Synthetic colloids: Useful tool or potential harm?

By Courtney Peck, DVM
www.angell.org/emergency
emergency@angell.org
781-902-8400

MSPCA-Angell West, Waltham

Veterinary medicine has historically looked to our human counterparts for procedures and therapy to improve patient care and outcomes. As veterinary medicine evolves, we often adopt drugs and treatment strategies based on human clinical trials. As in human medicine, intravenous fluid use remains a cornerstone in veterinary patient therapy, for a multitude of disease processes and stabilization techniques. There are currently many options available for fluid resuscitation, ranging from isotonic crystalloid solutions to natural colloids to artificial colloids. Artificial colloids have recently received significant criticism in human medicine, prompting the veterinary community to reevaluate our use of these products.

Colloid solutions contain high molecular weight (MW) particles, which affect the plasma colloid oncotic pressure (COP) and retain fluid within the intravascular space; they can be further classified as natural or synthetic solutions. Natural colloids include blood products (plasma, whole blood) and albumin solutions. Synthetic colloids include hydroxyethyl starch (HES) solutions as well as the less commonly used dextrans or gelatins. Tetrastarch solutions, such as Voluven, Vetstarch, and Tetraspan, are the most recently developed and are considered late generation HES solutions.

Artificial colloids were created as an alternate resuscitation fluid to albumin. Clinical use of HES solutions in humans first emerged in the 1970s; they are still the most commonly used synthetic colloid in human and veterinary patients in the United States. The first review articles evaluating the use of artificial colloids in veterinary medicine appeared in the early 1980s. Over the following decade, HES use became an integral part of modern fluid therapy. HES solutions consist of a mixture of heterogeneously sized modified natural polysaccharides, derived from amylopectin obtained from potatoes or waxy maize. Substitution of hydroxyethyl groups for hydroxyl groups alters the base polysaccharide and leads to an increased solubility and reduced rate of hydrolysis by serum amylase.

Colloids remain within the intravascular space for several hours, as opposed to most crystalloid solutions which extravasate after only 30 to 60 minutes. A revised Starling model emphasizes the importance of the glycocalyx, a web of membrane-bound glycoproteins and proteoglycans which covers the entire endothelial surface. It is the COP difference across the glycocalyx that opposes fluid exit and maintains vascular integrity. However, this only occurs in vivo with an intact glycocalyx layer, which may be destroyed in conditions leading to a systemic inflammatory response syndrome (trauma, surgery, severe illness, sepsis, hypervolemia). HES is likely superior to crystalloids in conditions where the glycocalyx remains intact (such as hypovolemia), but the volume expanding effects of HES may be lost when the glycocalyx is damaged.

Both natural and synthetic colloids contain large molecules that cannot cross an intact vascular barrier. This confers the appealing theoretical benefit of a volume-sparing effect with a decreased risk of inducing a positive fluid balance with secondary adverse effects (such as heart failure, pulmonary edema, peripheral edema). Despite their initial promise, multiple adverse effects as well as lack of a survival benefit have recently caused colloid therapy to fall out of favor in human medicine. Significant debate surrounds the safety of HES solutions with the most recent clinical data prompting the ban of their use in Europe and guidelines recommending against their use in certain patient populations.

The most significant adverse effects reported with synthetic colloids in humans are coagulation disorders, acute kidney injury (AKI), and increased mortality. Other documented complications include pruritis, tissue accumulation, reticuloendothelial dysfunction, hepatopathies, and anaphylactic reactions. Reports on the effects of HES in veterinary medicine are scarce and have mostly evaluated the effect of HES on hemodynamics, COP and coagulation in dogs.

The mechanism of HES-associated coagulopathy is not completely understood, but appears to be dose dependent and mediated by direct effects on the coagulation system. Use of HES leads to platelet dysfunction, reduced von Willebrand factor/ factor VIII complex activity, and an acquired fibrinogen deficiency or dysfunction, all of which lead to decreased clot strength. Dilution of clotting factors and platelets leading to a dilutional coagulopathy may also play a role. No studies have yet evaluated the potential effects of HES products on coagulation in cats; current data suggests that all HES products potentially affect coagulation. The risk of increased bleeding must be considered when using these products, especially in patients with underlying bleeding disorders.

Acute kidney injury is another common side effect associated with HES use. Many human studies have revealed an increased risk of AKI and need for renal replacement therapy (hemodialysis) in critically ill, septic or hypovolemic patients that received synthetic colloids. While all classes of synthetic colloids have been associated with renal injury, HES solutions are most frequently cited. Renal HES storage, called osmotic nephrosis, primarily affects the proximal tubular cells. Changes can last for years, but tend to be reversible and recovery takes place once HES therapy has been stopped. Studies investigating potential renal effects of HES in small animals are lacking.

Conflicting human data exists regarding the effects of HES on mortality; there are currently no data evaluating outcome in veterinary patients. A Cochrane meta-analysis on the effectiveness and safety of colloids versus crystalloids in critically ill humans concluded that “there is no evidence from randomized controlled trials that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery”. In 2012 the Surviving Sepsis Campaign advised against the use of HES for fluid resuscitation of severe sepsis and septic shock.

Current human recommendations state that HES should not be used in septic, burn and critically ill patients due to an increased risk of AKI and mortality, and because no clear benefit has been demonstrated with their use. HES use is approved in acute hypovolemia due to acute blood loss, but only for a 24 hour period, at the lowest dose possible, for the shortest duration possible, and renal function should be monitored for up to 90 days. Additional contraindications for HES use include severe coagulopathies and impaired kidney function.

The Association of Veterinary Anesthetists issued an advisory notice in 2013 stating that HES can still be used in veterinary patients, but recommends cautious decision making be used regarding its administration. Currently, no other official organization has provided recommendations for use of HES in veterinary patients. The FDA has not determined the safety or efficacy of HES products in veterinary patients; thus use of these products is considered unapproved.

Veterinarians should consider data and recommendations for the use of HES in humans when considering the use of HES in veterinary patients. No study has been conducted to establish safe daily doses for dogs and cats; previous recommendations were based on extrapolation from human studies. Additionally, dogs and cats may not respond in the same manner as people when treated with HES, leading to disparate side effects. Currently, we do not have sufficient data to establish evidence-based guidelines for HES use in our patients.

Currently, the main indications for HES use in veterinary medicine include perioperative fluid therapy, absolute or relative hypovolemia, nonresponse to crystalloids, hypoalbuminemia, and decreased COP. Veterinarians should carefully consider options when selecting fluids for small animals, especially those at high risk of adverse effects associated with HES use such as those with renal compromise, SIRS/sepsis, or coagulopathies. The lack of readily available alternatives (species-specific albumin and blood products) when crystalloids are not effective provides an argument for the continued use of HES in small animals. HES remains the best option in veterinary medicine for patients with acute hypoalbuminemia when blood products are unavailable. HES may also be safer than albumin in veterinary medicine as long as species-specific albumin is unavailable. Given the potential risks associated with use of HES, earlier use of vasopressors and inotrope therapy in the treatment of circulatory failure once initial fluid resuscitation has failed appears prudent.

For more information about Angell’s Emergency/Critical Care service, please visit www.angell.org/emergency or call MSPCA-Angell West in Waltham at 781-902-8400.

References:

Adamik, KN, Yozova ID and Regenscheit N. Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care. JVECC 2015; 25(1): 20-47.

Cazzolli D and Prittie J. The crystalloid-colloid debate: Consequences of resuscitation fluid selection in veterinary critical care. JVECC 2015; 25(1): 6-19.