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(Chest. 2003;124:1437-1442.)
© 2003 American College of Chest Physicians

Hetastarch and Bleeding Complications After Coronary Artery Surgery*

Jerry Avorn, MD; Minalkumar Patel, MD, MPH; Raisa Levin, MS and Wolfgang C. Winkelmayer, MD, ScD, MPH

* From the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Correspondence to: Jerry Avorn, MD, Chief, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, 221 Longwood Ave, BLI/341, Boston, MA 02115; e-mail: javorn{at}rics.bwh.harvard.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Controversy persists concerning the potential association between intraoperative use of hetastarch (ie, hydroxyethyl starch [HES]) and postoperative bleeding in patients undergoing surgery. To determine whether intraoperative HES use is associated with an increased risk of postoperative bleeding following coronary artery bypass graft (CABG) surgery.

Design: Case-control study.

Setting: A large academic medical center in the northeastern United States.

Participants: A consecutive sample of 238 patients undergoing CABG surgery.

Main outcome measures: Cases consisted of patients who had received either >= 3 U packed RBCs, >= 3 U platelets, >= 3 U fresh frozen plasma, or any cryoprecipitate within 72 h after undergoing a CABG procedure, or who had undergone surgical revision for bleeding. All other CABG surgery patients served as control subjects.

Results: In multivariate models that controlled for a wide variety of demographic and clinical characteristics, we found that, compared to patients who did not receive any HES during surgery, those who received 1 U intraoperative HES had more than twice the risk of a bleeding outcome (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.10 to 4.91), and those who received 2 or 3 U HES had more than four times the risk of postoperative bleeding (OR, 4.57; 95% CI, 1.74 to 12.00).

Conclusions: HES use in patients undergoing CABG surgery may be associated with a significant risk of postoperative bleeding. A double-blinded, randomized, controlled trial will be necessary to confirm this finding.

Key Words: adverse events • complications • epidemiology • hydroxyethyl starch • surgery


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hemorrhagic complications after open-heart surgery are not uncommon. Previous studies have indicated1 that between 0.6% and 15% of patients who undergo coronary artery bypass graft (CABG) surgery require surgical revision due to bleeding. In less severe cases, bleeding is treated with blood transfusions or other measures to improve coagulation. With over a half-million CABG procedures performed annually in the United States alone,2 the clinical and economic impacts of bleeding episodes after CABG surgery are large.3 As a result, interventions to reduce the risk of postoperative bleeding could be of considerable importance. Older age and female gender have been identified as risk factors for postoperative bleeding, making it possible to manage some high-risk patients proactively.4 Identifying additional modifiable risk factors for bleeding would contribute further to increasing the safety of this common procedure.

One potential modifiable risk factor the role of which has been controversial is the perioperative use of hetastarch (ie, hydroxyethyl starch [HES]), either used as the priming fluid for the extracorporeal cardiopulmonary bypass circuit or given directly to the patient intraoperatively. Several observational studies,1 5 6 7 8 randomized trials,9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 and meta-analyses25 investigating the possible association between HES use and bleeding after open-heart surgery have produced conflicting results. All nonrandomized studies have found associations between HES use and subsequent bleeding compared to that seen in patients who received crystalloids and/or albumin. However, the validity of these studies has been questioned because of concerns over whether the patients who received HES may have been sicker at baseline, despite attempts to adjust for these case-mix differences.

Cope et al7 found significant increases in both blood loss and hemostatic drug requirement in CABG surgery patients who had received intraoperative HES compared to those who received only HES postoperatively or no HES at all. However, their study did not attempt to adjust for potential confounders, such as the possibility that the patients who had been chosen to receive HES may have been more hemodynamically compromised or otherwise more ill than those who did not.7 Knutson et al5 used multivariate adjustment for several covariates and found HES to be associated with a significant increase in postoperative blood loss. However, patients who were exposed routinely to HES were drawn from an earlier time period. The non-HES patients had been treated more recently, at a time when HES use had been sharply reduced in order to reduce postoperative bleeding. The institution of this no-HES policy also may have increased awareness of bleeding as an important complication in such patients and thus may have triggered other changes in perioperative care.

Contrasting with the positive findings of these studies is the absence of significant differences in bleeding rates in most randomized studies of HES vs crystalloids or albumin. However, the number of patients included in such randomized trials has generally been quite small (largest study, 93 patients),15 so that their power to detect this risk was limited. There are also concerns in most of these studies about randomization and blinding. One randomized study19 that evaluated four groups of 15 patients each found a significant increase in postoperative blood loss in CABG surgery patients who had received high-molecular-weight HES compared to patients who had received no colloids. Other patients who received low-molecular-weight HES, albumin, or gelatin did not demonstrate such excess bleeding. By contrast, Moggio et al9 reported a nearly significant increase in postoperative blood drainage in cardiac surgery patients who had been randomized to receive albumin compared to those who received HES. All other randomized studies failed to demonstrate any significant differences in bleeding.

