Background
Synthetic colloids are widely used in veterinary medicine with hydroxyethyl starch (HES) being the most frequently used.1 Moreover, HES is currently the most studied synthetic colloid in human and veterinary medicine in contrast to dextran and gelatin. HES preparations are characterized by the mean molecular-weight (MW in kilo Dalton [kDa]) of the HES molecule (equals molecular size), molar substitution (MS, mole hydroxyethyl residue per mole glucose subunit), C2/C6-ratio (locations of hydroxyethyl residues on the carbon atom of the glucose subunits), its concentration (e.g., 6% [60 g/L] versus 10% [100 g/L]), the carrier solution (normal saline versus polyionic, buffered, and balanced) and the starch-source (potato [HES 130/0.42) versus maize starch [HES 130/0.4]). They are further classified according to the MW into high-molecular-weight (>450 kDa), medium-molecular-weight (>200 kDa), and low-molecular-weight (<130 kDa) solutions, and according to the MS into highly substituted (hetastarch; 0.62–0.75), medium-substituted (pentastarch; 0.5), and low-substituted solutions (tetrastarch; 0.4).2 The most frequently used HES preparation in small animals is the modern, low-molecular weight HES (6% HES 130/0.4, a maize-derived starch with 60 g HES per 1000 mL carrier solution).1
Two major concerns put the use of HES into question: Its anticipated effects (benefits) and its side effects (risks). Traditionally, the rationale for the use of HES preparations (and other colloids) was prevention of oedema formation by plugging capillary leaks, an increase in the intravascular colloid-osmotic pressure, reabsorption of fluid from the interstitium into the intravascular space with subsequent intravascular volume expansion, and reduction of existing peripheral oedema, and a volume-sparing effect compared to isotonic crystalloids.3,4 However, the concept of colloid therapy was strongly based on the Starling concept, which was discovered more than 100 years ago. Many of these expectations are invalid, due to recent findings in the area of microcirculation and endothelial glycocalyx layer (e.g., ‘revised Starling’ model). In particular, there is no reabsorption from the interstitial space into the intravascular space (‘no absorption rule’).5 Two reviews (2013 and 2018) of the benefits and risks of HES by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the European Medicines Agency were performed, which led to restrictions, contraindications, and changes to the warnings on HES product packaging (for people).6 The first review was triggered in 2012 by results from large randomized clinical trials (RCT) in people,7-9 which found an increased risk of mortality in patients with sepsis and an increased risk of kidney injury requiring dialysis in critically ill patients following treatment with HES. In addition to the already existing contraindications (e.g., renal failure), additional contraindications were introduced (e.g., sepsis, critically ill patients).6 The second review was triggered by the Swedish Medical Products Agency due to non-adherence to the restrictions from 2013 (e.g., HES solutions were used in patients with sepsis and kidney injury), with the aim to completely ban HES in the EU. The recommendation to ban HES was ultimately not endorsed; however, limitations on supply to only accredited hospitals, training of healthcare professionals, and additional packaging warnings were enacted. Several guidelines in human medicine recommend against HES due to the safety concerns. As such, current guidelines from the Surviving Sepsis Campaign recommend crystalloids for initial resuscitation and subsequent volume replacement with albumin when patients require ‘substantial’ amounts of crystalloids.10 In contrast, the International Fluid Optimization Group (peri-operative fluid therapy) did not recommend against HES, but instead the anaesthetist should assess patient specific risks (renal dysfunction and/or sepsis) prior to administering HES.11 In veterinary medicine, HES cannot be easily replaced by albumin or plasma as the safety profile for human serum albumin solutions is worse compared with HES,12-14 and allogenic plasma or albumin products are not ubiquitously available and are more expensive. Therefore, synthetic colloids might be the only alternative if crystalloids are not sufficient. Unfortunately, no guidelines yet exist on the use of synthetic colloids or HES in companion animals and the controversy is still ongoing. The following sections elucidate the current evidence of the cons and pros of HES.
Evidence Opposing the Use of HES
Use of HES solutions is controversial in human medicine because the use of these fluids may not achieve higher volume expansion than that expected crystalloids and may be associated not only with acute kidney injury but also with impaired coagulation.
