Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care.

State of the Art Review

Journal of Veterinary Emergency and Critical Care 25(1) 2015, pp 20–47 doi: 10.1111/vec.12283

Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care Katja N. Adamik, Dr vet med, DACVECC; Ivayla D. Yozova and Nadine Regenscheit, Dr med vet

Abstract

Objectives – To (1) review the development and medical applications of hydroxyethyl starch (HES) solutions with particular emphasis on its physiochemical properties; (2) critically appraise the available evidence in human and veterinary medicine, and (3) evaluate the potential risks and benefits associated with their use in critically ill small animals. Data Sources – Human and veterinary original research articles, scientific reviews, and textbook sources from 1950 to the present. Human Data Synthesis – HES solutions have been used extensively in people for over 30 years and ever since its introduction there has been a great deal of debate over its safety and efficacy. Recently, results of seminal trials and meta-analyses showing increased risks related to kidney dysfunction and mortality in septic and critically ill patients, have led to the restriction of HES use in these patient populations by European regulatory authorities. Although the initial ban on the use of HES in Europe has been eased, proof regarding the benefits and safety profile of HES in trauma and surgical patient populations has been requested by these same European regulatory authorities. Veterinary Data Synthesis – The veterinary literature is limited mostly to experimental studies and clinical investigations with small populations of patients with short-term end points and there is insufficient evidence to generate recommendations. Conclusions – Currently, there are no consensus recommendations regarding the use of HES in veterinary medicine. Veterinarians and institutions affected by the HES restrictions have had to critically reassess the risks and benefits related to HES usage based on the available information and sometimes adapt their procedures and policies based on their reassessment. Meanwhile, large, prospective, randomized veterinary studies evaluating HES use are needed to achieve relevant levels of evidence to enable formulation of specific veterinary guidelines. (J Vet Emerg Crit Care 2015; 25(1): 20–47) doi: 10.1111/vec.12283 Keywords: colloids, hypovolemia, safety, sepsis, side effects

Abbreviations

AKI AVA aPTT

acute kidney injury Association of Veterinary Anesthetists activated partial thromboplastin time

From the Department of Veterinary Clinical Medicine, Division of Small Animal Emergency and Critical Care (Adamik, Yozova), Department of Infectious Diseases and Pathobiology, Institute of Animal Pathology (Regenscheit), Vetsuisse Faculty, University of Bern, Bern Switzerland. The authors declare no conflict of interest. Address correspondence and reprint requests to Dr. Katja-Nicole Adamik, Department of Veterinary Clinical Medicine, Division of Small Animal Emergency and Critical Care, Vetsuisse Faculty, University of Bern, Länggassstrasse 124, 3012 Bern, Switzerland. Email: [email protected] Submitted May 13, 2014; Accepted August 14, 2014.

20

COP EMA ESL FDA GPIIbIIIa HES HTS LRS Mw MS PVP PT RCT RRT PRAC

colloid osmotic pressure European Medicines Agency endothelial surface layer Food and Drug Administration glycoprotein receptor GIIbIIIa hydroxyethyl starch hypertonic saline lactated Ringer’s solution molecular weight molar substitution polyvinyl pyrrolidone prothrombin time randomized clinical trials renal replacement therapy Pharmacovigilance Risk Assessment Committee C Veterinary Emergency and Critical Care Society 2015

Hydroxyethyl starch controversies small animals

SIRS vWf

systemic inflammatory response syndrome von Willebrand factor

use in critically ill small animals. Considerations for the use of HES products in veterinary medicine will be discussed based on the newest recommendations limiting the use of HES in human medicine.

Introduction Fluid therapy plays an important role in veterinary medicine in the treatment of dehydration, and in providing volume support during anesthesia and hypovolemic states. Both crystalloids and synthetic colloids are widely used and there are a number of guidelines for fluid resuscitation that have been published.1–4 There are also a number of review articles on the use of artificial colloids in veterinary medicine,5–11 with the first appearing in 1982.5 Hydroxyethyl starch (HES) was then recommended in particular for its long-lasting volume effect.5 In a second review published in 1992, hetastarch was described as “an extremely safe colloid for acute and longterm use” with equal or better ability to increase colloid osmotic pressure (COP) and plasma volume than dextran 70, 5% albumin, plasma, or whole blood.10 During the subsequent years, the use of HES evolved to become an integral part of modern fluid therapy in veterinary medicine.11–14 The recommendations for dosages, indications, and safety guidelines were, at least in part, based on studies and guidelines in people and animal experimental studies.3,6–9,11,15–17 Until recently, HES was the most widely used artificial colloid in human intensive care units throughout the world and was considered the fluid of choice for resuscitation, especially in Europe.18,19 However, evidence from recent large randomized clinical trials (RCTs), systematic reviews, and meta-analyses suggests a number of harmful effects. Of these, increased risk of renal dysfunction and mortality are the most serious.20–25 Reports on the effects of HES in veterinary medicine are sparse and have mainly focused on the effect of HES on hemodynamics,26–29 COP,30–32 and coagulation in dogs.33–42,a In addition, one retrospective report evaluated the efficacy and adverse effects of HES in a small number of cats.43 However, studies investigating potential renal effects of HES in small animals are lacking. Moreover, no study has been conducted to establish safe daily doses for dogs and cats. Although the controversy surrounding the safety of these products in people has now reached the realm of veterinary medicine, we do not currently have sufficient data to establish evidence-based guidelines for dogs and cats. The purposes of this article are to offer a historical review of the development and medical applications of HES products with particular emphasis on their physicochemical properties, to critically appraise the available evidence in human and veterinary medicine and to evaluate the potential risks and benefits associated with their C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283

