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Original Article

HES 130/0.4 (Voluven®) or human albumin in children younger than 2 yr undergoing non-cardiac surgery. A prospective, randomized, open label, multicentre trial

Standl, T.*,a; Lochbuehler, H.; Galli, C.; Reich, A.; Dietrich, G.§; Hagemann, H.∥,b

Author Information
European Journal of Anaesthesiology: June 2008 - Volume 25 - Issue 6 - p 437-445
doi: 10.1017/S0265021508003888

Abstract

Introduction

Treatment options for the maintenance of circulatory volume and the replacement of blood volume deficiencies in paediatric surgical patients include crystalloids and colloids. In case of acute and massive blood losses, colloids are often preferred due to a prolonged intravascular half-life and improved intravascular volume effect [1,2]. Human albumin (HA) has been frequently used for volume therapy in paediatric anaesthesia. Due to the physiological hypoproteinaemia in newborns and infants, HA 5% was regarded as a therapeutic gold standard in the past [1,3]. HA has several disadvantages compared with artificial colloids, e.g. higher price, production in glass bottles and concerns regarding prion transmission. However, prion validation studies gave some confidence regarding the safety of albumin [4].

While hydroxyethyl starch (HES) has already been clinically used for volume substitution in paediatric anaesthesia there is only limited data from controlled trials on the use of HES in paediatric anaesthesia, in contrast to extensive study experience in adults [5]. Boldt and colleagues [3] found no safety concerns for moderate amounts of HES (200/0.5) 6% in their study population of children aged less than 3 yr undergoing cardiac surgery. Aly Hassan and colleagues [6] found HES 200/0.5 to be both well tolerated and efficacious in preserving global tissue oxygenation during acute normovolaemic haemodilution in their paediatric study population.

Nevertheless, the use of colloids in children was the focus of scientific discussions and for the time being there is no commonly accepted position on the most appropriate colloid for paediatric use with regard to efficacy and safety [7,8]. In adult patients, HES solutions may replace HA as the first choice for volume replacement in many settings [9]. Assuming comparable efficacy regarding volume replacement HA has the theoretical advantage that it is a physiological protein. While HES is less costly and was reported to have a lower allergenic potential compared with other colloids including HA [10], HES preparations – depending on the exact type – may have effects on coagulation and are transiently stored in tissues [11]. These phenomena are closely related to pharmacokinetic properties of the HES type used, which in turn mainly depend on the molar substitution of the respective HES specification [12]. There are several reports demonstrating that with a lower molecular substitution, resulting in a lower in vivo molecular weight of HES, tissue storage and influence on coagulation can be significantly reduced [11–16].

HA has been the gold standard in the past. Controlled experience with HES in paediatric anaesthesia is still limited, but HES is used in some hospitals routinely in children for volume substitution. As a further step of the clinical development programme, the aim of this pilot study was to obtain first data on the use of HES 130/0.4 in paediatric non-cardiac surgery patients.

Methods

This prospective, controlled, randomized, open, multicentre pilot study was designed to investigate HES 130/0.4 (Voluven®; Fresenius Kabi, Bad Homburg, Germany) compared to HA (HA 5%, Immuno®; Baxter Hyland-Immuno Division, Heidelberg, Germany) in a parallel group design. The study protocol and the written patient information were approved by the Ethics Committees responsible for the study centres. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Parents or the legal representatives were informed orally and in writing about the study and were required to give written consent before a child was enrolled.

It was planned to include 2 × 40 male or female patients who were scheduled for major elective non-cardiac surgery with an expected blood or fluid loss of more than 10% of the estimated blood volume. The patients should be newborn infants (at least 30–36 weeks of gestation) and infants below 24 months of chronological age. The sample size estimation was empirical according to the experience of the investigators. Burn patients or patients with intracranial bleeding within 6 weeks prior to randomization were not eligible, as were patients with an ASA risk score higher than 3. Furthermore, patients with pre-existing severe organ insufficiencies (oliguria or anuria, liver function tests > 3× upper limit of normal) or coagulation abnormalities (e.g. F VIII or vWF deficiency) and patients with haemoglobin below critical age-appropriate levels were not enrolled. Finally, patients in whom the perioperative dopamine dose was expected to exceed 3 μg kg−1 body weight min−1 and patients with colloid infusions within 4 weeks prior to randomization were not enrolled.

