1University Department of Anaesthesia and Intensive Care Medicine, N5 Queen Elizabeth Hospital, Birmingham B15 2TH, UK. 2Classical & Bayesian Solutions, Orpington, Kent BR6 0EP, UK*Corresponding author
This paper was presented in abstract form at the Anaesthetic Research Society in Birmingham on July 11, 1996.
Accepted for publication: July 4, 2000
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2000; 85: 8505
Keywords: intensive care; neuromuscular block, atracurium; monitoring; children; liver, transplantation; monitoring, electromyography
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The use of atracurium administered by infusion has been reported in paediatric anaesthesia1 2 and intensive care,3 4 but there is little information about its pharmacokinetics and safety in critically ill children at risk of organ system dysfunction. Atracurium is metabolized by a combination of spontaneous degradation in plasma (Hofmann elimination) and ester hydrolysis by plasma esterases. These processes are independent of hepatic and renal dysfunction, and atracurium clearance remains relatively uniform and predictable even in adults with fulminant hepatic failure awaiting liver transplantation.5 However, this is not true of the main breakdown product of Hofmann degradation, laudanosine, which accumulates in these patients until successful graft function has been established.5 Laudanosine accumulation also occurs in patients with acute renal failure.6 The importance of this in clinical practice is unknown, but in animals laudanosine can cause electrophysiological seizure activity. The relationship between plasma laudanosine and seizure activity appears to be species-dependent. A steady-state laudanosine concentration of 17 µg ml1 produces seizures in dogs.7 In cats no EEG evidence of epileptiform activity occurs8 at plasma laudanosine concentrations of up to 100 µg ml1. In rabbits, a laudanosine concentration of 5 µg ml1 resulted in purposeless, uncoordinated movements of the entire body.9 There is one report of concentrations of 19 µg ml1 in a child after inadvertent overdose without any untoward effect.10 Plasma laudanosine concentrations have been monitored in adult ICU patients receiving atracurium by infusion11 and in children after a single bolus during surgery.12 There have been no reports of clinically apparent cerebral effects attributable to laudanosine in humans. The situation in paediatric ICU practice is less clear because of the paucity of information about the fate and potential toxicity of atracurium metabolites in children. The aim of this study was to evaluate the pharmacokinetics and also the efficacy and safety of atracurium infusions in children after OLT.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Arterial plasma samples for atracurium and its metabolites were taken from the indwelling arterial cannula on entry to the ICU and every 12 h during infusions. When the infusion was to be discontinued, samples were taken immediately before, then at 5, 10, 20, 30, 60 min and at 2, 6, 12, 24 and 48 h. Each heparinized 2 ml blood sample was centrifuged at 8000 g for 60 s, the plasma separated, 0.5 ml was acidified by addition to 2 ml of 15 mM sulphuric acid, mixed by inversion five times, and stored at 20°C. This process was completed within 3 min. Hourly urine volumes were recorded and the urine samples (0.5 ml) were stabilized by addition of 2 ml of cooled 0.5 M citrate buffer and then processed in the same way as the plasma samples. Samples were analysed at the Department of Bioanalysis and Drug Metabolism, Wellcome Research Laboratories, Beckenham, Kent, UK, using a modified high-performance liquid chromatography (HPLC) technique.13
The chromatographic conditions allowed separation and individual measurements of the three geometrical isomers of atracurium. The limit of quantification (LOQ) in plasma was about 5 ng ml1 for the atracurium isomers and assay reproducibility (from the lowest quality control sample at 10 ng ml1) was 18% (coefficient of variation). The plasma LOQ for the metabolites laudanosine, monoquaternary alcohol (MQA, cis isomer) and tetrahydropapaverine (THP) were 100, 70 and 100 ng ml1 respectively, and assay reproducibility at these limits was 12, 14 and 15% respectively.
The non-compartmental pharmacokinetics of atracurium (treated as the sum of the individual isomers), laudanosine, tetrahydropapaverine and the monoquaternary alcohol metabolite was studied. Safety was assessed by monitoring the plasma concentrations of laudanosine and other metabolites, recording adverse events, and daily electroencephalography (EEG). We recorded all drugs prescribed, daily fluid balance and physiological data relating to cardiac, renal, hepatic and cerebral function, and the PRISM (paediatric risk of mortality) score,14 an index of physiological stability and severity of illness.
Data are presented as either mean (range) or mean (SD). Linear correlation was used to examine univariate relationships; statistical significance was assumed at P<0.05.
The following pharmacokinetic abbreviations and calculations are used:5
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A typical plasma profile together with dosing details on return from the operating theatre is shown in Fig. 1.
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The half-lives of atracurium were similar to those reported for healthy children15 and children with stable impaired liver function.12 However, volumes of distribution and plasma clearances were much higher than in the other studies. A pharmacokinetic single-dose study12 comparing children with normal hepatic function with those awaiting liver transplantation showed no differences in atracurium pharmacokinetics (terminal t1/2 19.1 and 20.3 min respectively; CL 5.1 and 5.3 ml min1 kg1; VZ 139 and 152 ml kg1). Our patients after OLT had a similar mean t1/2 of 18.8 min but a considerably higher CL of 14.7 ml min1 kg1 and a VZ of 390 ml kg1. The constancy of t1/2 resulting from the predominance of elimination of atracurium from plasma by Hofmann degradation and ester hydrolysis suggests that the increase in VZ is a real volume change in paediatric ICU patients. The increase in CL compared with surgical paediatric patients is a consequence of the increase in VZ and lack of change in t1/2. Renal clearance is similar to that reported for adults.16
Comparison of these results with those which we have previously reported5 from adult patients with fulminant hepatic failure (FHF) undergoing liver transplantation shows that adults with functioning grafts have a similar t1/2 (17.6 min) but a lower CL (8.5 ml min1 kg1) and lower VZ (214 ml kg1). These comparisons imply that, on a body weight basis, ICU paediatric patients have a larger volume of distribution than corresponding adults, as reported by others.12 15 This is supported by the relatively lower atracurium infusion Cmax in our paediatric patients relative to the adult study (1712 vs 2723 ng ml1), even though maximum infusion rates were higher in the children (1.44 vs 0.96 mg kg1 h1). In agreement with the study in children of different ages,12 the increases in clearance and volume with weight (age) are not so marked if calculated on the basis of body surface area.