It is commonly assumed that 3 to 4 volumes of crystalloid solution achieve similar plasma volume expansion as 1 volume of colloid solution. Recent data suggest it might depend on the integrity of the endothelial glycocalyx. The CRYSTMAS trial, a RCT in patients with severe sepsis in whom capillary integrity was likely compromised, showed that in people with naturally occurring sepsis, the crystalloid to colloid volume ratio was close to 1.2:1.15 Therefore, in clinical situations where the integrity of the glycocalyx may be compromised, synthetic colloids such as HES cannot be relied upon to maintain their superiority over crystalloids in terms of plasma volume expansion.
The coagulopathy associated with HES solutions may involve several mechanisms, including:
1. Inhibition of the formation of the fibrin network because of binding and inactivation of factor VIII and von Willebrand’s factor (vWF)
2. Inhibition of blood clot formation by inhibition of glycoproteins GP IIb/IIIa located on the surface of activated platelets
3. Inhibition of the binding of GP IIb/IIIa platelet receptors to vWf and fibrinogen
4. Acceleration of fibrin degradation16,17
The properties of individual HES molecules vary according to their MW, MS ratio, and the C2/C6 ratio. A high C2/C6 ratio appears to have the largest impact on haemostasis.18 HES solutions with smaller MW and lower MS are more rapidly degraded and eliminated with an apparent reduction in some adverse effects.16 In humans, numerous studies and meta‐analyses show that patients receiving a synthetic colloid have increased risk of bleeding and require more blood product than patients receiving crystalloid fluid therapy.19 Likewise, some in vitro and in vivo studies in healthy dogs have demonstrated both primary and secondary haemostatic impairment with the administration of clinically relevant doses of synthetic colloids,20,21while others have not22,23. Although studies showed that coagulation can be impaired by tetrastarch, the clinical application of these findings is not clear because tetrastarch was compared to equal volumes of isotonic crystalloids.21,24 A recent study25 showed that the use of tetrastarch for volume resuscitation after haemorrhage in healthy dogs induced a transient hypocoagulable state (2–4 hours) suggesting that tetrastarch induces dilutional coagulopathy that can be avoided by using lower volumes.25 Notably, according to recent results in dogs suffering from spontaneous haemoperitoneum, HES should be used with caution in dogs with pre-existing coagulopathy and active haemorrhage.26,27
Three randomized clinical trials in people suggested an increased risk of AKI and mortality in critically ill human patients receiving HES compared with those receiving crystalloids.8,9 The pathophysiology of AKI secondary to synthetic colloid administration is not well understood, but is likely multifactorial. Osmotic nephrosis secondary to phagocytized HES molecules within proximal tubular cells is thought to be an important mechanism. HES induced AKI is dose‐ and time‐dependent and leads to potentially reversible cellular vacuolization, cellular swelling, and inflammation. Abnormal macrophage infiltration and “hyperoncotic AKI” have also been proposed as possible mechanisms for HES‐induced AKI. In addition, due to its oncotic properties, HES administration decreases renal filtration pressure.28 Phagocytosed intracellular HES can persist for up to 18 days in canine kidneys, depending on the dose received.29 In humans with severe sepsis, patients receiving LRS are less likely to develop AKI and need renal replacement therapy (RRT) than patients receiving HES.9 To date, only retrospective studies have been published in the veterinary literature and the results are conflicting. Interpretation of these studies is also hampered by the lack of agreement on the definition of AKI. In a prospective study in septic dogs undergoing emergency laparotomy, dogs that received HES had increased neutrophil gelatinase associated lipocalin (NGAL) concentration compared to those that did not receive synthetic colloids,30 suggesting that HES administration caused renal epithelial injury. A retrospective cohort study,31 found that critically ill dogs receiving HES 250/0.5 had a higher incidence of AKI and non-survival to discharge compared to a control group.
Most RCTs in humans have demonstrated a trend towards an increase in mortality in patients receiving HES compared to crystalloids. In one retrospective study of critically ill dogs, administration of HES was associated with an increase in mortality.31 Likewise, in the Yozova et al. study of dogs receiving HES, those that received HES had a higher mortality rate than those that did not.32 In all of these studies, dogs in the HES group were significantly sicker and had lower albumin concentrations. They were also more likely to suffer from sepsis.