Patients were randomly allocated to receive either HES 130/0.4 or HA for perioperative volume management. Due to noticeable differences in colour and viscosity of the study solutions blinding of the investigator to the infusion type was not possible. However, patients were randomized to one of the two treatment groups by sealed randomization envelopes that were opened by the investigator only after final enrolment of the patient. Randomization was conducted in blocks of 4 using a 1 : 1 ratio. Test or the control solutions were administered intravenously (i.v.) for volume substitution perioperatively. Infusion volume and infusion rate were individually adjusted to maintain normovolaemia defined by stable haemodynamics (i.e. blood pressure (BP) and heart rate (HR)) according to the clinical judgement of the anaesthesiologist. There were no dose limitations for the test or the control solution. Colloid solutions other than the study drugs were not allowed. Infusion of crystalloid solutions according to the patient's needs was allowed.

Patients with a body weight above 5 kg received oral midazolam as pre-medication prior to anaesthesia induction, if required. Anaesthesia was either induced with i.v. ketamine and midazolam or with sevoflurane via face mask. Vecuronium or rocuronium bromide was administered for muscle relaxation. Tracheal intubation was performed and all patients were mechanically ventilated. Anaesthesia was maintained with isoflurane and a maximum of 70% nitrous oxide. Fentanyl was administered in boluses of 2 μg kg−1 body weight. No regional anaesthesia was performed.

Baseline values were measured immediately prior to anaesthesia induction or preoperatively with the exception of systolic BP (SBP) and diastolic BP (DBP), mean arterial pressure (MAP) and HR for which the baseline values were recorded after anaesthesia induction. BP were measured non-invasively in 90% of the children using oscillometry on the right or left arm. Only in children undergoing major neurosurgical operations (N = 8) the radial artery was cannulated for invasive BP measurement.

Haemodynamics (SBP, DPB, MAP and HR) were recorded as the primary safety parameters at baseline, 15, 30, 60, 90, 120 and 180 min after start of study drug infusion, at the end and 4–6 h after the end of the surgical procedure and on the morning of the first postoperative day. In addition blood gases, colloid osmotic pressure (COP), coagulation parameters (Quick's test (prothrombin time), partial thromboplastin time (aPTT), platelet count), total amount of study medication infused, clinically estimated blood loss, amount of transfused blood products, fluid balance and laboratory parameters were recorded. Adverse events regardless of relationship to study medication were recorded meticulously from anaesthesia induction until the morning of the third postoperative day.

Statistics

This study was designed as a pilot study to obtain first data on the use of HES 130/0.4 in paediatric non-cardiac patients. All analyses were performed in an explorative way. For this reason, a power analysis to calculate the number of patients per group was not possible. In accordance with the recommendation of the German drug regulatory administration (BfArM), we designed a sample size of 80 evaluable patients (40 per treatment group).

Haemodynamics, body temperature, blood gases, COP, coagulation parameters and volume input and output were analysed descriptively by time point and treatment group. Since normal ranges of the coagulation parameters were different for the age groups ‘standardized values' were calculated using the following formula:

Standardized coagulation parameter values ranged from 0 to 1 for values within normal range, were negative for value below normal range and were greater than 1 for values above normal range. All statistical tests were conducted in an exploratory sense. Statistical significance was accepted if the two-sided P-value was equal or below 0.05. Covariance analyses (ANCOVA) were calculated for haemodynamics, body temperature and coagulation parameters per time point using centre, treatment and baseline value as covariates.

An analysis of variance (ANOVA) or when appropriate an analysis of covariance (ANCOVA) was calculated for haemodynamics, body temperature and coagulation parameters with type of surgery, body weight, surgery duration, total fluid input except study medication, age or gender as explanatory factors. Based on these models estimates and two-sided 95% CI for the treatment group difference HES 130/0.4 – HA were calculated.

