Pharmacokinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantation{dagger}

B. Chow1, M. I. Bowden1, E. Ho1, B. C. Weatherley2 and J. F. Bion1

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

{dagger}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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We examined the pharmacokinetics and pharmacodynamics of atracurium besylate and its metabolites in children after orthotopic liver transplantation (OLT), as a suitable model for critically ill children. Ten children were studied after OLT on return to the intensive care unit (ICU). The mean (range) age was 36 (7–78) months, and weight 6–24.2 kg. Atracurium was started at induction of anaesthesia and adjusted in the ICU according to clinical need. Neuromuscular block was measured using accelerometry (TOFguard) and the train-of-four (TOF) ratio or count. Arterial plasma samples for atracurium and metabolites taken before, 12-hourly during, and at frequent intervals after the infusion were analysed by HPLC. The mean (range) maximum infusion rate during steady-state conditions was 1.44 (0.48–3.13) mg kg–1 h–1 and the duration of infusion 36.9 (22.5–98.4) h. Tachyphylaxis was not observed. The mean terminal half-life (t1/2) for atracurium was 18.8 (12–32.3) min. The steady-state plasma clearance (CLss) was 13.9 (7.9–20.3) ml min–1 kg–1 and the terminal volume of distribution (VZ) 390 (124–551) ml kg–1; both were higher than in adults after successful OLT. The maximum concentration (Cmax) of laudanosine was 1190 (400–1890) ng ml–1 and t1/2 was 3.9 (1.1–6.7) h. The renal clearance of laudanosine was 0.9 (0.1–2.5) ml min–1 kg–1 and increased with urine flow, but there was no significant relationship with serum creatinine. EEG spikes were confirmed in one child only; the corresponding laudanosine Cmax was 720 ng ml–1. Monoquaternary alcohol Cmax was 986 (330–1770) ng ml–1 and t1/2 42.9 (30–57.7) min. Mean recovery time on stopping the atracurium infusion to a TOF ratio >0.75 was 23.6 (12–27) min. Atracurium is an effective and safe neuromuscular blocking agent in this population. Laudanosine concentrations are not excessive if graft function is satisfactory.

Br J Anaesth 2000; 85: 850–5

Keywords: intensive care; neuromuscular block, atracurium; monitoring; children; liver, transplantation; monitoring, electromyography


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
It is routine practice to sedate and mechanically ventilate children after orthotopic liver transplantation (OLT) until they are physiologically stable and there is evidence of satisfactory graft function. This ensures adequate oxygenation, and allows the administration of potent analgesic drugs without compromising respiratory function. It is often difficult to control ventilation without the use of a neuromuscular blocking drug. However, as both hepatic and renal dysfunction may occur after OLT, the ideal neuromuscular blocking drug for these patients would be one whose clearance and elimination were independent of these two organs, with inactive non-cumulative metabolites, no effects outside the neuromuscular junction, a relatively short duration of action avoiding the problems of prolonged block, and modest cost. Such an agent does not exist but, of those currently available, atracurium appears to satisfy most of these criteria.

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 ml–1 produces seizures in dogs.7 In cats no EEG evidence of epileptiform activity occurs8 at plasma laudanosine concentrations of up to 100 µg ml–1. In rabbits, a laudanosine concentration of 5 µg ml–1 resulted in purposeless, uncoordinated movements of the entire body.9 There is one report of concentrations of 19 µg ml–1 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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After local ethics committee approval, written informed consent for the study was obtained from the parents of 10 children who were to undergo OLT. The mean age (range) was 36 months (7–78). Five were male. The cause of liver failure was biliary atresia with portal hypertension in seven patients; the others had Crigler–Najjar syndrome (congenital deficiency of glucuronyl transferase causing non-haemolytic jaundice), type 1 tyrosinaemia, and hepatitis A (Table 1).


