Giving long-persistent starch as volume replacement can cause pruritus after cardiac surgery

P. W. Morgan1,* and J. C. Berridge2

1Department of Anaesthesia and 2Yorkshire Heart Centre, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK

Accepted for publication: June 15, 2000


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We reviewed the prevalence and severity of pruritus in 85 patients after cardiac surgery. EloHAES, a long-lasting hydroxyethylated starch, was given to 59 of these patients. None of the patients who did not receive EloHAES developed pruritus, compared with 22% of those who did (P=0.007). The timing of onset, duration and severity of the pruritus are similar to those found previously for other hydroxyethylated starches, and the cause of this pruritus is likely to be similar. Hydroxyethyl starch can cause long-term pruritus.

Br J Anaesth 2000; 85: 696–9

Keywords: fluids, i.v.; complications, pruritus


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There is continued interest in the types of intravenous fluid that are most appropriate for particular clinical indications. These fluids include crystalloids, plasma, albumin and the synthetic colloids, which include gelatin derivatives, dextran solutions and hydroxyethylated starches.

Many studies have compared different colloids. The variables most often assessed include maintenance of intravascular volume, cardiac function, coagulation variables1–3 and end-organ function.4 No one colloid has a clinical advantage, despite theoretical and in vitro advantages of one agent over another. Hydroxyethyl starch remains in the intravascular compartment for longer, so it is believed to cause less tissue oedema than other colloids. Some suggest that hydroxyethyl starch molecules can ‘plug’ leaky capillaries4 and prevent fluid moving from the vessels to the tissues.

Giving hydroxyethyl starch may cause significant and prolonged pruritus.5 We assessed the prevalence and severity of pruritus in patients who had received EloHAES (hydroxyethyl starch 200/0.62) for volume replacement during cardiac surgery, compared with cardiac surgical patients who had not.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Over a 9 week period, we reviewed 85 consecutive, unselected patients who had had cardiac revascularization or heart valve surgery within the previous year. This time period was chosen arbitrarily to allow good memory recall. A single unblinded observer carried out a structured interview according to a standard proforma (Fig. 1). Of the patients interviewed, 58 patients received EloHAES as part of their fluid management during or after surgery, and 27 patients received no hydroxyethyl starch. Other fluids used included 0.9% saline, Gelofusine and blood products as indicated clinically. The decision to administer starches to these patients was made by individual anaesthetists on the basis of their apparent relative merits. Case numbers and case mix were similar between anaesthetists. The numbers in each group reflected the number of anaesthetists who administered starches.



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Fig 1 Proforma of questions put to patients in the structured interview.

 
Pruritus was classified as mild, moderate or severe according to the following criteria: mild, present several times a week, but did not interfere with the patient’s daily routine; moderate, present every day and sometimes interfered with the daily routine; severe, was present every day, interfered with the daily routine and was of sufficient intensity for the patient to seek medical help. The onset, duration, aggravating and relieving factors, site of pruritus and the volume of EloHAES administered were also recorded.

Statistical analyses were performed using the SPSS 8.0 for Windows statistical package. The presence or absence of pruritus in individuals who had received EloHAES was compared with that in the control population using 2 x 2 contingency tables. Fischer’s exact test was performed, as the expected numbers were too small for {chi}2 results to be accurate. The volume of EloHAES administered was compared between patients with and without pruritus, and then in patients with no, mild, moderate and severe pruritus, using the Mann–Whitney U-test and Kruskal–Wallis tests, respectively. Two-tailed P values of <0.05 were considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
No patients experienced pruritus in the group who did not receive any EloHAES, compared with 22% in the EloHAES group (P=0.007). Pruritus was classed as mild in 54% and severe in 46% (Table 1). The mean (range) volume of EloHAES administered was as follows: no pruritus, 1.35 (0.5–2) litres; mild pruritus, 1.4 (0.5–2.5) litres; severe pruritus, 1.5 (1–2.4) litres (Table 2). There was no statistically significant difference between these groups, but a trend to greater volume given to the severely pruritic group was noticed. The median (range) onset of pruritus in the EloHAES group was 4 (1–12) weeks. Pruritus was still present in 77% of those affected at the time of interview; the greatest duration was >=9 months. The site of pruritus varied: 40% of patients experienced pruritus in the natal cleft, 30% on the lower back and 20% on the upper back. Other sites included the neck, feet, hands, chest and abdomen. There were no consistent aggravating or relieving factors.