A recent meta-analysis25 reported a significant increase in postoperative wound drainage volume in patients receiving HES compared to patients receiving albumin. However, the study was limited by the quality of the studies that were integrated.25 In addition to the problems with randomization in many of the studies used, as mentioned above, the authors may have omitted some studies that would have been appropriate for consideration. Some have questioned whether the sponsorship of the analysis by an industry group of albumin manufacturers may have introduced some bias in such selection and interpretation.26

In light of the uncertainty in the literature, and the widespread use of this agent in cardiac surgery, we sought to define the association between the intraoperative use of HES and postoperative bleeding in a large number of consecutive patients who were undergoing CABG surgery, adjusting for a wide variety of potential confounders.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We retrospectively reviewed the medical records of 238 consecutive patients who had undergone first-time or repeat CABG surgery at a large academic medical center. Patients who had undergone valve replacement during the same operation were excluded from the study. An experienced medical chart abstractor extracted the following demographic and presurgical covariates: age; gender; body surface area; type of hospital admission (ie, elective vs nonelective); serum albumin (S-Alb) level; serum creatinine (S-Crea) concentration; BUN; hematocrit (Hct); prothrombin time (PT); partial thromboplastin time (PTT); and platelet count.

In addition, we collected the following information related to the surgical procedure itself: extracorporeal bypass time; lowest body temperature; highest intraoperative activated clotting time (ACT); identity of the performing surgeon; receipt and volume of any interoperative blood; and receipt and dose of any intraoperative albumin or HES. Information on the patients’ experience within the first 72 h after surgery then was evaluated, including postoperative receipt and dose of albumin, HES, packed RBCs, platelets, fresh frozen plasma, or cryoprecipitate, and whether reoperation for bleeding complications had been required.

The study was conducted as a case-control analysis. Cases were patients who had received >= 3 U packed RBCs, >= 3 U fresh frozen plasma, >= 3 U platelets, or any cryoprecipitate within 72 h after undergoing their CABG procedure, or who had undergone reoperation for bleeding complications during this period. The patients undergoing CABG surgery during this period who did not have these outcomes served as control subjects. We excluded 29 patients from the study because important covariate information was unavailable from their medical records. This left a total of 209 patients (93 cases and 116 control subjects). Most cases (76%) were so defined because the patient had received >= 3 U RBCs postoperatively, with an additional 13% and 9% of patients so defined because of plasma use or the need for reoperation for bleeding.

All statistical analyses were performed using a statistical software package (SAS for UNIX, version 8.1; SAS Institute; Cary, NC). Univariate analyses were done using the {chi}2 test for categoric variables and the Student t test for continuous variables. Multivariate logistic regression was performed using the PROC LOGISTIC procedure of the software. The number of units of HES received was the main exposure variable. Age and gender were included in all models. Other independent covariates to be included in the final model were selected by an automated backward-selection procedure that was based on a p value of > 0.20. The model fit was tested using the Hosmer-Lemeshow goodness-of-fit test.27 To control for the variation of outcomes among individual surgeons, we matched the patients’ outcomes on the surgeon performing the procedure and built multivariate conditional regression models stratifying by surgeon.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients’ demographic and clinical characteristics are shown in Table 1 . The age and gender distribution was similar between the 116 control subjects and 93 patients, as was body surface area. In univariate analyses, patients who underwent nonelective surgery were more likely to experience a bleeding event postoperatively (odds ratio [OR], 2.84; 95% confidence interval [CI], 1.51 to 5.35). Higher S-Crea (p = 0.004) and lower S-Alb at baseline (p = 0.01) also predicted future case status. Preoperative Hct, platelet count, and coagulation measures at baseline were not significantly different between patients who later became cases vs those who became control subjects. The minimal intraoperative temperature was lower (p = 0.004), and extracorporeal bypass time was longer in those who bled vs those who did not (p < 0.001). Also in univariate analyses, patients received more HES during surgery than did control subjects. Those who had received 1 U had a 67% increase in the risk of bleeding compared to those who had received none (OR, 1.67; 95% CI, 0.90 to 3.12). Those who had received 2 or 3 U nearly quadrupled their risk of bleeding (OR, 3.74; 95% CI, 1.61 to 8.7).


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  		Table 1. Patient Characteristics*

 
We next further examined these associations in a multivariate model that controlled for a number of important potential confounders. The covariate selection procedure yielded a final model that included age, gender, HES use, highest intraoperative ACT, cardiopulmonary bypass time, as well as baseline Hct, creatinine level, and albumin level. This multivariate analysis confirmed that a greater use of HES was associated with a higher likelihood of bleeding, even after adjusting for patient and operative differences (Table 2 ). Those who had received 1 U HES during surgery were more than twice as likely to bleed postoperatively compared to those who had not received any HES during surgery (OR, 2.32; 95% CI, 1.10 to 4.91). The use of 2 or 3 U HES was associated with more than four times the risk of becoming a case than was the nonuse of HES (OR, 4.57; 95% CI, 1.74 to 12.00). (No patients received > 3 U HES intraoperatively.) Neither controlling for individual surgeons in the logistic model nor matching on the surgeon changed these results (data not shown).