View this table:
[in this window]
[in a new window]
 
Table 1 Individual patient diagnoses, biochemical data, PRISM score, laudanosine kinetics, EEG, atracurium infusion data, TOF recovery and outcome. *Aspartate transaminase at end of infusion period (IU/litre); {dagger}serum creatinine at end of infusion
 
Atracurium was started in the operating theatre with an intravenous bolus of 0.5 mg kg–1 followed by an infusion at an initial rate of 0.25 mg kg–1 h–1. The infusion was continued throughout the transplantation. On return to the ICU after OLT, the total dose of atracurium used during the procedure was recorded and arterial blood and urine samples were taken for subsequent analysis (see below). Analgesic sedation was provided using a continuous infusion of alfentanil (maximum 1 µg kg–1 min–1) supplemented with chloral hydrate 30–50 mg kg–1 (maximum 1 g) enterally if required. Neuromuscular block was measured using a peripheral transcutaneous nerve stimulator and an accelerometer. Central and peripheral temperatures were recorded with each plasma and urine sample. The train-of-four (TOF) ratio or TOF count was recorded as appropriate. The atracurium infusion rate was adjusted according to clinical need by the attending ICU medical staff; if there was no spontaneous muscle movement the infusion rate was reduced until a TOF count of more than 1 was recorded. The TOF count or ratio was checked every 30 min for the first 4 h on the ICU and then every 12 h throughout the infusion. The clinical adequacy of muscle relaxation was also noted during the infusion period. When the infusion was stopped, the time taken for clinical recovery and the time for the TOF ratio to reach 0.75 were recorded.

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 ml–1 for the atracurium isomers and assay reproducibility (from the lowest quality control sample at 10 ng ml–1) 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 ml–1 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


View this table:
[in this window]
[in a new window]
 
 

    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Data from nine patients (four male, five female), with successful liver transplants, of age 7–78 months and weight 6.0–24.2 kg, were analysed. The remaining patient (male, age 59 months, weight 15 kg) died shortly after an unsuccessful transplant. In this patient, only Cmax and tmax are reported, because samples after the termination of the atracurium infusion could not be obtained. One patient (patient 9) had chronic renal impairment; the remaining eight patients had normal renal function, as assessed by urine output and serum creatinine concentration (Table 1).

A typical plasma profile together with dosing details on return from the operating theatre is shown in Fig. 1.



View larger version (22K):
[in this window]
[in a new window]
 
Fig 1 Plasma concentrations of atracurium, laudanosine, monoquaternary alcohol and tetrahydropapaverine for a typical patient. The solid line (right ordinate) shows the infusion rate; arrows indicate bolus doses of 0.5mg kg–1. The vertical dashed line represents the end of transplantation and the vertical solid line the end of infusions, after which terminal half-lives were determined.

 
A summary of atracurium dose, duration and kinetics is shown in Table 2. The total dose of atracurium ranged from 13 to 73.9 mg kg–1 and the period of infusion from 22.5 to 98.4 h. Maximum supplementary bolus doses were 0.48–2.5 mg kg–1 (mean 1.28 mg kg–1) and maximum infusion rates were 0.48–3.13 mg kg–1 h–1 (mean 1.44 mg kg–1 h–1). Peak plasma concentrations of atracurium ranged from 887 to 2907 ng ml–1 with a mean of 1712 ng ml–1. Patient 10 was excluded from this calculation when Cmax occurred close to a bolus injection of atracurium immediately after transplantation. Mean t1/2 was 18.8 (6.4) min (12.0–32.3 min). Mean VZ was 390 (152) ml kg–1 (124–551 ml kg–1). Mean CLSS was 13.9 (4.2) ml min–1 kg–1, similar to the mean CL of 14.7 (5.9) ml min–1 kg–1. There were no obvious trends in CLSS with respect to time or infusion rate. The CLR increased with urine flow rate, averaging 1.7 (1.2) ml min–1 kg–1 (0.1–3.7 ml min–1 kg–1), which was around 12% of the total atracurium clearance.


View this table:
[in this window]
[in a new window]
 
Table 2 Atracurium infusion data and kinetics. *Patient 6 excluded; {dagger}patient 10 excluded (see text)
 
Peak concentrations of laudanosine ranged from 400 to 1890 ng ml–1, and mean Cmax was 1190 (548) ng ml–1 (Table 3). The mean tmax of 29.3 (12.7) h was about 2 h longer than the atracurium tmax. Half-lives ranged from 1.1 to 6.7 h and the mean laudanosine t1/2 was 3.9 (2.3) h. The mean ratio of laudanosine AUC to atracurium AUC (RAUC(m)) was 0.98 (0.6) (range 0.3–2.05). Mean CLR was 0.9 (0.8) ml min–1 kg–1 (0.1–2.5 ml min–1 kg–1). There was no relationship between laudanosine CLR and plasma creatinine concentration.