Results

In all, 95 patients in nine German centres were screened for eligibility. Of them, 13 patients were not treated with study medication due to low expected blood or fluid losses, postponed surgery or intolerable primary disease. The remaining 82 patients were randomized and treated; 41 patients were randomized to each treatment group. One patient of the HA group died before completion of the study. All other patients completed the study. The first patient was enrolled in May 2000 and the last patient was completed in April 2001. Recruitment differed between the study centres as 9 out of 12 study centres actively recruited patients with 3 study centres contributing 54 (67%) patients. The remaining 3 study centres did not recruit any patients. Patient characteristics and treatment details are summarized in Table 1. The youngest patients included were term newborns; 77% of all patients were below 1 yr of age. Both groups were comparable regarding demographics and length of anaesthesia and surgery. Types of scheduled surgeries (Table 2) were comparable between the groups. All patients received concomitant medications to induce or maintain anaesthesia, to substitute for fluid loss or for prevention of infections. There were no relevant differences between the groups regarding types and frequencies of concomitant medications.

Table 1
Table 1:
Patient characteristics.
Table 2
Table 2:
Type of scheduled surgery.

There were no statistically significant differences between the groups and treatment comparisons using standard ANCOVA for haemodynamics (SBP, DBP, MAP, HR) as well as for body temperature at baseline and on the first postoperative day. For the changes over time see Figures 1 and 2.

Figure 1
Figure 1:
Time course of systolic (a) and diastolic blood pressure (b); •: HES, hydroxyethyl starch; ▪: HA, human albumin. Data are presented as mean ± SD. E: patient enrolment; BSL: baseline; IND: anesthesia induction; INF: infusion start; 15…180 = 15…180 min after infusion start; EOS: end of surgery; OP+4 : 4 to 6 h after end of surgery; POD1: morning of first postoperative day.
Figure 2
Figure 2:
Time course of heart rate (a) and mean arterial pressure (b); •: HES, hydroxyethyl starch; ▪: HA, human albumin. Data are presented as mean ± SD. E: patient enrolment; BSL: baseline; IND = anesthesia induction; INF: infusion start; 15…180 = 15…180 min after infusion start; EOS: end of surgery; OP+4 : 4 to 6 h after end of surgery; POD1: morning of first postoperative day.

Average pCO2 values and SaO2 values were stable during surgery and afterwards. COP was well maintained, decreased only slightly in both groups during surgery, and increased again thereafter (Table 3). Mean ± SD arterial pH at baseline was 7.4 ± 0.1 in both groups. Until end of surgery, the mean ± SD change in the HES 130/0.4 group was 0.0 ± 0.1 and it was −0.1 ± 0.1 for HA. There were no significant differences between the groups.

Table 3
Table 3:
Blood gases and colloid osmotic pressure.

Concerning coagulation ANCOVA did not reveal any effect of treatment, centre or baseline value on the changes of Quick's test values, aPTT and mean platelet counts (Table 4). However, there was an effect of the type of surgery on the postoperative day 1 (POD1) values for all three parameters. For Quick's test the highest estimated mean value occurred for orofacial surgery (83.8%), the lowest for abdominal surgery (61.0%). For aPTT, the highest estimated mean value occurred for neurosurgery (43.2 s), the lowest for orofacial surgery (34.5 s). For platelets, the highest estimated mean value occurred for other surgery (406 × 109 L−1) and the lowest for neurosurgery (214 × 109 L−1).

Table 4
Table 4:
Coagulation parameters.

There were no statistically significant differences between the groups regarding the investigated fluid input and fluid output parameters (Table 5). From baseline until 4 to 6 h postoperatively average urine volume was slightly higher in the HES 130/0.4 group and blood loss was higher in the HA group.

Table 5
Table 5:
Fluid input/output.

