The choice of fluids for intravascular volume replacement has been debated for decades. As early as 1919, Benjamin Moore eloquently commented on the relative merits of colloids and crystalloids in different types of shock.1 More recently, this debate has focused not only on colloids versus crystalloids, but more specifically on the choice of colloid solutions. Hydroxyethyl starch (HES) solutions were developed as less-expensive alternatives to albumin. HES solutions vary in their median molecular weight, molecular weight distribution, ratio between C2:C6 hydroxyethylation, and the type of diluent used. The goal to reduce side effects was an important motivation for the different compositions, but clinical evidence for their improved safety is inadequate. Today, the safety of HES solutions is still debated, with the additional complicating factor of commercial interests attempting to influence the argument.
On October 28, 2010, Anesthesia & Analgesia retracted a recent publication of Joachim Boldt et al. based on an inference of fraudulent research and after an official inquiry by the Landesärztekammer Rheinland-Pfalz (the Rheinland-Pfalz State Medical Board).2 Because of the widespread use of HES solutions and the fact that their use may have increased as a result of research described in the retracted paper, it is important to address just how retraction of this paper may influence the debate on HES.
The recent retraction of a series of fraudulent publications by Scott Reuben profoundly shook the anesthesia community.3 Steven Shafer, Editor-in-Chief of Anesthesia & Analgesia, compared these events to ripping a thread from the interwoven tapestry of human understanding.4 At first glance, the now-retracted single-center report of 50 patients seems trivial in the context of the overall debate on efficacy of HES. Unfortunately, any scientific misconduct, no matter how trivial, casts a long shadow on the scientific work of all involved. In this particular case, a shadow is cast on a bulk of literature on HES safety and efficacy. According to the ISI Web of Science database, 85 of 346 publications authored by Dr. Boldt deal with intravascular volume therapy. Of these, 30 studies and 2 reviews were included in recent meta-analyses and consensus guidelines (Table 1). Because of the shadow cast on Dr. Boldt's publications by the recent retraction, we need to ask what evidence on the safety and efficacy of HES remains if his publications were not taken into account.
Cochrane meta-analyses on the effectiveness of crystalloid versus colloid fluid resuscitation in critically ill patients5 and on colloid versus colloid fluids in acute hypovolemia6 concluded that “there is no evidence from randomized controlled trials that resuscitation with colloids, instead of crystalloids, reduces the risk of death in patients with trauma, burns, or following surgery”5 and that “despite finding 70 trials we cannot make any conclusions about the relative effectiveness of different colloid solutions.”6 Excluding the studies of Boldt et al. from these meta-analyses is unlikely to change these conclusions.
In the current debate on HES, safety is of major concern. Another recent Cochrane meta-analysis on the safety of HES versus other fluid therapies on kidney function7 concluded that “medical practitioners should consider the potential for adverse kidney effects, including acute kidney injury and increased risk of renal replacement therapy when using HES for volume resuscitation, particularly in septic patients.” A recent systematic review and meta-analysis from the Canadian Critical Care Trials Group concluded that critically ill patients receiving HES were more likely to receive renal replacement therapy, and identified a trend toward increased risk of death in association with HES for patients with severe sepsis.8 Because most of the studies by Boldt et al. included in these meta-analyses favored HES, their exclusion would increase the safety concerns of HES.
For those whose clinical practice is strongly influenced by the available evidence, the approach to fluid therapy in hypovolemia is likely to remain largely unchanged despite the retraction of the article by Boldt et al. However, recent consensus guidelines on fluid therapy draw somewhat mixed conclusions on choice of fluid for volume therapy. For instance, the American Thoracic Society Guidelines urge a cautious approach in the use of HES and synthetic colloids in critically ill patients,9 whereas the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) caution against the use of older starches in patients at risk of renal dysfunction but not against the use of low-molecular-weight third-generation HES10 (Table 1). The shadow of doubt now cast on several studies supporting the lack of safety concerns for HES should prompt reconsideration of such recommendations as those in the GIFTASUP.