View this table:
[in this window]
[in a new window]
 
Table 3 Laudanosine kinetics (n=9). *n=6
 
Data for MQA and THP kinetics are shown in Table 4. Renal clearance of all atracurium metabolites increased with urine flow rate.


View this table:
[in this window]
[in a new window]
 
Table 4 Kinetics of monoquaternary alcohol (MQA) and tetrahydro papaverine (THP)
 
All patients had a satisfactory level of paralysis, as judged clinically or by transcutaneous nerve stimulation using acceleromyography. Despite prolonged infusion, when atracurium was discontinued the neuromuscular recovery time was rapid (mean 23.7 min with TOF >0.75). There was no clinical or electromyographic evidence of prolonged block. Only one patient demonstrated EEG evidence of spike activity; there was no apparent association with plasma laudanosine concentration (Table 1). No other adverse effects were reported during the study.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Although atracurium is used for neuromuscular block in children, there is little published data on the pharmacokinetics of atracurium, especially its metabolites in paediatric patients in general, and none for paediatric intensive care. We chose to study children after OLT because transient impairment of liver and renal function is common after this operation, and they may therefore provide a model for multiple organ dysfunction of relevance to paediatric intensive care practice. Moreover, laudanosine is probably metabolized by the liver5 and cleared both by this organ and by the kidneys.6

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 min–1 kg–1; VZ 139 and 152 ml kg–1). Our patients after OLT had a similar mean t1/2 of 18.8 min but a considerably higher CL of 14.7 ml min–1 kg–1 and a VZ of 390 ml kg–1. 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 min–1 kg–1) and lower VZ (214 ml kg–1). 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 ml–1), even though maximum infusion rates were higher in the children (1.44 vs 0.96 mg kg–1 h–1). 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 ml–1), 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 ml–1) was also lower than in adults with fulminant hepatic failure (1457 ng ml–1), 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 ml–1. 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 ml–1) 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
 
We wish to thank our nursing and medical colleagues for their help with this study, and to acknowledge Mr G. Lovell and Mr J. Morgan for their bioanalytical support. The study was funded by a research grant from Glaxo Wellcome, the manufacturer of atracurium (Tracrium). The authors have no financial interest in this company or its product.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Goudsouzian N, Martyn J, Rudd GD, Liu LMP, Lineberry CG. Continuous infusion of atracurium in children. Anesthesiology 1986; 64: 171–4[ISI][Medline]

2 Ridley SA, Hatch DJ. Post-tetanic count and profound neuromuscular blockade with atracurium infusion in paediatric patients. Br J Anaesth 1988; 60: 31–5[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: 781–3[Abstract]

4 Piotrowski A. Comparison of atracurium and pancuronium in mechanically ventilated neonates. Intensive Care Med 1993; 19: 401–5[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: S94–S98[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: 531–40[Abstract]

7 Chapple DJ, Miller AA, Ward JB, Wheatley PJ. Cardiovascular and neurological effects of laudanosine. Br J Anaesth 1987; 59: 218–25[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: 14S–18S[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: 598–600[Abstract]

10 Charlton AJ, Harper NJN, Edwards D, Wilson AC. Atracurium overdose in a small infant. Anaesthesia 1989; 44: 485–6[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: 211–7[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: 1210–3[Abstract]

13 Simmonds RJ. Determination of atracurium, laudanosine and related compounds in plasma by high performance liquid chromatography. J Chromatogr 1985; 343: 431–6[Medline]

14 Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988; 16: 1110–6[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: 697–706[Abstract]

16 Fisher DM, Canfell PC, Spellman MJ, Miller RD. Pharmacokinetics and Pharmacodynamics of atracurium in infants and children. Anesthesiology 1990; 73: 33–7[ISI][Medline]

17 Hodges UM. Vecuronium infusion requirements in paediatric patients in intensive care units: the use of acceleromyography. Br J Anaesth 1996; 76: 23–8[Abstract/Free Full Text]





This Article
Abstract
Full Text (PDF)
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (3)
Disclaimer
Request Permissions
Google Scholar
Articles by Chow, B.
Articles by Bion, J. F.
PubMed
PubMed Citation
Articles by Chow, B.
Articles by Bion, J. F.