Two (4.9%) patients in the HES 130 group and 4 (9.8%) patients in the HA group received dopamine at a dose exceeding 3 μg kg−1 body weight min−1. In 4 of these patients, dopamine was administered after treatment postoperatively – interference on the haemodynamics during treatment with study medication could be excluded. However, 2 patients were treated during surgery to increase renal perfusion.

Perioperative changes of laboratory parameters were found for haemoglobin, haematocrit, total protein and α-amylase. Both haemoglobin and haematocrit (medians: −3% for HES, −4% for HA until POD1) decreased comparably in both groups because of surgery-related blood loss. For haemoglobin 17 (41.5%) patients of the HES group and 15 (36.6%) patients of the HA group shifted to values below the reference range. Eleven (26.8%) patients of the HES group and 12 (29.3%) patients of the HA group showed values below the reference range already at baseline as well as at POD1. For haematocrit 20 (48.8%) patients of the HES group and 15 (36.6%) patients of the HA group shifted to values below the reference range. Five (12.2%) and 7 (17.1%) patients of the HES group and the HA group, respectively, had values below the reference range before surgery as well as on the first postoperative day. The local reference ranges were used for the analysis. There was an increase of α-amylase in the HES group (medians +2.0 U L−1 for HES, −3.5 U L−1 for HA). In the HES group, total protein decreased from baseline 6.0 g dL−1 by 0.103 g dL−1, compared with the HA group with a decrease from 6.1 g dL−1 by 0.070 g dL−1 (medians, until POD1). Minimum sodium values recorded after baseline were 131 mmol L−1 for HES and it was 132 mmol L−1 for HA.

Adverse events regardless of attributed relationship were observed in comparable numbers in both groups. Lid oedema was the most frequently observed adverse event in both groups, with 12 (29.3%) patients of the HES 130/0.4 group and in 8 (19.5%) patients of the HA group being reported (P = 0.31). In 4 patients of the HES 130/0.4 group and 3 patients of the albumin group, lid oedema may be caused by the neurosurgical procedure (craniotomy). During this operation, the skin of the head is removed and this results in a severe traumatic injury of the skin and the subcutaneous tissue. Generally, perioperative lid oedema is not unusual in newborns and infants and may represent a common surgical complication. The median total fluid input in patients with lid oedema was 217.8 mL kg−1 (HES 130/0.4) and 232.4 mL kg−1 (HA) and descriptively higher than median total fluid input of all patients of 168.9 mL kg−1 (HES 130/0.4) and 166.8 mL kg−1 (HA). In both groups, generally much higher volumes of crystalloids compared with colloids were given, especially post surgery. Anaemia was found in 7 (17.1%) patients of the HES 130/0.4 and in 9 (22.0%) of the HA group. One patient in the HA group died of cardiac arrest without close temporary relation to the control medication (one day after surgery), whereas no HES patient died. Other observed adverse events such as fever (body temperature >38.0°C in nine cases in each group, including two children in the HA group with signs of a respiratory infection presenting with enhanced bronchial secretion and cough), pain (status with a crying and/or restless child, which was resolved after application of analgesic in one case each), decreased urinary flow (<1.0 mL kg−1 h−1 in four cases each) and metabolic acidosis (standard bicarbonate concentration <20 mmol L−1 in the HES group in five cases, in the HA group in seven cases) were transient, and the patients recovered without sequelae. Length of ICU stay was 3.5 days (range 1–57 days, mean ± SD 7.6 ± 11.5 days) in the HES group and 6.0 days (range 1–71 days; mean ± SD 9.1 ± 14.2 days) in the HA group. There were no differences in length of hospital stay (median: 12 days for both groups).

Discussion

This prospective, controlled, randomized, open, multicentre pilot study investigated the effects of HES 130/0.4 for perioperative volume substitution in children below 2 yr of age in comparison to HA. HA is widely accepted as the standard therapy in this setting in terms of the benefits it offers over crystalloids because of the physiological hypoproteinaemia in newborns and infants [1,3,8]. Colloids such as HES are often preferred over pure crystalloid regimens because of their prolonged intravascular half-life, enhanced intravascular volume effect in cases of acute or massive blood losses [1,2] and their positive impact on blood rheology and tissue oxygenation [17–19].