Historical Background of Colloids and HES Solutions The development of different plasma substitutes, the artificial colloids, began at the beginning of the 20th century in a search for more effective intravenous fluids than saline.44,45 The first plasma volume substitute tested was gum Arabic, a natural colloid polysaccharide from the Acacia senegalis tree. After its successful experimental use in dogs in 1906,44 it was clinically applied in people during World War I,46 but its use was stopped after adverse effects, including liver toxicity, and antigenic and pyrogenic reactions, became apparent.45 At the same time, (native) gelatin was first infused in wounded soldiers during World War I and the use of gelatins was again studied during World War II.47 However, there were difficulties with preparation and handling, solutions became solid in the cold and degraded on heating. The first synthetic colloid introduced was polyvinyl pyrrolidone (PVP), developed by a German chemist in 1939.48 Under the trade names Periston and Kollidon, PVP was clinically used during World War II in 1943, and nearly 1 million PVP infusions were administered in total.48–51 However, PVP resulted in long-term storage of the larger (>25 kDa) nondegradable molecules within the reticuloendothelial system, liver, and kidney, and was subsequently withdrawn from the market in the early 1960s.52 Later progress in the development of plasma expanders was marked by the introduction of dextrans, modified gelatin products, and HES.44 Dextran is a macromolecular polysaccharide produced from lactic-acid bacterial fermentation of sucrose. It was introduced to the market in Sweden in 194453 and was approved by the U.S. Food and Drug Administration (FDA) in 1952.45 Dextrans are neutral, high-molecular weight (Mw ) glucopolysaccharides (up to several million Daltons), which require hydrolysis into lower Mw between 40 and 70 kDa, suitable for intravenous infusion.44,45 The advantages of dextrans include their low manufacturing costs and long shelf life. Major adverse effects include anaphylactic reactions,54,55 osmotic kidney failure with hypertonic dextran preparations,56 and impaired coagulation. Allergic reactions to dextrans are the result of naturally occurring dextran-reactive antibodies, causing a type III or immune complex reaction.55 The risk of severe dextran-induced anaphylactoid reactions can be reduced by prior administration of a monovalent hapten dextran, 21

K. N. Adamik et al.

which is thought to bind dextran-reactive antibodies and form inactive complexes.57 Acute kidney injury (AKI) has most often been reported following administration of 10% dextran 40 solutions, and most published case reports suggest contributing factors, such as age, repeated infusion of large quantities, and arteritis.58 Hemostatic abnormalities are related to a decrease in vWf/FVIII-complex, weaker clot strength, and platelet dysfunction.59 The latter is also considered a desired effect, in addition to volume replacement, for perioperative thrombosis and thromboembolism prophylaxis.60–62 In dogs, dextran and hypertonic dextran have been studied in septic shock secondary to pyometra,63 hypovolemic shock secondary to hemorrhagic shock,64,65 and gastric dilatation voluvlus,66,67 and also in investigations of their cardiovascular efficacy29,68,69 and effects on hemostasis.70,71 However, dextrans have been withdrawn from the market in a number of countries due to their adverse effects as described above.45 Modern gelatin products are derived from the degradation of bovine collagen with subsequent chemical modifications as native gelatin is only soluble at temperatures above 50 °C.45 Denaturation and hydrolysation of collagens produce polypeptide fractions that are crosslinked using different additives. Available gelatin preparations include oxypolygelatin, polygelin, or gelatin polysuccinate. Like dextran, gelatin is inexpensive and has a long shelf life. However, the low mean Mw (30–40 kDa) results in rapid renal excretion and the volume expanding effect of 70–80% is very short lived (2–3 hours). Only rare reports on the use of gelatins in dogs and no reports in cats have been published.71,72 Adverse effects reported in people include increased diuresis, AKI, and increased blood viscosity.44,45,73 Moreover, a high rate of anaphylactic reactions compared to dextran and HES are reported.45 HES was first investigated in experimental animals as a new plasma substitute in 1957 under the name oxyethyl starch, and was subsequently used extensively to treat wounded soldiers during the Vietnam War.45,74,75 The first HES product was approved in 1972 in Germany, Japan, and the United States and was a waxy maizederived hetastarch (6% HES 450/0.7).74,76,77 At that time, it was believed that prolonged intravascular retention associated with a high Mw would benefit both efficacy and safety.78 Since then, further generations of HES were developed with lower Mw and molar substitutions (MS) with the aim of improved pharmacokinetics and reduction of adverse effects.77 In Europe, the second generation waxy maize-derived HES (HES 200/0.5) was approved on the market in Germany in 1983 but was not licensed in the United States. Between 1999 and 2000, HES 130/0.4 received approval in many European countries and in the United States in 2007. Promoted for its many 22

pharmacochemical improvements, especially decreased tissue accumulation and limited effects on coagulation and the inflammatory response, this represented a landmark in the development of artificial colloids with more than 30 million patients treated with the product.79,80

The Rise and Fall of HES Although colloids are more expensive than crystalloids and potentially harmful, until recently they were widely used as a first choice fluid for resuscitation.18 Indeed, according to an international survey of preferred plasma expanders carried out in 2004, HES was used in 58%, gelatins in 35%, dextran in 4% of patients overall,19 with variations in the choice of fluid being more dependent on country and local practices rather than patient characteristics.18 Several factors helped secure the wide spread use of HES. First, early HES products were designed in the early 1970s, before the drug licensing laws in Germany became active in 1978. During this period, drugs in Germany were merely registered without any requirement for thorough efficacy, safety, and quality testing. As subsequent generations of HES products were regarded as minor innovations of previously existing products, they were approved for marketing based on previous registrations attained prior to 1978 and small bridging studies, but no pivotal phase III studies were performed.80 This approach was widely accepted throughout Europe. Furthermore, manufacturing companies have very actively promoted the use of HES products over the last 30 years, justifying their clinical safety and efficacy by the results of several prominent studies and widespread ongoing use, and by subsidizing further studies to maintain a high degree of medical evidence in favor of their use.80–82 Since the 1970s, a flood of studies comparing crystalloids to HES, including RCTs, have been published.83 One of the most prolific authors of studies on HES and perioperative fluids was Joachim Boldt. However, in December 2010, a study by Boldt and his colleagues on cardiopulmonary bypass priming using high dose HES84 was retracted due to failure to acquire ethical approval from the institutional review board and fabrication of data.84–86 This was followed by an investigation of all of Boldt’s previous research publications, culminating in March 2011 with a statement of the editors-in-chief of 16 different medical journals retracting 88 of 102 publications by Boldt since 1999 due to unethical research practices.87 The scandalous retraction of these papers destabilized the body of evidence as to the benefits and safety of HES, and led to the temporary withdrawal and revision of the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients.88 C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283

