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In Response

Van Der Linden, Philippe MD, PhD; James, Michael MB ChB, PhD, FRCA, FCA(SA); Mythen, Michael MD, FRCA; Weiskopf, Richard B. MD

doi: 10.1213/ANE.0b013e3182969219
Letters to the Editor: Letter to the Editor

Service d’Anesthésie-Réanimation, CHU Brugmann-HUDERF, Free University of Brussels, Bruxelles, Belgium,

Department of Anaesthesia, University of Cape Town, Cape Town, South Africa

University of California, San Francisco, San Francisco, California

We absolutely and fundamentally disagree with the accusation from Hartog et al.1 and Farag et al.2 that the conclusions of our review on the safety of modern starches used during surgery are misleading. Rather, we suggest that the use of results from studies of critically ill patients to inform perioperative practice is both misleading and potentially dangerous.

The use of hydroxyethyl starches (HESs) in sepsis and septic shock might be associated with greater use of renal replacement therapy;3 although in that trial there were no prospectively defined criteria for renal replacement therapy use, the adjusted result did not reach statistical significance. In addition, when using a 5-category scoring system to evaluate the effects of studied fluids on the kidney (Risk, Injury, Failure, Loss, End-stage renal failure: RIFLE score) the incidence of RIFLE-R (risk) and RIFLE-I (injury) criteria favored HES and the incidence of RIFLE-F (failure) did not differ between groups.

Use of HES in an intensive care unit (ICU) setting was not the subject of our review, as we stated clearly in our paper,4 and this is why we did not cite the consensus statement of the European Society of Intensive Care Medicine.5 We do agree that there is no evidence to support the use of colloids, either natural or synthetic, in the critically ill with sepsis or septic shock, particularly in the days after initial fluid resuscitation, when boluses are commonly used to treat dips in blood pressure and/or oliguria with no evidence of a new volume deficit such as hemorrhage. The 2 recent trials of tetrastarch in an ICU setting did not study acute resuscitation, as the patients were enrolled many hours after their admission.3,6 In addition, criteria used to define hypovolemia were vague and fluids were not titrated according to predefined therapeutic objectives.

The focus of our review was the safety of tetrastarches in surgery, where they are much more commonly used to treat a true volume deficit resulting from blood loss. Most of these patients recover and leave the hospital within a week. As we clearly stated in our publication, in our view it is plausible that the safety and the efficacy of tetrastarches when used in surgery are likely to be substantially different from that seen in the critically ill and particularly in the patients with severe sepsis, owing to a degraded glycocalyx in the latter, with extravasation of large molecules, such as HES, that would otherwise be retained intravascularly. There is increasing evidence that perioperative goal-directed fluid therapy might reduce patient harm but when applied to patients with established critical illness it had little effect or was harmful. These are completely different contexts, and the results may be quite different. Our views regarding perioperative fluid therapy have been strongly supported by an editorial and 2 accompanying articles published recently.7–9

The vast majority of patients exposed to colloids are outside the ICU. We looked for evidence of harm from tetrastarches in the existing perioperative literature. As explained at some length in our paper, we chose specifically not to perform a meta-analysis or construct Forest plots as both can hide small signals (i.e., trials that show the opposite results can be overwhelmed). We took the worst-case approach and examined each trial in detail, looking for signals of harm. Hartog et al.1 stated that our analyses are meaningless and yet the “high-quality” meta-analyses that have reviewed much of the same perioperative literature but bundled with trauma and critically ill/sepsis studies reached similar conclusions.10,11 In particular, the Cochrane meta-analysis that examined the effects of HES on kidney function compared with other fluid resuscitation therapies in different patient populations stated that “sub-group analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients.”12

Use of a colloid rather than a crystalloid is more efficient and effective to treat blood volume deficits during surgery, in the presence of an intact glycocalyx, and results in less salt and water overload, particularly when used in a goal-directed strategy. However, colloid given to patients without a volume deficit causes release of atrial natriuretic factor that can degrade the glycocalyx.13 Rather than implicating the type of fluid, one may question the way the fluids were used in the Perner et al.6 and Myburgh et al.3 studies.

We acknowledged in our paper the limitations in the available literature with regards to size of perioperative trials and duration of follow-up with regards to safety and suggested that examining existing high-quality data sets and registries might be a better initial approach rather than large randomized controlled trials which are difficult to perform in true resuscitation as more substantial bleeding requiring true “resuscitation” is hard to predict.