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  		Table 2. Results From Multivariate Logistic Regression Model (Odds of Becoming a Case vs Control)*

 
Not surprisingly, the multivariate model also confirmed that patients who had been admitted to the hospital under urgent or emergent conditions rather than electively had three times the risk of bleeding complications (OR, 2.97; 95% CI, 1.17 to 7.57). Similarly, a longer duration of cardiopulmonary bypass was associated with a higher likelihood of bleeding (OR [per incremental 30 min], 1.50; 95% CI, 1.12 to 2.00). An increased time spent on bypass was likely a proxy for more complicated patients or complex procedures. Higher baseline Hct was associated with a lower risk of the outcome studied, probably because the lower the baseline Hct, the sooner the transfusion threshold would be reached at comparable rates of bleeding. Lower S-Alb level, which is a marker of poor nutrition, frailty, and comorbidity, also was associated with a higher risk of bleeding. Neither age nor gender was associated with the risk of becoming a case vs that for becoming a control subject.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study suggests that the intraoperative use of HES appears to be associated with a higher likelihood of postoperative bleeding, even after controlling for a wide variety of patient characteristics, operative events, and even surgeon factors. There was also evidence for a dose-dependent effect. In multivariate models, patients who received 1 U HES had twice the risk of bleeding as those who did not receive any HES intraoperatively (OR, 2.32; 95% CI, 1.10 to 4.91), and patients who were administered 2 or 3 U HES had more than four times the odds of bleeding compared to nonexposed patients (OR, 4.56; 95% CI, 1.74 to 12.00). These findings are based on an unselected population of consecutive patients who had undergone CABG surgery at a large institution. The number of patients evaluated here exceeds those available in all but one study published thus far. That study (444 patients) evaluated a historical group of patients who had received HES during CABG surgery compared to a more current cohort who did not receive HES, raising important concerns of confounding by temporal changes in surgical or anesthesia practice, or in the case mix.5

An association between HES use and bleeding complications, if real, could have a biologically plausible mechanism. Studies28 in healthy volunteers have demonstrated that HES may lead to decreases in the levels of factor VIII, fibrinogen, and von Willebrand factor, and to increases in PTT, PT, and bleeding time. Similar changes as well as decreases in prothrombin, factor VII, factor IX, and platelet aggregation have been found in studies of patients undergoing cardiac surgery. However, the actual mechanism by which HES might lead to changes in coagulation factor levels (beyond what is explainable by hemodilution alone) is not well-understood. It has been speculated that HES may precipitate certain clotting factors and make them unavailable for the coagulation cascade. HES also has been suggested to impair platelet function by coating the surface or inducing platelet damage.28 29 30

Several limitations to the present analysis must be considered. While the multivariate regression model was designed to control for all available information on patient and surgeon characteristics, it is possible that residual differences between cases and control subjects may have biased our findings. However, we adjusted for all of the characteristics that have been shown to be important in previous studies. A more important concern is the presence of protopathic bias, in which anesthesiologists might have been more likely to administer HES rather than crystalloids to patients who showed early signs of bleeding. However, anesthesiologists in the medical center studied were aware of the hypothesized association between HES and bleeding complications, and reported that they would actually have been less likely to use HES in patients with bleeding, which would have created a bias in the opposite direction. In addition, the standard approach to volume replacement in a patient with bleeding would be packed RBCs, rather than HES administration. This, too, would have served to reduce the observed use of HES in patients whose bleeding began intraoperatively. In testing this concern more formally, we did not find any correlation between intraoperative HES use and the intraoperative administration of packed RBCs (r = -0.03; p = 0.64), indicating that HES was not given to patients who showed early signs of bleeding. The outcome measure studied included reoperation for bleeding. We did not examine other potentially relevant outcomes such as costs, death, or prolongation of ICU or hospital stay.

Another potential limitation of the study is the assessment of exposures and outcomes. We used a well-defined time interval for the measurement of HES use in the operating room only, which is where most HES is used at the study institution. No postoperative HES use was considered in the analysis presented. However, HES use after the exposure window was not different between cases and control subjects (p = 0.31), again suggesting that HES was not used as adjunctive therapy in patients who bled.

These findings extend the concern about the potential relationship between HES use and postoperative bleeding, and underscore the need for a double-blind, randomized, controlled trial to clarify this issue.


   Acknowledgements
 
The authors wish to express their gratitude to Ms. Sharon Hawley for her excellent research assistance.


   Footnotes
 
Abbreviations: ACT = activated clotting time; CABG = coronary artery bypass graft; CI = confidence interval; Hct = hematocrit; HES = hydroxyethyl starch; OR = odds ratio; PT = prothrombin time; PTT = partial thromboplastin time; S-Alb = serum albumin; S-Crea = serum creatinine;

Received for publication December 17, 2002. Accepted for publication February 4, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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