 2013 has been a tumultuous one for the clinical status of hydroxyethyl starches (HES). An initial press statement by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) in June 2013 recommended the withdrawal from all indications of all HES solutions to European authorities due to a putatively negative risk-benefit ratio.1 However, the United States Food and Drug Administration (FDA) and the Canadian authorities did not ban HES but declared that they would limit their regulations to an emphasis on HES contraindications: patients with severe sepsis, renal, and liver insufficiency.2,3 The FDA concluded that HES solutions should not be used in critically ill adult patients, including patients with sepsis and those admitted to the intensive care unit (ICU), and that a Boxed Warning to include the risk of mortality and severe renal injury was warranted. In addition, the FDA also cautioned regarding monitoring the coagulation status of patients undergoing open heart surgery, owing, in their view, to an increased possibility of excessive bleeding with HES 130/0.4 (the other HES available in the United States, HES 450/0.7, is not recommended to be used in cardiopulmonary bypass).4 Subsequently, in October 2013, in a span of just 4 months, the Pharmacovigilance Risk Assessment Committee reversed its earlier ban on HES in surgical patients, keeping the same previous stance on the use of HES in critically ill patients and those with sepsis.5 These divergent perspectives of government authorities highlight the controversy over the use of the type of colloids appropriate for volume therapy. The debate was fuelled mainly by 2 ICU publications in 2012. The Scandinavian Starch for Severe Sepsis (“6S”) trial6 reported significantly increased 90-day mortality and use of renal replacement therapy (RRT) in patients with severe sepsis receiving HES 130/0.42 as compared with Ringer’s acetate solution. Then, the Crystalloid versus Hydroxyethyl Starch (“CHEST”) trial,7 which was nearly 9 times larger, and was conducted with a different HES (HES 130/0.4) found, prima facie, a borderline increase in RRT (significant only in unadjusted analysis) but no significant increase in mortality in mixed ICU patients receiving HES in comparison with 0.9% saline. CHEST and 6S were performed in different patient groups, using different HES, different crystalloid comparators, and also resulted in very divergent outcomes for HES in both the studies. The pros and cons of these 2 trials have been eloquently discussed in a recent editorial.8 Unlike the 6S trial, CHEST demonstrated significantly less use of fluid (about 30% less), and a significantly lower incidence of new cardiovascular failure associated with HES. CHEST also found a significantly lower incidence of acute renal injury with HES than with 0.9% saline (by RIFLE criteria: 54.0% vs 57.3%; relative risk, 0.94 [95% confidence interval, 0.90–0.98]; P = 0.007) and no difference in the primary end point of death by 90 days (18% with HES vs 17% with 0.9% saline; relative risk, 1.06 [95% confidence interval, 0.96–1.18]; P = 0.26). Furthermore, these results were consistent across all 6 predefined subgroups, including sepsis. After the publication of CHEST, 5 meta-analyses9–13 on use of HES were published within about 6 months. Although they mathematically combined the clinical data of disparate HES with known chemically different formulae, assuming them all to be a single chemical entity and did not consider the basic pharmacologic principle of structure-activity relationship, they unanimously declared that HES was bad for critically ill patients. It is interesting that some of these contrary decisions were actually based on different conclusions from the same evidence. As HES 130/0.42 increased mortality and the incidence of RRT in patients with severe sepsis, the contraindication for patients with sepsis could seem justified. To extrapolate the same to patients undergoing elective surgery is difficult to warrant. In contrast to the intraoperative use of HES, wherein the need for colloid resuscitation is hemodynamically evident, both 6S and CHEST protocols allowed patients to be stabilized hemodynamically with up to 1000 mL colloids before randomization (e.g. median 500 mL in CHEST or 700 mL in 6S). In fact, targets for volume resuscitation according to the Surviving Sepsis Guidelines14 seem to have been reached already at baseline in more than half of the patients. Over 15% of crystalloid group patients in CHEST had received HES before randomization, and a post hoc critique reported over 60% of the crystalloid group patients having received colloid resuscitation15 in the 6S study. Consequently, it is possible that the crystalloid groups in both studies had, in fact, also achieved a benefit from colloids that was not considered. The huge standard deviation (SD) of time from ICU admission until recruitment in CHEST (nearly 1 week) lends itself to doubt whether the use of HES could be considered as “early resuscitation” at all in this study. The conclusion concerning renal damage of HES is based on the incidence of RRT in ICU populations. This is a somewhat tricky parameter given the many factors influencing the decision to initiate RRT in ICU trials, besides the subjective and vastly differing nature of RRT initiation criteria across ICUs. Neither 6S nor CHEST had laid down criteria for RRT initiation in their protocols. A detailed analysis of these trials, in the context of acute renal injury, has been published16 that also advocates caution