Background

Several case reports and clinical lore have suggested that exposure to the colloid hydroxyethyl starch may impair renal function, but few studies have systematically addressed this issue, and several have produced conflicting results. We sought to study the question in a formal analysis of postoperative change in renal function in patients undergoing coronary artery bypass graft (CABG) surgery.

Methods

We identified 238 consecutive patients who underwent CABG surgery at a large academic medical center. Glomerular filtration rate (GFR) was estimated using the Cockroft-Gault formula at baseline as well as on postoperative days 3 and 5. Linear regression analysis was used to study the relation between changes in GFR and intraoperative hydroxyethyl starch administration. Multivariate models controlled for potential demographic, clinical, and surgery-related confounders.

Results

Hydroxyethyl starch use was independently associated with a reduction in GFR on both postoperative days 3 and 5, with GFR declining by 7.2 mL/min/1.73 m² on day 3 per unit of hydroxyethyl starch administered (95% CI, 1.7 to 12.7; P = 0.012), and by 6.6 mL/min/1.73 m² on day 5 (95% CI, 1.2 to 11.9; P = 0.018).

Conclusion

Intraoperative use of hydroxyethyl starch may be associated with modest impairment in renal function in patients undergoing CABG surgery. Randomized clinical trials will be necessary to confirm these findings and to further investigate their clinical implications.

METHODS

We reviewed the medical records of 238 consecutive patients who underwent CABG surgery at a large teaching hospital over 1 year. Those who underwent valvular repair or replacement during the same surgical session were not considered. An experienced medical chart abstractor extracted the following demographic and clinical covariates: age, gender, body surface area, type of admission (elective vs. nonelective), and preoperative measures (serum albumin level, creatinine, blood urea nitrogen, and use of catecholamines or an intra-aortic balloon pump). We also assessed information about the procedure itself (extracorporeal bypass time, lowest blood temperature during surgery, and use and dose of intraoperative albumin or hydroxyethyl starch). Only a single hydroxyethyl starch preparation was used at this institution during the study period (molecular weight, 670 kD; molar substitution, 0.75). One unit of hydroxyethyl starch contained 500 mL. We then assessed serum creatinine on postoperative days 3 and 5 and applied the Cockroft-Gault formula to estimate glomerular filtration rate (GFR) prior to surgery, as well as on postoperative days 3 and 5.¹³ From this information, we calculated two outcomes measures: (1) the differences between estimated GFR at baseline and on day 3 after surgery, and (2) between baseline and postoperative day 5, respectively.

As both of these measures were normally distributed, we initially used simple linear regression to test for crude relationships between each difference measure and intraoperative hydroxyethyl starch use as well as the other covariates. Multivariate linear regression was then used to evaluate a possible association between intraoperative hydroxyethyl starch use and difference in GFR while controlling for other potential confounders. All independent covariates were included in the final models without a fixed significance threshold. Statistical tests were two-sided and outcomes were regarded as significant at P < 0.05. All statistical analyses used the SAS for UNIX software, version 8.1 (The SAS Institute, Inc., Cary, NC, USA). The study was approved by the Institutional Review Board of the Brigham and Women's Hospital.

RESULTS

Of the 238 consecutive CABG patients initially identified, important covariate information was missing in 29, leaving 209 patients for analysis. Only one patient died in the hospital, 17 days after surgery. During their procedures, 114 patients were not exposed to hydroxyethyl starch, and 95 were, receiving a mean 1.3 units of hydroxyethyl starch (SD, 0.52). Baseline covariate information for the groups exposed and not exposed to hydroxyethyl starch can be found in Table 1. On postoperative days 3 and 5, the GFR estimates among patients who did not receive any hydroxyethyl starch were 90.0 mL/min/1.73 m² (SD 45.9) and 86.9 mL/min/1.73 m² (SD 49.6), respectively. Univariate analyses indicated that patients who received any dose of hydroxyethyl starch during surgery had a greater body surface area (P = 0.014), longer intraoperative bypass time (P = 0.014), and were more likely to be male (P = 0.036) compared to those patients who were not exposed to hydroxyethyl starch.

Table 1 - Characteristics of the study population.

Full table

Multivariate analyses revealed that intraoperative exposure to hydroxyethyl starch was associated with a decline in renal function from baseline after controlling for all available potential confounders. By postoperative day 3, estimated GFR declined by a mean 7.2 mL/min/1.73 m² per unit of hydroxyethyl starch administered (95% CI, 1.7 to 12.7) Figure 1. By postoperative day 5, estimated GFR was 6.6 mL/min/1.73 m² lower than baseline per unit administered (95% CI, 1.2 to 11.9).

Figure 1.

Difference in estimated glomerular filtration rate [per 500 mL of hydroxyethyl starch received (in mL/min/m²)]. From multivariate linear regression models controlling for age, gender, mode of admission, baseline albumin, baseline estimated glomerular filtration rate, body surface area, preoperative catecholamines, intraoperative bypass time, lowest intraoperative temperature.

Full figure and legend (11K)

We next sought to determine whether any factors put patients at particular risk of experiencing this outcome after hydroxyethyl starch use and tested for effect modification by several covariates, including age, baseline GFR, and intraoperative bypass time. None of the interaction terms were found to be statistically significant.