Scandinavian Starch for Severe Sepsis/Septic Shock Crystalloid versus Hydroxyethyl Starch Trial Colloids versus Crystalloids for the Resuscitation of the Critically Ill

6S23 (2012)

C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283

Crystalloids Morbidity Associated with severe Sepsis

Fluids in Resuscitation of Severe Trauma

Volume Substitution and Insulin Therapy in Severe Sepsis

CRYSTMAS89 (2012)

FIRST217 (2011)

VISEP21 (2008)

CRISTAL219 (2013)

CHEST22 (2012)

Full name of trial/ study group

Study abbreviation (year)

Effects of fluid resuscitation with colloids versus crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 versus 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (fluids in resuscitation of severe trauma). Intensive insulin therapy and pentastarch resuscitation in severe sepsis.

Hydroxyethyl starch or saline for fluid resuscitation in intensive care.

Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis.

Title of main publication

Table 1: Overview of the most important HES studies (alphabetical order)

10% HES 200/0.5

6% HES 130/0.4

6% HES 130/0.4

HES, gelatins, dextrans, 4% albumin, 20% albumin

6% HES 130/0.4

6% HES 130/0.42

Colloid solution

Modified LRS

0.9% NaCl

0.9% NaCl

Hypertonic saline, 0.9% NaCl, LRS

0.9% NaCl

Ringer’s acetate

Comparator solution

Severe sepsis patients

Penetrating and blunt trauma patients


Hypovolemic shock patients

Intensive care patients


Study population


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Independently, a review of the safety of HES solutions was triggered by the German medicines agency, the Federal Institute for Drugs and Medical Devices, in November 2012 following publication of the results of 3 large RCTs, which found an increased risk of renal dysfunction or mortality in critically ill or septic patients who received HES products compared with crystalloids.22,23,89 These were the 6S trial,23 comparing the use of Ringer’s acetate to 6% HES 130/0.42 in 800 septic patients, the CHEST trial,22 randomizing 7,000 patients after admission to ICU to receive saline or 6% HES 130/0.4 for fluid resuscitation, and the CRYSTMAS study,89 comparing saline and HES 130/0.4 in 197 patients with severe sepsis. Meta-analyses and observational studies further supporting these findings followed.24,25,90–95 In one meta-analysis, evaluating mortality and the occurrence of AKI associated with HES administration, the authors analyzed results from RCTs and the influence of the recently retracted research articles, concluding that not only is HES not associated with decreased mortality but that, after exclusion of results from 7 nonretracted trials by Boldt et al (conducted before 1999), HES is associated with a significant risk of mortality and AKI.24 An overview of the characteristics of the most important large HES clinical trials is presented in Table 1. The review called for by the Federal Institute for Drugs and Medical Devices was carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), responsible for assessing all aspects of risk management regarding drug use in people. The PRAC published their recommendation to suspend marketing authorizations for all HES-containing fluids on the website of the European Medicines Agency (EMA) in June 2013.96 Following an appeal by HES-manufacturing companies, a second EMA-PRAC review was carried out in September 2013. This concluded that HES solutions should no longer be used to treat patients with sepsis or burn injuries or in critically ill patients because of an increased risk of AKI and mortality, findings that were endorsed on October 23rd 2013 by the Coordination Group for Mutual Recognition and Decentralized Procedures.97 In the interim, HES was completely suspended from the market by the Medicines and Healthcare products Regulatory Agency in the United Kingdom and a class 2 medicines recall was issued, calling for the return of all HES products to the manufacturers.98 In addition, the FDA placed a black-box warning on HES due to a possible increased risk of mortality and renal replacement therapy (RRT) and updated their contraindications, warnings, precautions, adverse reactions, and clinical studies section.99 The European Commission’s final decision letter, published on the EMA website in March 2014, stated that HES solutions may be used to 24

treat hypovolemia caused by acute blood loss, where treatment with crystalloids alone is not sufficient, and that to minimize potential risks, HES solutions should not be used for more than 24 hours and kidney function should be monitored. The manufacturing companies were advised to update their product information and to provide data on the use of HES for elective surgeries and trauma patients. Furthermore, HES-containing solutions were only to be considered as second choice and under consideration of the new contraindications.97,100 Current guidelines and recommendations are available on pharmacovigilance websites for most countries that have authorized the use of HES.

Chemical Characteristics of HES Solutions HES solutions are characterized based on their raw material, concentration, mean Mw , MS, ratio of C2/C6 hydroxylation, and the carrier solution.77 Examples of different available HES solutions can be found in Table 2. Two different raw materials have been used to extract amylopectin, the highly-branched starch used in HES solutions. The first products manufactured were made from waxy maize, composed of 95% amylopectin76 and, since 1992, products were also manufactured from potato-based starch, composed of 80% amylopectin and 20% amylose.76,101 Due to the differences in composition and fine structure with regards to the degree of branching, C2/C6 ratio, intrinsic viscosity, and positioning of the hydroxyethyl groups, waxy maize- and potato starch-based HES solutions are not necessarily bioequivalent and cannot be assumed to have identical properties.102 Indeed, some evidence suggests that the less branched, more viscous potato starch-based HES may compromise blood coagulation more than maizederived HES,103 although others studies found no differences regarding hemorheology and pharmacokinetics101 or in effects on blood coagulation and pulmonary, renal, and hepatic function.104 However, as most of these findings were based on in vitro studies, clinically relevant potential differences are largely unconfirmed. The percentage concentration of HES solutions mainly affects the initial immediate volume effect after administration. This is approximately 145% for 10% HES solutions compared to 100% for 6% HES solutions.105–107 However, the oncotic effect actually depends on the number of oncotically active particles and not so much the concentration per se. Thus, a product with molecules of low Mw is likely to exert greater COP at similar concentrations than products with molecules of high Mw .78,108 In contrast to albumin, HES solutions are polydisperse with a wide range of molecular sizes from dozens to thousands of kDa following a bell-shaped distribution.15,77 As such, their molecular mass is C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283