In answer to specific questions raised by Hartog et al.,1 we locked the search and review strategy in advance of reviewing the literature; that is standard practice for a high-quality review. Not all reviews have specified this, and some appear to have included non–peer-reviewed data.14 Our approach resulted in inclusion of the 2 studies evaluating a third-generation hemoglobin-based oxygen carrier. Exclusion of these studies does not impact the conclusions. The odds ratio remains 0.72 (95% confidence interval, 0.58–0.90), P = 0.004. However, those studies were relatively large and thus we would have been rightly criticized had we omitted them. Likewise, the FIRST (Fluids in Resuscitation of Severe Trauma) trial evaluated trauma patients and similar criticism might apply. However, it is a trial with less risk of bias than most in this area. The question regarding the “extra” deaths in this trial has been covered in the letter to which Hartog et al. refer,15 and these authors should already be fully aware of the answer and the fallacy of their criticism.16 These were deaths from trauma deemed by the investigators before breaking the blind to have been unlikely influenced by the study fluid. The study of Feldheiser et al.17 which was the first to assess 90-day mortality in the surgical setting has been clearly misquoted by Hartog et al.1 Although the authors reported 5 deaths of the 24 patients randomized to receive a balanced tetrastarch compared with 0 of 24 patients randomized to the balance crystalloid group, they clearly stated that “before unblinding, all deaths were assessed to be not related to the study protocol and two subjects were excluded from the analysis.” Of interest, the authors concluded that when using a goal-directed hemodynamic algorithm to optimize stroke volume, a balanced tetrastarch solution is associated with better hemodynamic stability and reduced need for fresh frozen plasma. They reported no signs of renal impairment by the studied colloid solution when fluid administration is targeted to optimize cardiac preload in major abdominal surgery. Hartog et al.1 also question the affiliation of Dr. Burdett who conducted the initial literature search. He is a consultant at University College of London Hospitals and a Cochrane collaborator.18 They also question the industry employees’ role, although we clearly stated that “no one from Fresenius-Kabi had any influence on any decisions related to this report: outcomes to be evaluated, searches/search strategy, data evaluation, and manuscript writing.”

In response to the specific question raised by Farag et al.2 regarding the effects of tetrastarches on coagulation, we agree that the administration of these solutions can result in a weaker clot. However, as stated in our paper, interpretation of the results observed in the small blunt trauma population of the James et al.’s publication19 is difficult as they may have been related to a clinically and statistically significant greater severity of injury in the starch group. Of note, among the 38 reviewed studies having evaluated the effects of tetrastarches on blood loss in the surgical context, none reported increased blood loss associated with the use of tetrastarches. Finally, we did not cite the systematic review published by Hartog et al.14 because we do not believe this was a “systematic” review, with several important papers having been “omitted.”20,21

We suggest that application of conclusions based on data collected in the septic and critically ill may be misleading when applied to other contexts. We look forward to the results of 2 large trials addressing outcomes in patients requiring true resuscitation. The CRISTAL (efficacy and safety of colloids versus crystalloids for fluid resuscitation in critically ill patients) trial (NCT 0318942), a European multicenter trial of colloids versus crystalloids studied more than a 1000 patients needing true resuscitation (i.e., marked hypotension at time of randomization—many having surgery) with most of the colloid used having been a tetrastarch. Although the results have been presented at a meeting, we prefer to wait until this study has been published before including it in the debate. The RELIEF (restrictive versus liberal fluid therapy in major abdominal surgery) study (NCT 01424150) will study the effect of a restrictive fluid replacement strategy on 30-day septic complications and mortality with or without the use of a goal-directed therapy in patients undergoing major abdominal surgery.

In conclusion, we assert that our systematic review was soundly based using all valid available information. Attempting to confound a review of perioperative data with controversial information from ICU-dominated studies does not constitute a valid criticism, but rather has the potential for misinforming the use of HES in the immediate perioperative period in patients without sepsis.

Philippe Van Der Linden, MD, PhD

Service d’Anesthésie-Réanimation


Free University of Brussels

Bruxelles, Belgium

Michael James, MB ChB, PhD, FRCA, FCA(SA)

Department of Anaesthesia

University of Cape Town

Cape Town, South Africa

Michael Mythen, MD, FRCA

Richard B. Weiskopf, MD

University of California, San Francisco

San Francisco, California

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1. Hartog C, Takala J, Reinhart K. Safety of modern starches used during surgery: misleading conclusions. Anesth Analg. 2013;117:527–8
2. Farag E, Argalious M, O’Hara J, Doyle DJ. Safety of HES 130/0.4 not yet settled. Anesth Analg. 2013;117:528–9
3. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SACHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. . Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–11
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© 2013 International Anesthesia Research Society