Despite the meta-analyses5,6 and systematic reviews,11,12 a large-scale fluid trial,13 and a plethora of possible side effects associated with the use of various colloids (including albumin), colloids are widely used in clinical practice. A recent international cross-sectional study in 391 intensive care units (ICUs) confirmed that colloid solutions are the fluid of choice to correct abnormal perfusion and abnormal vital signs and that starches account for 43% of colloids followed by human albumin and gelatins.14 A Swiss survey found that 66% of responding intensive care physicians believed that use of starches improves patient survival and therefore switched to starches.15
The renal risks of “old” 10% HES 200/0.5 have now been recognized.7,16 HES 130/0.4 was introduced in 2001 with claims of a better safety profile than older HES solutions; the latest “balanced” HES 130/0.4 with less saline content should be even better.17 Safety and efficacy of new drugs are assessed using a rigorous regulatory process. Despite this, already licensed drugs are regularly withdrawn from the market because of safety issues.18 Of greater concern is the lack of safety data on new IV solutions in the circumstances of their intended clinical use, let alone the questionable quality of the efficacy data.7,8,19,20 HES 130/0.4 was approved on the basis of equivalence studies, which focus on acute hypovolemia, mostly in the setting of elective surgery, use predominantly other synthetic colloids as comparators, have small sample sizes, use short-term and moderate-volume exposure, and are not suitable for assessing safety.21
Despite these limitations, HES 130/0.4 has rapidly become a widely used IV solution. This success story is difficult to understand. Unfortunately, the shadow cast by the retraction of the article by Boldt et al. extends to the studies on HES 130/0.4. There are 56 randomized controlled trials (RCTs) on HES 130/0.4.21 One-third of these RCTs were published by Boldt et al., all in the elective surgical setting. The remaining 28 surgical RCTs have low power (median patients n = 27 in HES vs n = 33 in control groups), a median study period of 18 hours, a median HES dose well below the daily dose limit, and two-thirds use other starches or gelatins as control fluids. Together with previous findings from 4 RCTs on severely ill patients and 6 RCTs on colloid hemodilution before surgery, the results remain the same: published clinical data are inadequate to support the conclusion that HES 130/0.4 is safer than other HES solutions in surgical and critically ill patients.
What lessons are to be learned from this unfortunate episode of retraction of a scientific paper? Scientific misconduct involving fabrication of studies is difficult to prevent. The best preventive measure to reduce the impact of fraud is the conduct of appropriately designed and powered clinical trials to provide definitive evidence of safety and efficacy. The gray area between “simple” infusion fluids and pharmacologic products such as synthetic colloids should be better defined, and new products aimed at use in vulnerable patient populations such as intensive care patients should be evaluated in studies that appropriately consider safety. Such trials are underway: the CHEST trial by the ANZICS clinical trials group (clinicaltrials.gov: NCT00935168), currently enrolling, is designed to include up to 7000 ICU patients, and the Scandinavian 6S sepsis trial (clinicaltrials.gov: NCT00962156) plans to enroll 800. Furthermore, the SAFE Trips investigators' suggestion that “regulatory agencies should consider reviewing and perhaps revising their criteria for granting marketing approval to resuscitation fluids; in particular they should require evidence from clinical trials that examine longer term patient safety and efficacy outcomes”14 is timely and should receive broad attention.
We as caregivers and clinical scientists should be persistent and critical in reviewing the available information and knowledge base before promoting and implementing potentially harmful and costly changes in clinical practice. Lastly, although the burden of proof for the clinical effectiveness and safety of currently available and novel resuscitation fluids lies with the manufacturers, clinicians involved in pharmaceutical studies must accept the responsibility of only being involved in studies that are conducted ethically and maintain equipoise in the study design, implementation, analysis, and reporting.
Name: Konrad Reinhart, MD
Conflicts of Interest: Konrad Reinhart has in the past received honoraria from B.Braun, Melsungen, Germany. More than 5 years ago, his clinical trials group, SepNet, also received an unrestricted grant of 600,000 Euros from Braun Melsungen for the conduct of the VISEP trial.
Name: Jukka Takala, MD, PhD
Conflicts of Interest: Jukka Takala has no personal conflicts of interest. The Department of Intensive Care Medicine 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 Corporation; and research & development/consulting contracts with Edwards Lifesciences SA, Maquet Critical Care AB, and Néstle. The money is/was paid into a departmental fund; no author receives/received any personal financial gain.
The department has received an unrestricted educational grant 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.
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21. Hartog CS, Kohl M, Reinhart K. A systematic review of 3rd generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg (in press)