Table 2: Examples of hydroxyethyl starch solutions and their physicochemical properties

Trade name

Concentration

Mw/ MS

Starch

Carrier solution

C2/C6 ratio

COP mm Hg

Vol (%)

T1/2 (h)

Max. mL/kg/d††

Venofundin*

6%

130/0.42

Potato

0.9% saline

6:1

36

100

12

50 mL/kg

VitaHES† Tetraspan*

Balanced / buffered

Vitafusal† Tetraspan* Voluven

‡

30 mL/kg 10% 6%

130/0.40

Volulyte‡

Maize

0.9% saline

9:1

60

150

n/a

36

100

12.1

70-80

200

12.8

15-18

60

n/a

Balanced / buffered

Voluven‡

10%

Haes Steril‡

3%

Haes Steril‡

6%

30-35

100

Haes Steril‡

10%

50-60

145

30.6

Elohes‡

6%

0.9% saline 200/0.5

5:1

200/0.62

9:1

25

110

69.7

Hespan§

450/0.7

5:1

26

100

300

Hetastarch ρ

600/0.7

n/a

n/a

n/a

Hextend**

450/0.75

Balanced / buffered

HESpan††

600/0.75

0.9% saline

Hextend‡

50 ml/kg

Balanced / buffered

20 mL/kg

n/a

4:1

100

∗

B. Braun Melsungen AG, Germany; † Serumwerk Bernburg AG, Germany; ‡ Fresenius Kabi AG, Switzerland; § Du Pont Merck Pharmaceutical Company, USA; ¶ Hospira, Inc, USA; ∗∗ BioTime, Inc, USA; †† Braun Medical Inc, USA; Mw , molecular weight; MS, molar substitution; T1/2, elimination half-life; vol (%), initial volume effect in % ; n/a, not available; ‡‡ the doses are currently under review by the manufacturers and might be changed soon. The dose of Vitafusal† was changed from 50 to 30 mL/kg/day and published in the product insert 1/2014.

described as a number-averaged (Mn ) or weightaveraged (Mw ) molecular weight, the later usually given by the manufacturers in the product description (ie, HES 130 has a Mw of 130 kDa). The Mn represents the total weight of polymer divided by the number of molecules. The calculation of the Mw requires knowledge of the weight fraction of each type of molecule, and therefore takes into account that the polymers are of different sizes. The distribution of Mw in a polymer sample is often described by the Mw /Mn ratio which accounts for the degree of polydispersity of the system.15,77 These characteristics affect the ability of HES to maintain intravascular volume, the rapidity of excretion, the degree of tissue accumulation, and the effects on coagulation.77 Based on the Mw , HES products are divided into first


generation solutions with Mw > 400 kDa (ie, HES 670/0.75, HES 600/0.7, HES 450/0.7), second generation solutions with Mw of 200 to 400 kDa (ie, HES 200/0.5) and third generation solutions with Mw < 200 (ie, HES 130/0.4, HES 130/0.42).77,78,108 By increasing medium-sized molecules and decreasing both large molecules with very long half-lives and very small molecules below the renal threshold, the modern third generation starch products are characterized by a lower Mw with a narrower range (ie, HES 130/0.4) and a leptokurtic distribution curve in an attempt to reduce adverse effects and improve pharmacokinetics (Figure 1).45,109 However, the in vivo Mw differs from that of the in vitro product as the larger molecules are split by ␣-amylase and molecules smaller than the renal

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Figure 1: Molecular weight distribution in HES solutions. The abscissa determines the molecular weight in logarithmic scale in relation to the number of molecules displayed on the ordinate axis. Perpendicular lines reflect the mean molecular weights of either preparation. From: Ertmer C, Rehberg S, Van Aken H, et al. Relevance of nonalbumin colloids in intensive care medicine. Best Pract Res Clin Anaesthesiol 2009;23:193–212. With permission from Elsevier.

threshold are rapidly excreted.77 As an example, the mean in vivo Mw of HES 130/0.4 in plasma is 70–80 kDa immediately following administration.110 Interestingly, the rate of enzymatic breakdown of larger molecules depends on the MS and the ratio of C2/C6 hydroxyethylation and not merely on molecular size.78,108,111 Besides the Mw and concentration, which account for many of the effects of HES, the degree of MS and the substitution pattern (C2/C6 ratio) play a key role in the pharmacokinetics of HES products.78 Natural amylopectin is chemically modified by hydroxyethylation at the glucose subunits C2, C3, or C6 to increase solubility and inhibit degradation by ␣-amylase.77,78 The average number of hydroxyethyl residues per glucose subunit defines the MS, with higher substitution associated with delayed enzymatic degradation.107 Based on the MS, HES solutions are categorized as hetastarch (MS = 0.7), hexastarch (MS = 0.6), pentastarch (MS = 0.5), or tetrastarch (MS = 0.4).77,111 In studies comparing HES solutions with identical Mw and MS, but different C2/C6 ratios, higher plasma concentrations and a longer duration of the oncotic effect was found with higher C2/C6 ratios due to slower enzymatic degradation.112,113 Likewise, the waxy maize- and potato-derived tetrastarch products available differ in their C2/C6 ratio such that despite equal concentrations, Mw and MS, the potatoderived starch is more rapidly degraded.45,77,113 26

Due to the known risk of hyperchloremic acidosis and electrolyte derangements after high doses of nonbuffered solutions, buffered and balanced carrier solutions for HES are available in addition to traditional HES solutions in 0.9% saline. Significantly lower serum chloride concentrations and less acidosis were found after administration of balanced electrolyte and buffered carrier solutions.114,115 Because the results of studies on the effects on coagulation are inconsistent, no conclusion can currently be made.116–118 However, balanced HES resuscitation was shown to be superior in terms of improved renal perfusion.119