regarding use of HES in ICU settings but leaves the question of intraoperative use of HES unanswered. Furthermore, the so-called negative RRT result of CHEST is significant only in unadjusted analysis, and the absolute RRT incidence difference between groups is only 1.2%, thus raising a concern about the clinical significance of this finding, especially since there were no worse primary outcomes or resource utilization outcomes in the HES group. This concern is further enhanced by data found in the Appendix of CHEST, stating errors in administration of study fluid in 9.5% of patients (>300 patients) in each group. This has an important clinical relevance to the safety conclusions, wherein actual drug administration is more important to causality of harm rather than just a blinded allocation. In fact, until the impact of such errors of study fluid administration (in excess of incidences of RRT) is disclosed at least in a post hoc analysis, it is hard to fully judge the external validity of the RRT finding in CHEST, the largest published ICU study involving HES 130/0.4. While it is critically important to pay attention to any information suggesting possible harm, it is reasonable to question whether such ICU studies can be summarily extrapolated to the broader perioperative surgical population that does not typically have the same baseline extent of organ dysfunction. In fact, when looking at studies on low molecular weight HES (HES 130) in general, the statement of “no benefit” with HES 13012 is debatable. In surgery, goal-directed therapy with HES provides real outcome benefits: reduced rates of complications such as postoperative nausea and vomiting as well as earlier return to bowel function,17–19 reduced time on mechanical ventilation,20 and reduction of hospital length of stay.21 It is interesting to note that in penetrating trauma, renal injury occurred more frequently when 0.9% saline was used for resuscitation compared with HES, and maximum sequential organ function scores were lower with HES than with saline.22 There is also no sign of renal harm or coagulopathy in perioperative settings as assessed in 2 reviews dedicated to the use of HES in surgical patients,23,24 although volumes used are generally much lower than the ICU studies, and crystalloids are normally used contemporaneously. The differences between starches, including differences between HES 130/0.4 and HES 130/0.42, and their suitability for short-term resuscitation intraoperatively have been discussed in a well-balanced and informative editorial25 accompanying one of the reviews24 previously mentioned. Therefore, the strongest message from the new studies might be that, after initial hemodynamic resuscitation, HES 130 should not be used in critically ill patients, especially those with severe sepsis. In fact, this may be the case for all colloids. Possible benefit in critically ill patients also needs to be explored by further studies or 6S and CHEST post hoc analyses. Of note, apart from 2 recent reviews23,24 highlighting the safety of HES 130 in the perioperative setting, the latest evidence in the recently published CRISTAL study26 and the RaFTinG registry data (which are not yet published independently but have been presented to the EMA)27 actually show that there may be some place for HES even in the ICU setting where certain benefits may actually outweigh risks. On the one hand, 6S demonstrated that HES 130/0.42 is harmful in severe sepsis; however, CRISTAL tells us HES (type unspecified) may actually improve 90-day survival in the ICU. While CHEST shows no survival benefit of HES, the RaFTinG data seem to suggest an improved ICU survival with HES 130/0.4 (but not with HES 130/0.42).27 Recently, there has been a surge in demand for the pharmaceutical industry to make their unpublished raw study data available.28 De-identified raw data from investigator-initiated clinical trials may also help our understanding of the various facets of such large studies particularly when, as we have seen, the results have such significant implications for clinical practice elsewhere. We urge the investigators of the 6S and CHEST studies to share their raw data in a de-identified manner for the scientific community to conduct a post hoc analysis. In summary, although the new studies such as 6S and CHEST have generated valuable data on usage of HES in the ICU, the initial reaction of the EMA to consider banning all HES from all indications appears not to be justified. Further results from studies such as CRISTAL show improved survival in ICU patients. There are, as yet, no convincing data demonstrating worse outcome with HES outside the ICU population. Hence, the continued usage of HES 130/0.4 in the perioperative setting seems fully justified on the basis of available relevant evidence and preliminary information from, as yet unpublished, RaFTinG.27 DISCLOSURES Name: Michael G. Irwin, MD, FHKAM, FANZCA, FRCA, DA, MB ChB. Contribution: This author helped write the manuscript. Attestation: Michael G. Irwin attests to having approved the final manuscript. Conflicts of Interest: Michael G. Irwin has received speaking honoraria from Fresenius Kabi. Name: Tong J. Gan, MD, MHS, FRCA. Contribution: This author helped write the manuscript. Attestation: Tong J. Gan attests to having approved the final manuscript. Conflicts of Interest: Tong J. Gan has received speaking honoraria from Fresenius Kabi. This manuscript was handled by: Steven L. Shafer, MD.

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