Evidence on the Positive Aspects of HES
As described above, the use of HES may not achieve the expected higher volume expansion compared to isotonic crystalloids in patients with a non-intact endothelial glycocalyx. Inflammation, sepsis, ischaemia/reperfusion, and increased atrial natriuretic peptide are some of the conditions leading to glycocalyx layer destruction, with resultant increased vascular permeability, and oedema formation.33,34 Moreover, rapid administration of intravenous fluid can lead to endothelial glycocalyx damage.35 However, in dogs with experimental haemorrhagic shock, endothelial glycocalyx shedding, and inflammation were found to be significantly less after tetrastarch compared with the 4-fold volume of isotonic crystalloid.36 Nevertheless, many studies aiming to prove the volume expanding effect of HES were performed in healthy or non-septic individuals. In non-septic people with hypovolaemia, the volume effect of tetrastarch is 90% compared to only 20% with isotonic crystalloids.37 Likewise, in normovolaemic, healthy dogs, hetastarch led to the highest volume expanding efficiency after 30 minutes (blood volume increase by 140%) compared with hypertonic saline and normal saline, which lasted up to 4 hours.38 Moreover, tetrastarch had a volume-sparing effect in experimental haemorrhagic shock in healthy non-septic dogs.39 In dogs with LPS induced systemic inflammation, tetrastarch led to a transient increase in blood pressure compared with the same volume of crystalloid.40 Similar to critically ill people,41 in critically ill hospitalized dogs and cats, fluid overload is a possible complication, which is associated with an increased mortality.42 Crystalloids have a marked redistribution, whereby 50% of the volume effect is lost within 20 minutes.43 The addition of a colloid during the resuscitation phase after a certain amount of crystalloids, may help to reduce the total volume of crystalloids and prevent fluid overload. A large human randomized controlled trial requiring fluid resuscitation for acute hypovolaemia with either colloids (the majority received HES) or crystalloids (CRISTAL trial) found a significant reduction in 90-day mortality, more vasopressor-free, and more ventilator-free days by day 28 in the colloid group. Subgroup analysis confirmed a significantly reduced 90-day mortality in patients treated with HES when compared with patients treated with 0.9% saline.44
As described above, one major concern is the risk of AKI in patients receiving HES due to tissue storage and subsequent osmotic nephrosis. Notably, various drugs are described to cause osmotic nephrosis (e.g., intravenous immune globulins, mannitol, low-molecular-weight dextran, radiocontrast preparations).45 According to the restrictions on the use of HES from 2013 (e.g., HES is contraindicated in septic and critically-ill people), newer studies on the risk for AKI in people were performed in surgical or peri-operative populations. Interestingly, data in this population revealed that fluid therapy with HES was not associated with more AKI compared to crystalloids.46,47 Moreover, long-term follow-up (up to 12 months) revealed no difference in renal function between patients that received HES vs. crystalloids.48 In recent retrospective studies in critically ill dogs and cats (including some patients with sepsis), HES-treated patients (tetrastarch) were not more prone to develop AKI than HES-untreated (crystalloids),49-52 although prolonged administration time (several days) led to AKI in some dogs in one study49. The authors of that study recommended to keep the time period of administration as short as possible. The retrospective character of the aforementioned studies are a major drawback and plasma creatinine might not adequately represent real kidney injury after HES. Nevertheless, recent data suggest that tetrastarch may not cause AKI, as measured by several renal biomarkers for AKI and renal histology, when used for volume resuscitation in experimental haemorrhagic shock in healthy non-septic dogs.53,54 However, no prospective clinical studies in naturally ill dogs or cats evaluating AKI after HES are available.
HES-induced coagulopathy is a known side effect in dogs and cats which is transient and dose dependent.21 However, in dogs without pre-existing coagulopathy, tetrastarch did not impair platelet function beyond the effect of haemodilution, and only mildly impaired clot firmness and clot formation time was found.22,25,55 It also remains unclear to what extent the changes in viscoelastic coagulation analyses after HES are clinically significant.
Summary
In specific patient populations, tetrastarch is a potent volume expander with a volume-sparing and longer lasting effect compared with crystalloids. It is unclear, if the initial positive volume effect is associated with an improved outcome in dogs and cats. HES is undoubtedly a fluid with side effects which are dose and time-dependent. It should be administered only in states of acute hypovolaemia or peri-operative hypotension, and at the lowest effective dose and over a short period of time.
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