This article provides a scientific overview of synthetic colloids including tetrastarches and gelatin
Colloid solutions are fluids for intravenous use containing large molecules, which prolong the time they remain in the circulation. The larger molecules used to obtain the colloidal effects are human albumin, which is a plasma protein, or synthetically modified sugars or collagens. The most frequently used synthetic colloid solutions are hydroxyethyl starch (HES) and gelatin.
Colloid solutions have been widely used for volume expansion in patients, who are either intravascular depleted of fluid or at risk of becoming so.1
Large trials in critically ill patients have assessed the effects and harms of colloids.2-4 The conclusions of these trials have questioned the overall effects of colloids, detailed their side-effects and the harm induced by these side-effects. In This article provides an overview of synthetic colloids (HES and gelatin solutions), with regard to characteristics, effects, side-effects and their potential role as volume expanders in critical care medicine.
Hydroxyethyl starches were the most commonly used colloid solution world-wide according to a point prevalence study.1 They are derived from either potatoes or maize and characterised by their molecular weight, degree of hydroxyethylation (substitution ratio) and C2:C6 pattern for hydroxyethylation. HES is degraded by amylase and excreted in the urine, but a substantial part leaves the circulation even in healthy persons, in whom 50% of the infused volume cannot be accounted for at 24 hours.5 The fate of this 50% is unknown, but some of it is likely taken up in tissues, where further degradation is unlikely as amylase is not expressed in most tissues. In the tissues, HES will act as a foreign body.
When the first generation of starches were approved for medical treatment many years ago, the solutions had not been adequately tested, as this was not required at that time. After some time, safety concerns were raised after HES treatment, including risk of renal and haemostatic impairment, tissue deposition and persistent itching. Consequently, new generations of HES were developed, with lower molecular weights and lower substitution ratios, allowing for a faster elimination from the circulation. Over time, the tetrastarches (HES with molecular weight 130 kDa and substitution ratio ranging from 0.38 to 0.45) have been preferred in various carrier solutions. Similar to earlier HES products, the tetrastarches did not undergo large-scale clinical testing prior to marketing. The concerns about side-effects continued, in particular in critically ill patients, leading to recommendations against the general use of HES in the intensive care setting.6
Evidence from systematic reviews
Several systematic reviews have investigated the effects of HES versus other fluids on patient-important outcome measures7-10 (Table 1). The results are quite homogenous even though there are differences in the inclusion of trial data regarding HES solutions, comparators and patient categories. The systematic reviews provide us with high-level evidence indicating that HES in general causes renal impairment as measured as increased use of renal replacement therapy and increased mortality. None of the systematic reviews found evidence to support the notion that tetrastarch has a better safety profile than other HES solutions. In fact, the two largest trials (CHEST and the 6S trial) compared tetrastarch to crystalloid solutions and found increased use of renal replacement therapy and even increased mortality in one trial (the 6S trial).3,4
The results of the Colloids Compared to Crystalloids in Fluid Resuscitation of Critically Ill Patients (CRISTAL) trial were published in 2013.11 In this trial, ICU patients with shock were randomised to open-labelled resuscitation with HES 130, albumin or gelatin versus any crystalloid solution.
HES in peri- and postoperative care
In general, trials of tetrastarch in surgery are relatively small, with short-term follow-up only and high risk of bias.9-12 Therefore, these trials cannot inform us about effects and side-effects of HES beyond the first few days. After the retraction of the trials by Boldt, there are only few trials comparing the potency of tetrastarch versus crystalloid in the surgical setting. Therefore, the potency difference remains largely unknown.
As the harmful effects of HES may occur late, at least in patients with sepsis,3,13 the lack of long-term safety data on tetrastarch in surgery is a dilemma for the clinicians who continue to use HES in these patients. Even though acute kidney injury is unlikely in low-risk patients, it is problematic that the rate and severity of itching is unknown after the use of tetrastarch in patients undergoing elective surgery. There are updated systematic reviews on the use of tetrastarch in surgical patients,14,15 but these included healthy persons and trials with other HES solutions as comparator hampering the interpretation of the results. In addition, the recommendations of the Cochrane Collaboration were not followed in these reviews and they were sponsored by industry, both of which increase the risk of bias.
Compared to HES, gelatin was used less frequently in the worldwide point prevalence study.1 In some countries, such as the UK and Hong Hong, gelatin was the most frequently used colloid.
The gelatins are polypeptides produced by hydrolysis of collagen, most often from cattle bone. The products are now modified by urea cross-linking or succinylation. The gelatins used in fluid therapy have a molecular weight around 20 kDa with a wide range and are excreted by the kidneys without prior metabolism. Gelatins have lower molecular weight than both HES and albumin, but there are no high-quality trial data showing gelatins potency as plasma expander compared to crystalloids.
Overall, the evidence for the use of gelatin is poor and no large, randomised trials have been performed to assess the efficacy and harm of this class of colloid. A recent systematic review identified that the trials comparing gelatin with crystalloid or albumin solutions were small, done in elective surgery mainly, and had follow-up time of less than 24h.16 The side-effects of gelatin are comparable to those observed with HES, including impairment of kidney function and haemostasis. Thus, overall beneficial effects of gelatin are unlikely in critically ill patients, a notion supported by data from a meta-analysis15 and from a before-and-after study in a single ICU.17 In the latter study, gelatin was associated with acute kidney injury in patients with severe sepsis. In line with this, the European Society of Intensive Care Medicine (ESICM) Task Force on colloids recommended that gelatin is only used in the context of randomised clinical trials.6
The evidence to support that resuscitation with colloids may result in less fluid use and improved haemodynamics is sparse. In contrast, it is clear from several high-quality trials and meta-analyses in critically ill patients that treatment with tetrastarches causes impaired renal function and haemostasis and may even increase mortality. Therefore, HES should not be used in these patients. Gelatin is considerably less studied, but the overall effects of colloids are likely to be minor compared to crystalloids and the side-effects of gelatins comparable to starch. Following this, the use of synthetic colloids should be limited in all patient categories.
- Finfer S et al. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care 2010;14:R185.
- Finfer S et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–56.
- Perner A et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012;367:124–34.
- Myburgh JA et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901–11.
- Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet 2012;51:225–36.
- Reinhart K et al. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med 2012;38:368–83.
- Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2013;2:CD000567.
- Zarychanski R et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA 2013;309:678–88.
- Gattas DJ et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy. Intens Care Med 2013;39:558–68.
- Haase N et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ 2013;346:f839.
- Annane D et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013;310:1809–17.
- Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg 2011; 112:635–45.
- Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–39.
- Van der Linden P et al. Safety of modern starches used during surgery. Anesth Analg 2013;116:35–48.
- Martin C et al. Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. Anesthesiology 2013;118:387–94.
- Thomas-Rueddel DO et al. Safety of gelatin for volume resuscitation – a systematic review and meta-analysis. Intensive Care Med 2012;38:1134–42.
- Bayer O et al Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med 2012;40:2543–51.