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Does Hetastarch cause acute kidney injury in dogs? | VETgirl Veterinary CE Podcasts

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In the last several years, the debate over the use of hydroxyethyl starch (HES) solutions in veterinary medicine has intensified. In human patients, HES products now have a boxed warning recommending against their use in critically ill patients, based on evidence that they contribute to coagulopathy, acute kidney injury (AKI), and increased risk of mortality.1 In veterinary patients, no studies of AKI or outcome in clinical patients receiving HES have been performed. So, Hayes et al out of Ontario Veterinary College set out to determine if HES administration was associated with outcome or AKI in canine ICU patients in a study called “Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010).” Because many of these patients would already be considered critically ill based on their admission to the ICU, a retrospective cohort study was designed with an illness severity measure included.

In order to perform the study, the authors looked for canine patients admitted to their ICU from 2007-2010, and divided them into two groups: a group that received HES, and a randomly selected sample group that did not. Both groups had data collected regarding outcome, illness severity scoring (APPLEfast), and whether new onset AKI developed, which they defined as a ≥2x increase in admission creatinine or development of oliguria/anuria < 0.5 ml/kg/hr for ≥12 hours. When they compared these two groups, they identified 180 dogs in the HES group, and 242 in the non-HES group. The HES group patients were “sicker” overall, with greater illness severity scores (p<0.001), lower albumin concentration at admission (p<0.001) and longer ICU stays (p<0.001). They were also more commonly surgical patients, trauma patients, or patient with sepsis.

While the HES patients received more crystalloid fluids overall, there was no difference in median hourly crystalloid fluid rates between the groups. The HES patients received more blood products (p=0.002). For all patients, mortality was 28% (120 dogs) with most of them euthanized due to severity of illness (80 dogs), terminal diagnosis (20 dogs) or financial constraints (2 dogs). 18 dogs died of cardiorespiratory arrest. For all patients, the incidence of AKI was 3.6% (n=15): 11 in the HES group, and 4 in the non-HES group (p=0.017). Of these 15 dogs, 8 died or were euthanized and 7 survived to hospital discharge.

While a number of statistics were performed using univariate analysis to compare the groups, the important results here come from the multivariate analysis, since the patients in the HES group were “sicker” than the non-HES patients to start and thus predisposed to development of AKI or worse outcomes. For the multivariate analysis: After controlling for illness severity scores, emergency surgery classification and administration of blood products, patients in the HES group were still more likely to have adverse outcomes (death or AKI) (Odds Ratio 1.98, p-0.005). The authors note that this Odds Ratio is equivalent to a number needed to harm of 6, meaning that if 6 patients are treated with HES, one will have an adverse outcome.

In evaluating the dose relationship of HES and outcome, higher per kilogram doses of HES were also associated with increased risk of death or AKI (Odds Ratio 12.15, p<0.001). This study is pretty exciting in the veterinary world because it is the first study involving clinical patients that suggests that AKI may actually occur in our patients receiving HES products. The authors state that their findings were twofold: 1) HES administration is an independent risk factor for in-hospital adverse events (AKI, death) in critically ill canine patients, and 2) a dose-related relationship was noted, with higher doses per kg per hr associated with increased risk.

While the mechanisms of HES-induced AKI aren’t completely understood, possible explanations include the idea that the colloid particles are broken down into lysosomes, which sit in the proximal tubule of the kidney and contribute to tubular cell swelling and interstitial inflammation. Renal filtration pressure is also decreased by the oncotic force of HES. In terms of study design, the authors mention a couple of important points to be aware of: first, a “composite outcome” was used to evaluate outcomes, which included both development of AKI and death; second, illness severity scoring was used to adjust for differences in patient populations, since sicker patients may be more likely to develop organ dysfunction or die independent from HES use. Incidence of coagulopathy or clinical bleeding was not evaluated in this study.

Patients in this study received HES via either bolus dosing or CRI, with the majority receiving a CRI (73%). CRI administration of HES is fairly common in veterinary medicine, and may be associated with increased risk due to increased tissue uptake and limited renal elimination. The HES product used in this study (10% 250/0.5) is Pentaspana, and has a higher molecular weight and a higher degree of molecular substitution than some of the other commonly used HES products, so the authors are unable to speculate if their results apply to all HES products. That being said, they do note that in human critical care, there is no “safe” HES product.

This study is big in the veterinary critical care world, and it will be interesting to see how it affects future use of HES products. While the study was well-designed and has a fair number of patients for a veterinary study, major issues with it include the differences in baseline characteristics of the two populations: the patients receiving HES were “sicker” with worse illness severity scores, and more likely to have sepsis, both of which predispose them to AKI and worse outcomes. Although the authors tried to account for these differences, an ideal study would involve two similar populations at baseline.

The number needed to harm results, suggesting that if six patients are administered HES, one will have an adverse outcome, seem extreme, as does the conclusion that for every 1 ml/kg/hr increase in HES dosing, the odds of an adverse outcome increase 12-fold. These results need to be verified through further studies.

This study suggests that critically ill dogs treated in an ICU setting are at increased risk of adverse outcomes including acute kidney injury and death if they receive HES products. This retrospective study suggests that the use of HES is associated with an increased risk of both AKI and death in dogs treated in an ICU. If you are treating patients in your ICU who are critically ill, avoiding HES as a type of fluid therapy may be recommended.

References:
1. Glover P, Rudloff E, Kirby R. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits and uses. JVECC 2014;24(6):642-661.
2. Hayes G, Benedicenti L, Mathews K. Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010). JVECC 2015;00 (0):1-6.

Footnotes:
a. Pentaspan, Bristol-Myers Squibb, Montreal, QU, Canada.

Abbreviations:
AKI: acute kidney injury
HES: hydroxyethyl starch

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