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© Borgis - Anaesthesiology Intensive Therapy 1/2001
Bogumiła Wołoszczuk-Gębicka
Pharmacodynamics of atracurium in children during nitrous oxide/opioid anaesthesia
Department t of Anaesthesiology and Intensive Therapy,
Head: prof. T. Szreter, "Child Health Centre-Memorial" Institute, Warsaw, Poland
Summary
Neuromuscular block, produced by atracurium, was assessed in 25 children (2-11 yrs), ASA I and II, undergoing surgery under N2O/O2/fentanyl anaesthesia. Neuromuscular transmision was monitored using Relaxograph (Datex) monitor and train-of-four stimulation, at the ulnar nerve at wrist every 20 seconds. An electromyographic potentials were recorded from the adductor pollicis muscle.
An initial (intubating) doses of atracurium: 0,1, 0,2, 0,3, 0,4, or 0,5 mg/kg were given to five groups of children (n=5). The maximum neuromuscular block obtained from each dose and the onest time to the maximum block were noted. ED50 and ED95 were calculated. Exponential fitting curves, describing the onest of the neuromuscular block were constructed for each group, and the time to the T1 90% recovery block the first twitch (T1) was noted.
Additional doses of atracurium, 0.1 mg/kg were given when T1 returned to 25% of the control value. The duration of the clinical block (T1<25%) after the maintenance doses was noted. In 19 children the spontaneous recovery of the neuromuscular transmission was allowed. Recovery index and the time from the administration of the last dose of atracurium to the T1=90% and TR=70% were also measured.
The ones time (to the atraumatic intubation) was app. 2.5 minutes, clinical duration of the block - 14 minutes and time from last dose of atracurium to T1>= 90% and TR>= 70% was 30 minutes and was significantly shorter than in adults.
Atracurium (atracurium benzylsulfonate, Tracrium®, Glaxo Wellcome) is a non-depolarising muscle relaxant belonging to the group of benzylisochinolones. It was synthesised in 1979 and introduced to clinical practice in Great Britain in 1982. It is characterised by a moderately long time of action. The difference between atracurium and all other non-depolarising muscle relaxants is its spontaneous degradation through the Hoffman elimination pathway. This reaction, described in 1951, consists of spontaneous degradation of quaternary ammonium salts to tertiary amines at high temperature (100°C) and highly alkaline pH. The analogic reaction for atracurium is observed at pH 7.4 and temperature 37°C [1]. Owing to the phenomenon of Hoffman's elimination the recovery of muscle function after atracurium is independent from hepatic and renal function. Atracurium is also hydrolysed by non-specific plasma esterases (e.g. aliesterase). Diminished esterase activity of does not significantly influence atracurium pharmacokinetics. A lack of typical cholinesterase as well as the presence of its atypical form does not influence the duration of muscle relaxation [2]. The degradation process, however, is markedly prolonged in hypothermia. At normal temperature and pH the half-time of atracurium elimination equals about 25 minutes and does not differ in patients with renal [3, 4] or hepatic failure from that in otherwise healthy persons. That is why atracurium can be safely used in patients with severely compromised kidney or liver function [5].
The main product of atracurium metabolism is laudanosine, exerting a weak muscle relaxant action. It can cross to the cerebrospinal fluid (CSF) and may cause seizures (in dogs at a concentration of 17 µm/ml)[6]. In humans, during general anaesthesia the CSF concentration of laudanosine averages 200 nm/ml [6], and in intensive care patients (receiving atracurium in continuous i.v. infusion) - 5 µm/ml [7]. These concentrations are much lower than those causing seizures in experimental dogs are. The metabolites of atracurium are detected in bile and urine seven hours after its administration.
Atracurium does not accumulate during repeated dosage or continuous i.v. infusion and the neuromuscular blockade can easily be reversed by neostigmine or edrofonium. Inhalation anaesthetic agents minimally enhance the degree of neuromuscular block caused by atracurium [8], but their presence slows down the spontaneous return of neuromuscular transmission [9].
Similar to other benzylisochinolone compounds, atracurium triggers histamine release, manifesting clinically by skin flushing and tachycardia [10]. The incidence of adverse effects related to histamine release increases proportionally to the dose of atracurium [11]. A severe bronchospastic reaction after a dose of 1 mg/kg of atracurium has been described [12]. In children aged 1-3.5 years no histamine concentration increase in serum was noted after an intubation dose of the drug [13].
The blocking of transmission in neural plexuses, causing tachycardia and hypotension, develops after high doses of atracurium, much higher than required for neuromuscular block [14].
The rate of adverse reactions after atracurium administration is similar to that observed with other muscle relaxants [15,16]. Atracurium has found its place both in adult and paediatric anaesthesia [17].
The aim of the present study was to analyse the course of muscle relaxation in children anaesthetised with a N2O/O2 mixture and fentanyl.
METHODS
After obtaining permission of he local Ethical Committee, the degree of neuromuscular blockade caused by atracurium was monitored in 25 children, aged from 2 to 11 years. All children were classified as ASA grade I or II and underwent elective general, urologic or ophthalmologic surgical procedures requiring muscle relaxation. Children with nervous system diseases, myopathy, electrolyte disturbances, kidney and liver insufficiency, morbid obesity, as well as those receiving drugs influencing neuromuscular transmission were excluded from the study.