Following our study, information on the use of HES 130/0.4 (Voluven®) in children was recently added to the product information in an European regulatory procedure. Although package labelling is not meant to rigidly determine medical practice and is no substitute for sound medical judgement [20], it is of advantage to have products available for the use in children not requiring off-label use.

HES 130/0.4 from maize starch is a relatively new HES preparation with the following physicochemical characteristics: a mean ± SD molecular weight of 130 000 ± 20 000, a molecular substitution of 0.4, a C2/C6 hydroxyethylation ratio of >8 and a more narrow molecular weight distribution curve compared with other HES specifications. Since the first HES generation (hetastarch, labelled, e.g. as HES 450/0.7, 550/0.7, 670/0.75), new formulations have been developed in order to improve the safety profile of HES. Pentastarch (HES 200/0.5) was the standard colloid volume substitution in Europe for about 20 yr. HES 130/0.4 represents the newest generation of HES formulations. Pharmacokinetic data in adults showed practically absent plasma accumulation after single [21] and multiple dose application [22] in contrast to less rapidly metabolizable HES products with a higher molar substitution [12]. Excretion of HES was still possible in cases of mild to severe non-anuric renal failure, and HES peak concentrations as well as terminal half-life were not affected. The area under the time concentration curve (AUC) only moderately increased by a factor of 1.7 when comparing subjects with a baseline creatinine clearance of <50 mL min−1 to those with ≥50 mL min−1 [23]. Despite improved pharmacokinetics and renal excretion, HES 130/0.4 was found equally effective as the less metabolizable HES 200/0.5 in prospective, randomized, double-blind studies [16,24,25]. Recently, James and colleagues [26] showed that the volume effect after HES 130/0.4 (6%) was more sustained compared with hetastarch in volunteers. A double-blind study in major orthopaedic patients confirmed similar effects of HES 130/0.4 and hetastarch in saline; equivalence of volume requirements for haemodynamic stabilization was statistically proven [27]. Based on these results it was reasonable to conclude that HES 130/0.4 can also be used effectively as a volume substitute in newborns and infants. Therefore, no invasive monitoring was justified or regarded as necessary for our setting.

Influence on haemostasis was recognized with the use of older HES solutions for perioperative volume replacement [14]. This effect is in part directly caused by HES molecules and partly due to the inevitable perioperative haemodilution. In our setting, there was no evidence for a difference in safety between HES 130/0.4 and HA in terms of haemostasis, regarding blood loss, use of blood products and measured coagulation parameters. Observed effects on Quick's value, aPTT and platelets were only related to the duration and the type of surgery.

The increase of α-amylase in the HES group was to be expected due to the well-known formation of HES–amylase complexes resulting in a decreased renal elimination of α-amylase. Interestingly, decreases of total protein did not differ much between groups despite the fact that HES does not contain protein.

Lid oedema was seen in some patients. This symptom is frequently encountered perioperatively in newborns and infants and probably related to postural factors, type of surgery (e.g. neurosurgery and maxillofacial surgery), as well as to crystalloid overload rather than colloid infusions. In our study, both groups received more crystalloids than colloids, especially in the postoperative period. During surgery and until 4 h postoperatively, the mean relation of crystalloids to colloids was about 4 : 1–5 : 1, and increased to >1 : 30 until the first postoperative day.

Concerns have been raised regarding the risk of hyponatraemia in the peri- and postoperative setting with the use of hypo-osmolar solutions [28,29]. In our study using iso-osmolar solutions, no case of hyponatraemia was reported.

Given the developmental physiological differences between newborns, infants and older children and the variety of surgical settings, a uniform perioperative dosing of volume therapy with colloids is not meaningful. Dosing has always to be adapted to the individual requirements. Hence, the volume replacement strategies used in this clinical study were those routinely used in the participating hospitals.