Physiologic Background Transcapillary fluid shifts, first described by Ernest Starling in 1896, depend on both hydrostatic and oncotic forces acting on either side of a semipermeable membrane and were described by the Starling equation.15,62,120–122 The plasma COP (␲c), which opposes fluid filtration out of the vascular space, depends largely on the concentration of albumin and, to a lesser degree, on other plasma proteins.121 The plasma hydrostatic pressure (Pc), which is the driving force for fluid filtration out of the vascular space, depends on arterial blood pressure and vascular resistance.62 The interstitial COP (␲t), which contributes to fluid filtration out of the C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283


vessel, varies between tissues depending on interstitial albumin content, with higher ␲t in the lungs compared to skeletal muscle or subcutaneous tissue.15 Based on the Starling equation, a constant outward movement of fluid occurs on the arterial side of the capillary while a slight inward movement occurs on the venous side due to differences in hydrostatic pressure.123,124 Excess interstitial fluid, which is not resorbed on the venous side, returns to the circulation via lymphatic vessels. Any imbalance between these forces or changes to the coefficient of filtration, such as occurs with hypoalbuminemia or capillary leak, result in edema formation.125 This model of transendothelial filtration and absorption driven by pressure differences has become embedded in medical literature. However, the validity of this model in describing fluid shifts across capillaries has been questioned in recent years. As a result, a revised Starling model was proposed, in which, instead of fluid filtration on one end and resorption on the other end of a capillary, fluid exit occurs over the entire length of the capillary. In this model, a COP difference exists between the intravascular space and a small, almost protein-free, subglycocalyx zone, which serves as the principal determinant of fluid flux from the vasculature. The glycocalyx is a web of membrane-bound glycoproteins and proteoglycans carrying negatively charged side chains, which covers the entire endothelial surface. Outwardly shifting proteins are bound in this filter-like structure, which becomes loaded with plasma proteins.124 This layer together with the subglycocalyx and bound proteins form the endothelial surface layer (ESL), which is the noncirculating portion of the intravascular space estimated to be about 700–1000 mL in adult humans. It is the COP difference across the glycocalyx that opposes fluid exit and maintains vascular integrity.126 Almost no absorption occurs from the interstitium into the intravascular space, even at low capillary pressures.124,125,127,128 It is important to note that this nonlinear relationship between the capillary pressure and the movement of fluid through the capillary wall is achieved only where the capillary is in its so-called steady state, adapted to low pressure. Interestingly, a linear relationship and reabsorption from the interstitium does occur when the capillary pressure is lowered abruptly (ie, acute hypovolemia) in a so-called transient state.129 The glycocalyx has a transmural vascular barrier function, anti-inflammatory properties, and impedes blood cells from direct contact with the endothelium. Based on experimental studies, inflammation, sepsis, ischemia/reperfusion, increased atrial natriuretic peptide, and diabetes are some of the conditions leading to a reduction of the endothelial glycocalyx layer, mainly through shedding of glycosaminoglycans, with resultant platelet aggregation,


leukocyte adhesion, increased vascular permeability, and edema formation.125,127,130,131 One aspect of the endothelial glycocalyx relevant to fluid therapy is that iatrogenic hypervolemia leads to degradation of this layer. During acute hypervolemia, atrial natriuretic peptide is secreted which causes rapid shedding of the glycocalyx with a subsequent increase in permeability.132 Furthermore, degradation of the glycocalyx is described due to global ischemia/reperfusion during major vascular surgery.133 The understanding of the important role of this layer and the consequences of its destruction has imposed new considerations regarding fluid therapy and volume overload. Whether HES and other synthetic colloids exert a protective role on the glycocalyx or on the contrary contributes to its destruction remains controversial.124,130,132

Crystalloids versus HES – The Rationale Behind the Debate Crystalloid solutions represent the mainstay of fluid therapy and consist of water-based solutions with various electrolytes, sugars, and buffers. Colloid solutions contain high Mw particles, which affect the plasma COP and retain fluid within the intravascular space, and can be further classified as natural or synthetic solutions. Natural colloids include blood products (ie, plasma and whole blood) and albumin solutions. Synthetic colloids include dextran, gelatin, and HES.9 Both crystalloids and synthetic colloids are widely used and recommended in different guidelines for fluid resuscitation.1–4 Claims regarding the superiority of HES over crystalloids that have been put forward in human medicine and, for the most part, adopted in veterinary medicine are as follows.

HES Exerts a Better Volume Effect Than Crystalloids As stated in textbooks134 and demonstrated in people135–137 and experimental animal studies,138–142 approximately 3 to 4 times more crystalloids than colloids are required to achieve an equivalent plasma volume expansion. In contrast to crystalloid solutions, which equilibrate rapidly between the intravascular and the interstitial fluid spaces, the large molecules of colloids may adsorb to the glycocalyx layer and restrict ultrafiltration.127 In consequence, colloids remain for several hours within the intravascular space as opposed to only 30–60 minutes for most crystalloid solutions.142 However, this only occurs in vivo with an intact glycocalyx layer,143 which may be destroyed in conditions leading to a systemic inflammatory response syndrome

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(SIRS), such as trauma, surgery, severe illness, and sepsis, as well as in hypervolemia.2,131 The true volume expanding effect in patients may therefore be very different from that expected in vitro or in healthy individuals. Indeed, recent large RCTs comparing required fluid volumes of colloids and crystalloids have shown that the crystalloid-to-colloid volume ratio was far inferior to the 3-to 4-fold difference expected, and ranged between zero (6% dextran 70 and 6% HES 200/0.5 versus 0.9% saline),144 1.2 (6% HES 130/0.4 versus 0.9% saline),89 and 1.4 (10% HES 200/0.5 versus lactated Ringer’s solution [LRS]).21 These studies were notably performed in patients with dengue shock syndrome144 and severe sepsis.21,89 In recent studies evaluating the loading effect in nonseptic preoperative patients, HES exerted 60 kD) require enzymatic degradation by the reticuloendothelial system (RES) or hydrolytic cleavage by ␣-amylase in the plasma before they can be excreted in the urine. The lysosomal enzyme acid ␣-glucosidase only slowly degrades intracellular starch deposits into glucose.