DISCUSSION

In this study of 238 consecutive patients undergoing CABG surgery, we found that intraoperative use of hydroxyethyl starch was associated with a modest decline in renal function at days 3 and 5 after surgery, with estimated GFR declining by 7.2 mL/min/1.73 m² per unit hydroxyethyl starch applied by day 3 and by 6.6 mL/min/1.73 m² by day 5. These findings were based on models that controlled for a large number of patient characteristics and descriptors of the duration and severity of the surgical procedure. Therefore, the estimated average loss of renal function after exposure to 2 units of hydroxyethyl starch is approximately 14 mL/min/1.73 m². To put the magnitude of these results into perspective, this was twice as large as the difference in creatinine clearance found after 6 years of enalapril vs. placebo exposure in normotensive and normoalbuminuric patients with type 2 diabetes (3.6 mL/min)¹⁴. Similarly, the difference in decline in GFR between patients with insulin-dependent diabetes and diabetic nephropathy receiving enalapril vs. metoprolol after 2 years of treatment was <5 mL/min¹⁵. These and similar studies have been used for generally accepted treatment recommendations and quality assurance programs designed to reduce even mild degrees of renal impairment¹⁶.

The present study has certain limitations. While we controlled for information on several important patient characteristics and indicators of invasiveness or complexity of the surgical procedure, we cannot exclude the possibility that other confounding factors might have remained unobserved or incompletely controlled, and therefore were not accounted for adequately in our analyses. Such a factor would need to be an early indicator or cause of postoperative renal damage that would also make anethesiologists more likely to administer patients hydroxyethyl starch. In addition, these data do not address whether the observed decline in renal function is temporary or irreversible, or if there are any morphologic correlates of the functional impairment. If the short-term effects on renal function reported here are replicated in long-term follow-up, it will be essential to also evaluate the long-term consequences of hydroxyethyl starch therapy on other domains of morbidity and on cost. Finally, the study did not have sufficient power to evaluate clinical factors that might modify the association between hydroxyethyl starch exposure and renal function.

The present study adds to the scarce information available regarding the possible detrimental effect of hydroxyethyl starch use and renal function. While there have been several case reports that attributed functional or morphologic damage to this agent^3,4,5,6, few systematic studies have been available thus far. In a research letter to Lancet, Legendre⁷ reported an association between hydroxyethyl starch exposure of organ donors and osmotic nephrosis-like lesions in the transplant recipients. They retrospectively compared 90 patients from a single institution, but for two distinct time periods: one before hydroxyethyl starch was made available for use in France and a subsequent period where hydroxyethyl starch was widely used. The appearance of osmotic nephrosis-like lesions was observed more frequently during the latter time period (80% vs. 14%; P < 0.01). Similar histologic findings were reported after aggressive isovolemic hemodilution with hydroxyethyl starch in anaesthetized dogs¹². Cittanova et al⁸ later investigated prospectively whether hydroxyethyl starch use in brain-dead kidney transplant donors was a determinant of renal function in the organ recipient after transplantation. Twenty-seven kidney donors were randomized to either a hydroxyethyl starch gelatin regimen for fluid management, or to a gelatin-only regimen. A significantly higher proportion of kidney recipients in the hydroxyethyl starch group required hemodialysis or hemodiafiltration in the first 8 days after transplantation compared to the gelatin group (33% vs. 5%; P = 0.029). In addition, at 10 days after transplantation, serum creatinine concentrations were significantly higher in recipients of kidneys of donors randomized to the hydroxyethyl starch group compared to the gelatin group (312 mol/L vs. 145 mol/L; P = 0.009). However, Deman, Peeters, and Sennesael⁹ failed to confirm these findings in a retrospective, multicenter analysis of kidney transplant recipients that used delayed graft function as the main outcome measure. They did find that mean posttransplant serum creatinine concentrations were higher in one of the hydroxyethyl starch groups (molecular weight in kilodalton/degree of substitution) (200/0.5) compared to the control group as well as to a second hydroxyethyl starch group (450/0.7). By 14 days posttransplantation, no difference was observed among the three groups. These findings did not appear to make use of multivariate analysis, and so provide only limited evidence.

Kumle at al¹⁰ evaluated the effects of three different intravascular volume replacement regimens on renal function in 60 patients undergoing major abdominal surgery: two hydroxyethyl starch preparations (70/0.5 and 200/0.5) and modified gelatin. Creatinine clearance appears not to have differed among the three regimens over the 3-day period of observation. Unfortunately, data were not presented beyond this brief period, and no test statistics were provided for the other functional indicators studied (N-acetyl--glucosaminidase, ₁-microglobulin, and fractional sodium excretion). The small sample size would have yielded only limited power to detect any meaningful differences in outcomes.

Schortgen et al¹¹ conducted a randomized multicenter study comparing the effects of hydroxyethyl starch (200/0.66) and fluid-modified gelatin on renal function in 129 patients with severe sepsis. They found that the frequency of acute renal failure (42% vs. 23%; P = 0.028) and oliguria (56% vs. 37%; P = 0.025) as well as peak serum creatinine concentration (225 mol/L vs. 169 mol/L; P = 0.04) were higher in the hydroxyethyl starch group than in the gelatin group. However, this study was followed by considerable criticism. Serum creatinines were higher in the hydroxyethyl starch group at baseline, and critics argued that this chance difference should have been accounted for in the data analysis^17,18,19,20.

The present study is the largest to date to evaluate a possible association between hydroxyethyl starch exposure and renal function. Our analysis of a cohort of patients undergoing a frequently performed surgical procedure suggests that exposure to hydroxyethyl starch may be associated with a decrement in renal function independent of renal functional status at baseline. This study points toward opportunities for future research with important clinical implications. It seems necessary to conduct a sufficiently large randomized controlled trial to confirm these findings, to describe long-term effects, and to identify patients who are particularly susceptible to this potentially important side effect of hydroxyethyl starch use.

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