Some limitations of our study should be mentioned: Cardiac surgery patients were not studied, since we aimed to reduce heterogeneity. Secondly, no premature children were enrolled; therefore, no data for this patient group can be presented. Groups were compared using descriptive statistics, because due to the pilot nature of the study not one single parameter, but the entirety of several parameters, especially haemodynamics, adverse event profile and laboratory results was regarded as more relevant. The only death occurred in the HA group, but the study was not powered to show differences in mortality.

Prior study experience with HES types other than HES 130/0.4 is limited, but well in agreement with our results. Boldt and colleagues applied HES 200/0.5 (6%; n = 15; mean dose: 12.1 mL kg−1) or HA (20%; n = 15; mean dose: 8.5 mL kg−1) in the preoperative phase of cardiac surgery. COP was similar in both groups, despite expectedly higher plasma albumin concentrations in the HA group. The authors found no differences in the use of blood products and blood loss between groups [3]. In our study, COP decreased less and there was no relevant difference at all time points between groups. Liet and colleagues [30] gave fixed doses (10 mL kg−1) of either HES 200/0.5 (6%; n = 13) or HA (5%, n = 13) to neonates in order to facilitate placement of a central venous catheter. No increase in creatinine was found. Paul and colleagues [31] compared HES 70/0.5 (6%; n = 32) and Ringer's lactate (n = 30) during urologic surgery. Intraoperatively both groups received about 20 mL kg−1 fluids h−1. Input data for later time points is not given. Haemodilution effect was found greater in the HES group. Lid oedema similarly occurred in both groups in about half of the patients at 24 h [31]. Our coagulation results are in good agreement with those reported by Chong Sung and colleagues [32]. They studied 42 children scheduled for cardiac surgery and found that the choice of either 10 mL kg−1 HES 130/0.4 or fresh frozen plasma (FFP) directly after bypass had only a minor influence on coagulation parameters. The total use of FFP (including additional FFP) was higher in the FFP group (13.8 vs. 7.3 mL kg−1), without differences in RBC transfusion or blood loss.

In a non-surgical setting, resuscitation in dengue-shock syndrome, Wills and colleagues [33] compared Ringer's lactate, dextran 70 and HES 200/0.5 (6%). The randomization scheme was complex, with only two arms (either colloid) for the severe-shock cases. HES was found equally safe as Ringer's lactate in this setting, but significantly more possible adverse reactions were found with dextran compared with HES [33]. Dextrans are known to have the highest incidence of allergic reactions of all colloids because of preformed antibodies in some patients [10,34].

In our study, HES 130/0.4 has been clinically evaluated in newborns and infants. Overall, HES 130/0.4 and HA were well tolerated and there were no differences in the safety profiles of the two treatment groups of our study. HES 130/0.4 can be regarded as an alternative to HA for volume therapy in newborns and infants. Concluding from studies in adults HES 130/0.4 should be preferred to older, less rapidly metabolizable HES products.

Acknowledgements

Supported by a grant from Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany. Authors would like to thank their co-investigators Dr C. Stratmann (†), Department of Anaesthesiology, Childrens' Hospital, Cologne; Dr G. Schwarzmann, former affiliation: Clinic of Anaesthesiology and Intensive Medicine, University Hospital, Würzburg; Prof Dr D. Olthoff, Professor Emeritus and former Chairman of the Department of Anesthesiology and Intensive Medicine, University Hospital Leipzig; and Dr C. Becker, Department of Anesthesiology, University Hospital Hamburg-Eppendorf. Data management and statistical analysis were performed by Datamap GmbH (Biostatistics Institute), Freiburg, Germany. The authors are also greatly indebted to all participating study group members, the research fellows and the study nurses in every respective study centre.

Exclusion statement:

All authors exclude any type of conflict of interest with Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany.

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Keywords:

NEWBORN; INFANT; SURGERY; COLLOID; HYDROXYETHYL STARCH; HUMAN ALBUMIN

© 2008 European Society of Anaesthesiology