Figure 3: Pathogenesis of osmotic nephrosis and proximal tubular damage in the kidney with three possible mechanisms leading to the HES induced renal lesions. (A) HES is visible as intracellular vacuoles, interpreted as an acquired lysosomal storage disease. (B) Due to the intracellular HES retention, an oncotic gradient develops. This leads to water influx, cytoplasmatic swelling, and finally cell rupture. (C) Hypoxic kidney damage as a major determinant in the pathogenesis of osmotic nephrosis-related acute kidney injury.


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kidney disease, advanced age, hypovolemia, sepsis or septic shock, and kidney transplantation.290,292,294,301 The contribution of these predisposing factors to renal failure makes the interpretation of the different reports difficult. In a dog model of complete blood exchange with HES, renal histology revealed severe alterations of proximal tubules as dilated tubules, cytoplasmic blebs, and tubular epithelial cell necrosis, which were potentially irreversible.288 In dogs no data are available for tissue storage of tetrastarch preparations.

investigation (ie, time of skin biopsy after HES infusion) in sheep.287,295,304 To date, no reports of pruritus after HES administration in animals exist. Further investigations are needed to evaluate the effects of tissue accumulation and possible pathologic organ lesions in small animal medicine. For specific detection of HES molecules in tissues, the lesions need to be identified by light- and electron microscopy and by use of specific anti-HES antibodies.

Acute Kidney Injury Liver Storage Several studies in humans and animals describe HES associated hepatic insufficiency, although a relationship between the vacuolar storage of HES in the liver and clinical signs is unproven. In a dog model of complete blood exchange with HES, liver biopsies revealed only discrete histological lesions (sporadic necrosis), and no signs of hepatocellular lesions were seen with electron microscopy.288 Swollen and vacuolated Kupffer cells, as well as vacuolated liver parenchyma cells, were found in rodent models.286,302 Nevertheless, in rats, an immunohistochemical positive cytoplasmic HES accumulation in the sinusoidal lining of cells was seen, whereas only few of the vacuoles in the parenchymal cells stained positive.286 However, repeated administration of HES may account for severe portal hypertension, liver failure, and sepsis, particularly in patients with chronic liver disease.303 Indeed, in CHEST (2012) the incidence of new hepatic organ failure was significantly higher in the HES group than in the saline group in ICU patients.22 Further investigations into tissue accumulation of HES in the liver and its clinical relevance are needed, both in human and veterinary medicine.

Skin Storage and Pruritus Deposition of HES in the skin, detected as intracytoplasmic vacuoles in dermal macrophages, endoneural connective tissue cells, endothelial cells, Langerhans’ cells, perineural cells, and Schwann cells is thought to be responsible for persistent pruritus in people.292,295,297,304–306 HES can appear in skin cell vacuoles as soon as 90 minutes after a single dose of 30 g, with symptoms starting during or after treatment (repetitive doses of HES over 2–3 weeks) and persisting for long periods of time.305,307 Mediators other than histamine must be responsible for the pruritus, as no histamine release from mast cells has been detected morphologically.297 The degree of vacuolization in the skin was not related to the type of HES, whereas degree of macrophage HES storage correlated with both the cumulative effect and the time point of the 36

The effects of HES on kidney function have become one of the most heated topics of discussion surrounding the use of HES in people. In the early 1990s, HES was first considered potentially nephrotoxic after cases of AKI were described in people following repeated (1 L/day over 10–12 days) hemodilutional therapy with pentastarch in oto-neurological disorders.308,309 However, studies from other research groups found that compensated renal failure in otherwise healthy volunteers did not significantly affect elimination of HES and the same perioperative volume substitution with HES was recommended in patients both with and without renal impairment.310,311 Following tensions between HES proponents and HES detractors, a variety of studies were performed evaluating serum creatinine concentrations, urine parameters, staging systems, renal biomarkers, electron microscopy, or need for RRT in patients receiving HES products. Several studies reported no negative effects or even positive effects of HES administration on kidney function. These included studies in critically ill patients,312 patients with severe trauma,217 severe sepsis,89,313 and patients undergoing surgery,314,315 as well as animal experiments of endotoxemic shock in which creatinine clearance and ultrastructural tubular integrity was preserved following tetrastarch administration.316,317 However, a study in kidney-transplant recipients found significant renal impairment after treatment of the brain-dead kidney donors with HES.301 Additionally, a study in a small group of surgical intensive care patients found renal tubular injury and impaired tubular resorption after the administration of HES 200/0.5.318 Further concerns about detrimental effects on kidney function were raised after an increased incidence of AKI was found in patients with severe sepsis and septic shock treated with 6% HES 200/0.6 compared to 3% gelatin.20 Although most of these studies were performed on relatively small numbers of patients, recent large, seminal RCTs comparing HES and crystalloids were subsequently published.21–23,89 In patients with severe sepsis (VISEP trial), treatment with 10% HES 200/0.5 was associated with higher rates of AKI and RRT compared to LRS.21 C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283