Laudanosine Cmax in the paediatric patients was lower than that in successfully transplanted adults with FHF (1190 vs 3993 ng ml1), probably because of better graft and renal function in the children. Laudanosine t1/2 was shorter in children compared with adults (3.9 vs 5.3 h) and the laudanosine:atracurium AUC ratio was correspondingly lower at 1.0 vs 1.3 in adults, confirming that the higher atracurium CL in children does not lead to greater relative exposure to laudanosine. Renal clearance of all atracurium metabolites increased with higher urine flow rates, a finding which was also reported in our corresponding adult study.5
The MQA Cmax in paediatric patients (986 ng ml1) was also lower than in adults with fulminant hepatic failure (1457 ng ml1), t1/2 was slightly longer (42.9 vs 36.8 min) and the MQA:atracurium AUC ratio was lower (0.6 vs 0.8). The pharmacokinetics of THP was only available for three patients, the others having plasma concentrations below the limit of quantification of 100 ng ml1. The behaviour of THP was broadly similar to that of the other metabolites. Cmax was lower than that in the adults (170 vs 777 ng ml1) and t1/2 shorter (15 vs 69 h).
We found the accelerometer an acceptable instrument for monitoring the intensity of, and recovery from, neuromuscular block in these children. An ICU study of accelerometry in neonates and children receiving vecuronium also found the technique useful, and demonstrated lower dose requirements for this neuromuscular blocking drug in those aged less than 1 yr.17
In conclusion, we have found that, although children require higher atracurium infusion rates on a body weight basis than adults to produce acceptable degrees of neuromuscular block for assisted ventilation after successful liver transplantation, plasma concentrations of atracurium are lower, because of higher clearance and greater volume of distribution per unit of body weight. Metabolite exposures, judged by ratios of plasma AUCs to those of atracurium, are also lower. These pharmacokinetic properties of atracurium make it a suitable choice for further evaluation in paediatric intensive care practice.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Ridley SA, Hatch DJ. Post-tetanic count and profound neuromuscular blockade with atracurium infusion in paediatric patients. Br J Anaesth 1988; 60: 315[Abstract]
3 Kushimo OT, Darowski MJ, Morris P, Hollis S, Meakin G. Dose requirements of atracurium in paediatric intensive care patients. Br J Anaesth 1991; 67: 7813[Abstract]
4 Piotrowski A. Comparison of atracurium and pancuronium in mechanically ventilated neonates. Intensive Care Med 1993; 19: 4015[ISI][Medline]
5 Bion JF, Bowden MI, Chow B, Honisberger L, Weatherley B. Atracurium infusions in patients with fulminant hepatic failure awaiting liver transplantation. Intensive Care Med 1993; 19: S94S98[ISI][Medline]
6 Parker CJ, Jones JE, Hunter JM. Disposition of infusions of atracurium and its metabolite, laudanosine, in patients in renal and respiratory failure in an ITU. Br J Anaesth 1988; 61: 53140[Abstract]
7 Chapple DJ, Miller AA, Ward JB, Wheatley PJ. Cardiovascular and neurological effects of laudanosine. Br J Anaesth 1987; 59: 21825[Abstract]
8 Ingram MD, Sclabassi RJ, Cook DR, Still RL, Bennett MH. Cardiovascular and electroencephalographic effects of laudanosine in nephrectomised cats. Br J Anaesth 1986; 58: 14S18S[Medline]
9 Shi W-Z, Fahey MR, Fisher DM, Miller RD. Modification of central nervous system effects of laudanosine by inhalation anaesthetics. Br J Anaesth 1989; 63: 598600[Abstract]
10 Charlton AJ, Harper NJN, Edwards D, Wilson AC. Atracurium overdose in a small infant. Anaesthesia 1989; 44: 4856[ISI][Medline]
11 Yate PM, Flynn PJ, Arnold RW, Weatherley BC, Simmonds RJ, Dopson J. Clinical experience and plasma laudanosine concentrations during the infusion of atracurium in the intensive therapy unit. Br J Anaesth 1987; 59: 2117[Abstract]
12 Brandom WB, Stiller RL, Cook DR, Woefel SK, Chakravorti S, Lai A. Pharmacokinetics of atracurium in anaesthetised infants and children. Br J Anaesth 1986; 58: 12103[Abstract]
13 Simmonds RJ. Determination of atracurium, laudanosine and related compounds in plasma by high performance liquid chromatography. J Chromatogr 1985; 343: 4316[Medline]
14 Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988; 16: 11106[ISI][Medline]
15 Ward S, Boheimer N, Weatherley BC, Simmonds RJ, Dopson TA. Pharmacokinetics of atracurium and its metabolites in patients with normal renal function, and in patients in renal failure. Br J Anaesth 1987; 59: 697706[Abstract]
16 Fisher DM, Canfell PC, Spellman MJ, Miller RD. Pharmacokinetics and Pharmacodynamics of atracurium in infants and children. Anesthesiology 1990; 73: 337[ISI][Medline]
17 Hodges UM. Vecuronium infusion requirements in paediatric patients in intensive care units: the use of acceleromyography. Br J Anaesth 1996; 76: 238