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Table 1 Frequency and severity of pruritus in EloHAES and control groups
 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We found that volume replacement with EloHAES in patients undergoing cardiac surgery was associated with pruritus.

Pruritus after administration of hydroxyethyl starch was first reported in a patient undergoing leucophoresis.5 Subsequent reports have demonstrated an association between various hydroxyethyl starches and pruritus. The clinical features vary and skin changes are often absent. The pruritus may be generalized or localized, have a delayed onset of up to several weeks; it may have precipitating factors such as warmth and mechanical irritation.6–9 The pruritus is frequently persistent, lasting months or even years,10 and is usually refractory to treatment with antihistamines or steroids, although some benefit has been reported with capsaicin,11 hydroxyzine9 12 13 and amantidine.14

Hydroxyethyl starches have hydroxyethyl groups bound to a high molecular weight amylopectin backbone, which delays rapid hydrolysis by plasma {alpha}-amylase. The main difference between the different hydroxyethyl starch products is in their molecular weights and in the level of substitution with hydroxyethyl groups. The latter is now thought to be the major determinant of pharmacological behaviour.15 16 EloHAES is a medium molecular weight hydroxyethyl starch, with a mean molecular weight of 200 000 Da (80% between 13 700 and 500 000), and has a molar substitution of 0.62, that is every 100 glucose moieties have 62 hydroxyethyl groups attached. The low molecular weight molecules and breakdown products are excreted in the urine, so hydroxyethyl starch solutions are contraindicated in severe chronic renal insufficiency. Hydroxyethyl starches are deposited in various tissues and delayed excretion occurs following metabolism by tissue glucosidases.1725 Skin biopsies from individuals who developed pruritus have shown deposits of hydroxyethyl starch within the intracellular vacuoles of macrophages, Langerhans cells, keratinocytes, vascular endothelium, perineural cells and sweat gland epithelia.6 26 The size and severity of the deposits may depend on the dose and preparation administered.10 Symptomatic improvement can occur as hydroxyethyl starch deposits diminish in size, which may take <=3 years.6

A correlation between the volume of hydroxyethyl starch infused and the severity of pruritus has been found.6 10 21 26 27 In one study, the mean dose of hydroxyethyl starch in the group suffering from pruritus was 7.8 g kg–1, equivalent to 9.75 litres of EloHAES, compared with 1 litre equivalent in the non-pruritic group.21 Individuals given 150 g of hydroxyethyl starch in another study had a 1% incidence of pruritus, which increased by 5.5% with each additional 50 g dose.26 The incidence of pruritus associated with Pentastarch in an intensive care population28 was slightly higher than that found in the present study. This was possibly because a greater volume of starch was administered. A similar proportion also suffered severe pruritus, although not defined, with a comparable duration to our study. We were unable to demonstrate a correlation between dose and response in our study, either because we used less starch, or because the smaller range of doses administered may not have had sufficient power to detect a correlation. One study failed to demonstrate an increase in pruritus in a group receiving hydroxyethyl starch when compared with a group receiving lactated Ringer’s solution.29 The volumes of hydroxyethyl starch in that study were much smaller (around 650 ml in total) than those in other studies where pruritus was found, suggesting that there may be a ‘threshold dose’ for pruritus to occur. Cox and Popple suggested that metabolic polymorphism could be responsible for abnormal handling of hydroxyethyl starches, thus predisposing certain patients to larger tissue deposits of hydroxyethyl starch.7 This could help to explain why in our study some patients developed pruritus and others did not, despite similar volumes of starch administered.

We found that 22% of cardiac surgical patients who received EloHAES suffered from pruritus, often with sufficient severity to interfere with their daily routine. Our findings support previous work that has linked administration of other hydroxyethyl starches with pruritus. As EloHAES contains the same basic molecular structure as other hydroxyethyl starch solutions, we propose that the mechanism of pruritus is similar.10 27 Many hydroxyethyl starches can cause long-term pruritus, and this should be considered in the choice of volume replacement therapy.


    Acknowledgements
 
The authors thank Mr J. P. McGoldrick, Mr C. M. Munsch and Mr U. Nair for access to their patients.


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Table 2 Volumes of EloHAES administered for each grade of pruritus
 

    Footnotes
 
* Corresponding author Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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