In this study, the recommended daily dose limit of HES 200/0.5 (20 mL/kg/day) was exceeded by more than 10% in over 38% of patients (median cumulative dose 70 mL/kg), and those receiving doses within the recommended range were no different than the crystalloid group in terms of kidney function.319 The 6S trial enrolled patients with sepsis to receive either 6% HES 130/0.42 or Ringer’s acetate and found the need for RRT was higher in patients receiving HES (22%) than those receiving Ringer’s acetate (16%).23 In this study, the median cumulative dose was 44 mL/kg, which was within the recommended dose limit of 50 mL/kg/day. In another recent large trial (CHEST), comparing 6% HES 130/0.4 with 0.9% saline in a heterogeneous population of ICU patients, more patients in the HES group needed RRT (7.0%) than those in the saline group (5.8%).21 Finally, a study of patients with severe sepsis (CRYSTMAS trial) found a trend toward increased RRT in patients receiving 6% HES 130/0.4 compared to those receiving 0.9% saline.89 In many of these studies, 0.9% saline was used in comparison to HES although infusion of 0.9% saline is associated with negative effects, such as hyperchloremic metabolic acidosis, decrease in strong ion difference, decrease in pH, kidney injury, and increased mortality.320–322 A chloride-restricted strategy has been linked to a decreased incidence of AKI in ICU patients.323 The potential negative side effects of saline raised questions as to its adequacy as a comparator fluid. Furthermore, much larger volumes of saline were often administered, exacerbating its potential detrimental effects and biasing study results in favor of HES.324 Despite the debate over its deleterious effects, saline remains the most used resuscitation crystalloid. However, further discussion about dose and type of crystalloid fluid therapy is beyond the scope of this article. In addition to RCTs, several meta-analyses evaluating an association between AKI or a need for RRT and tetrastarch25,90,91,325–329 or tetrastarch and other HES types24,319,330,331 were published in 2013. Comparators were isotonic or hypertonic crystalloids, albumin, gelatin, or dextran. The majority of these analyses focused on the use of starch in critically ill, septic, or acutely hypovolemic patients. In these patients, an increased risk for AKI and RRT was found to be associated with HES therapy.24,25,90,91,319,326,330–332 The recent Cochrane Review concluded that “all HES products increase the risk for AKI and RRT in all patient populations and a safe volume of any HES solution has yet to be determined.”330 In contrast, 2 meta-analyses evaluating the renal injury in surgical patients treated with HES did not find evidence for renal dysfunction or a difference in the incidence of death or AKI.328,329 After publication of these 2 meta-analyses, HES detractors criticized their quality C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283

and validity,325,327 claiming that they failed to provide convincing evidence that surgical patients are at low risk of HES-induced renal injury and strong criticism concerning the quality of the review and “misleading conclusions” was expressed.333,334 Studies evaluating renal function in dogs or cats after HES administration are greatly lacking. One study demonstrated an effective restoration of renal function (arterial and venous blood pressure, creatinine clearance, urinary flow rate, and urinary sodium and potassium excretion) after HES administration in experimentally induced hemorrhagic shock in dogs.335 Another study showed reversal of experimentally induced AKI (occlusion of the renal artery in unilateral nephrectomized dogs for 2 hours) in 7 dogs using hemodilution with HES.336 A retrospective analysis of 96 hospitalized dogs over a period of 3 years performed by the authors did not reveal evidence of any difference in creatinine concentrations following administration of a balanced 6% HES 130/0.4 compared to crystalloids.337 In the same study the cumulative dose of HES was 88 mL/kg (range; 13– 336 mL/kg) over the treatment period. In another recent study in dogs with SIRS undergoing emergency laparotomy, urine neutrophil gelatinase-associated lipocalin was significantly higher in dogs receiving HES compared to dogs receiving crystalloids.338 However, neither study was randomized and results may have been biased by dogs with greater disease severity being preferentially more likely to receive HES. However, prospective, RCTs are necessary to fully assess the risk of renal injury associated with HES administration in dogs and cats.

Mortality In a meta-analysis of 28 trials published between 1982 and 2012 that included 10,290 patients (after exclusion of studies retracted for misconduct) with sepsis, trauma, or both in acute care settings, patients receiving HES were found to have a slight increased risk ratio (1.09) of death compared to patients receiving other resuscitation fluids.23 Recent other meta-analyses and large RCTs came to similar conclusions.21–23,92,330,331 In the VISEP trial (2008), a trend toward higher 90-day mortality (P = 0.09) in septic patients was observed in patients receiving 10% pentastarch (41%) compared to LRS (33.9%).21 Indeed, mortality was significantly increased (57.6% vs. 30.9%) among patients receiving high doses of HES (median cumulative dose of 136 mL/kg) compared to those receiving lower doses (median cumulative dose 48.3 mL).21 The trial was stopped early for safety reasons, including a higher rate of severe hypoglycemia, serious adverse events in the intensive-insulin therapy 37

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group compared to the conventional therapy group, and higher rates of AKI and RRT in the pentastarch group compared to the LRS group.21 However, no study has thus far established a safe threshold dose for high-risk patients using long observation periods.185 Another RCT, the 6S trial (2012), also found higher mortality in patients receiving HES 130/0.42 (51%) compared to Ringer’s acetate (43%).23 Despite the use of different HES products in these 2 studies, the separation of survival curves occurred around day 20 in both studies, suggesting that increased mortality associated with HES is a late finding. Both trials additionally demonstrate that HES was associated with impaired kidney function and an increased need of RRT, which further contributes to higher mortality.21,23 However, the CHEST trial (2012) did not find a significant difference in mortality in critically ill (septic and nonseptic) patients receiving HES 130/0.4 (18%) compared to those receiving saline (17%) although the HES group did have a greater need of RRT.22 Whether or not this was due to lower initial severity of illness scores and predicted mortality rate (25% in CHEST patients compared to 50% in 6S patients) is unclear.319 Factors implicated in contributing to apparent HES-associated mortality include impaired renal function, increased risk of hemorrhage, and toxic effects of HES deposition in tissues. Unfortunately, the actual cause of death in the aforementioned population of patients was not reported. Limitations to these studies included variable patient randomization, study inclusion up to 24 hours after diagnosis, administration of up to 1000 mL colloids for stabilization before study inclusion, inclusion of hemodynamically stable patients in which the indication for colloids was questionable or even contra indicated, and preexisting renal failure in 36% of the randomized patients. Additionally, the “golden 6 hours” were not evaluated.339 Therefore, interpretation of the results and conclusions of some of these studies is not straightforward. To the authors’ knowledge, no data are available on short- or long-term outcome in veterinary small animal patients.

Recommendations The current PRAC recommendation, based on their review in October 2013, proscribes the use of HES in septic, burn, and critically-ill patients due to an increased risk of AKI and mortality and because no clear benefit has been demonstrated. Additionally, severe coagulopathies or impaired kidney function, including a need of RRT, are considered contraindications for the use of HES. Prospective RCTs to evaluate the safety and benefit of HES use in trauma and elective surgery were deemed necessary by PRAC. The recommendation was that HES can continue to be used in patients with acute 38

hypovolemia due to acute blood loss, but only for a period of 24 hours, at the lowest dose possible, and for the shortest duration possible, and that kidney function should be monitored for up to 90 days.100 The Surviving Sepsis Campaign (a collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine) recommends against the use of HES products for fluid resuscitation of severe sepsis and septic shock and suggests the use of albumin in patients requiring colloids in its International Guidelines for Management of Severe Sepsis and Septic Shock published in 2012.241 In response to multiple queries following the recall of HES products in the United Kingdom, an advisory note was issued by the AVA in July 2013, informing that HES can still be used in veterinary patients, but suggesting cautious decision making in its administration given the reasons for the recall.248 Currently, no other official organization has provided recommendations for the use of HES in small animals following the recent changes in recommendations for people. Moreover, the safety or effectiveness of HES products have never been approved in animals by the FDA and are, therefore, considered unapproved drug use.340 To the authors’ knowledge, no information on the use of HES in veterinary medicine has been made available by the EMA. Until data are available in dogs and cats and concrete recommendations can be made, veterinarians must consider data and recommendations for the use of HES in people when considering a choice of fluid therapy in small animal patients. Moreover, no safe dose or treatment duration has been established in small animals and previous recommendations were largely based on extrapolation from early reports in people or empirical use.3,6 These are provided in Table 3. As indications for the use of HES have previously been largely based on human guidelines, it may be logical to continue doing so by adopting the newest PRAC and FDA recommendations. Nevertheless, dogs and cats cannot be assumed to respond similarly to people when treated with HES in light of their metabolic characteristics and may differ in some aspects of tissue accumulation.341,342 Regardless of their value as experimental models in the field of colloids, results of previous experimental studies have often been contradictory and are superseded by results of large human RCTs. Despite their abundance, experimental data evaluating the effects of HES on animals were mostly based on equivalence studies, which focus on acute standardized hypovolemia, such as models of hemorrhagic shock in rats, pigs, and dogs. In addition, many were carried out with older HES products or other colloids, or were conducted on only a small number of animals without long-term follow-up. Whether large RCTs assessing the safety and efficacy in animals are truly necessary is debatable given the data available from human RCTs. C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12283


An argument in favor of the continued use of HES in small animals is the lack of readily available alternatives (species-specific albumin and blood products) when crystalloids are not effective. However, as suggested by the AVA, the authors recommend that clinicians carefully consider their options when selecting fluids for small animals, in particular for dogs and cats at high risk, such as those with renal compromise, SIRS, or coagulopathies.

Conclusion HES has been extensively used in human and veterinary medicine for over 30 years. The decision to use HES instead of crystalloids or other colloidal solutions has apparently largely been a matter of national and local preference rather than specific targeting of patients’ needs in both human and veterinary medicine. Although adverse effects have been reported throughout the years, recent studies revealed side effects sufficient to warrant restrictions in the use of HES in people. The focus on HES safety was triggered by scandal regarding scientific misconduct of a prolific author and has greatly polarized opinions on HES. This is evident on reviewing published data, which often showed that the same research groups conducting different studies always seemed to reach the same “pro-” or “contra-” HES conclusions, and the interpretation of data in reviews and meta-analyses is swayed by opinion. The debate in human medicine has reached a point of such controversy that the authors of this review have struggled to forge a critical opinion, especially as data in veterinary medicine are largely lacking. Nevertheless, the recent changes in use of HES should prompt an increase in awareness in veterinary medicine. Efforts should now be made to increase and disseminate reporting of adverse effects with the use of HES in animals and to conduct investigations specific to questions of risk and benefit in veterinary medicine.

Acknowledgments The authors would like to thank Dr. Judith Howard (Diagnostic Clinical Laboratory, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland) for critical review of the manuscript.

Footnote a

Wurlod V, Howard J, Francey T, et al. Comparison of the in vitro effects of saline, hypertonic hydroxyethyl starch, hypertonic saline, and two forms of hydroxyethyl starch on whole blood coagulation and platelet function in dogs. J Vet Emerg Crit Care 2015 (in press).

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[Hydroxyethyl starch].

Stability and activity of hydroxyethyl starch-coated polyplexes in frozen solutions or lyophilizates.

Effect of hydroxyethyl starch solutions on blood glucose concentrations in diabetic and nondiabetic rats.

To use or not to use hydroxyethyl starch in intraoperative care: are we ready to answer the 'Gretchen question'?

Research in Emergency and Critical Care Settings: Debates, Obstacles and Solutions.

Intravascular persistence of hydroxyethyl starch in man.

Emergency and critical care.

Acute kidney injury in cardiac surgery patients receiving hydroxyethyl starch solutions.

The clinical value of whole blood point-of-care biomarkers in large animal emergency and critical care medicine.

Hypertonic solutions and hydroxyethyl starch during CPR--is there any benefit?

Hydroxyeyhyl starch: Controversies revisited.

Short time impact of different hydroxyethyl starch solutions on the mesenteric microcirculation in experimental sepsis in rats.

Use of hydroxyethyl starch to improve granulocyte collection in the Latham blood processor.

Comparison of the effects of glycerol, dimethyl sulfoxide, and hydroxyethyl starch solutions for cryopreservation of avian red blood cells.

Comparison of low molecular weight hydroxyethyl starch and human albumin as priming solutions in children undergoing cardiac surgery.

emergency medicine 2013.

The use of heliox in critical care.

Hydroxyethyl-starch use and PBM: a necessary update to the Italian national guidelines.

Adverse reactions to 6% hydroxyethyl starch in the operating room.

Comparison of the in vitro effects of saline, hypertonic hydroxyethyl starch, hypertonic saline, and two forms of hydroxyethyl starch on whole blood coagulation and platelet function in dogs.

Simulation in cardiac critical care: New times and new solutions.

Comparison of Melatonin, Hypertonic Saline, and Hydroxyethyl Starch for Resuscitation of Secondary Intra-Abdominal Hypertension in an Animal Model.