Premedication consisted of atropine 0.02 mg/kg and pethidine 1 mg/kg. i.m., 30 minutes before the induction of anaesthesia. At induction, thiopentone 5 mg/kg and fentanyl 5-10 µg/kg were administered intravenously. The maintenance of anaesthesia consisted of a N2O/O2 mixture (60% N2O) and fractionated doses of fentanyl (1-5 µg/kg per dose). All children were artificially ventilated, the end-tidal CO2 pressure was maintained at 30-40 mmHg (4-5.33 kPa).
Neuromuscular relaxation was monitored electromyographically (Relaxograph, Datex, Finland) [18]. Electromyographic (EMG) potential was recorded from the adductor pollicis muscle by 2 superficially placed electrodes, after ulnar nerve stimulation. The nerve was stimulated with 4 supramaximum impulses (frequency 2 MHz) repeated every 20 seconds (train-of-four {TOF} technique). Two superficial stimulating electrodes were placed at the patients' wrist. Measurements were started after the induction of anaesthesia. The degree of neuromuscular block was assessed by two parameters: the ratio of the response after the first TOF stimulation in comparison with the baseline value (before administering of muscle relaxant) - T1, and the ratio of the response to the fourth TOF impulse as compared with the first one in a given series - TR (%).
Patients were divided into 5 groups of 5 children each according to the intubation dose of atracurium: group I - 0.1 mg/kg; group II - 0.2 mg/kg; group III - 0.3 mg/kg group IV - 0.4 mg/kg and group V - 0.5 mg/kg. When the initial dose of the drug did not result in muscle relaxation enabling the smooth tracheal intubation, the dose of atracurium was increased to reach in total 0.4 mg/kg. Additional doses, of 0.1 mg/kg., were administered if the response to the first stimulation during 4 consecutive T1 returned to 25% of the baseline level.
In the majority of children, normal neuromuscular transmission returned spontaneously. In only 6 of them, in whom surgery was shorter than anticipated, the block was reversed with neostygmine 0.03-0.06 mg/kg after atropine 0.02-0.03 mg/kg administration.
Fig. 1. Intraoperative relaxograph tracing.
Parameters analysed:
the action of the initial dose of atracurium (E1max) and the time interval from its administration to the maximal effect of the drug (tE1 max); time to reach 90% of T1 block (t90); the action of maintenance doses (E2max ... E4max) and the duration of "clinical" muscle relaxation after each dose (tklin2 ... tklin4); the recovery factor: interval between T1=25% to T1=75% of the baseline (RF25-75); time interval from the last maintenance dose to the disappearance of major clinical signs of neuromuscular blockade (T1>=90% and TR>=70%).

The following parameters were analysed (Fig.1):
– the action of the intubation dose of atracurium (E1max) and the time interval from its administration to the maximal effect of the drug (tE1 max);
– dynamics of development of muscle relaxation after the intubation dose and the time to reach 90% of block to the first stimulation at the TOF test (t90);
– ED50 dose (i.e. the dose causing at its peak, diminishing of T1 by 50% as compared with the baseline value);
– the action of maintenance doses (E2 max ... E4max) and the duration of "clinical muscle relaxation" after each dose (manifested by T1 not exceeding 25% of the baseline).
A spontaneous return of neuromuscular function was observed in 19 children.
Parameters analysed in this group included:
– the recovery index: interval between T1=25% to T1=75% (R25-75);
– time interval from the last maintenance dose to the disappearance of major clinical signs of neuromuscular block (T1>=90% and TR>=70%).
Statistical analysis of the results was performed with ANOVA and Student-Newman-Keuls tests. Significance between differences was established at a p level <0.05.
The efficient doses (ED50 and ED95) were calculated according to probit-logarythmic method [19].
The neuromuscular block development was assessed by measuring T1 value every 20 seconds). For each group the curves were plotted (Statistica software) according to the method of the smallest squares. The curves illustrated the T1 values as a function of time (Fig. 2). Time to 90% block at T1 was calculated from the graphs.
Fig. 2. The dynamics of neuromuscular blockade after administration of 0.3 mg/kg atracurium. The "best-fit" curve plotted according to the smallest squares method.
Statistical analysis was performed with the analysis of variance and Student-Newman-Keuls tests. Significance between differences was established at a p level <0.05.
RESULTS
The muscle relaxation dynamics was analysed in 25 children aged 5.7 ± 2.7 years, weighing 20.8 ± 8.1 kg. Age (p.<0.99) and body weight (p.<0.76) did not differ significantly between groups (Tab. I).
Table I. Patients' age and body weight
GroupNumberAge [years]
(mean ± SD)
Body weight [kgs] 
(mean ± SD)
I55.44 ± 3.2722.1 ± 9.3
II56.10 ± 5.5120.0 ± 8.3
III56.10 ± 3.5120.4 ± 7.5
IV54.48 ± 3.2124.6 ± 14.2
V55.88 ± 1.7217.1 ± 1.8
The action of the first atracurium dose (E1max), time interval to the maximal intensity of neuromuscular blockade (tE1max) and to the 90% blockade at T1 (t90) are presented in Table II.
Table II. The action of the intubation dose of atracurium
GroupAtracurium dose [mg/kg]E1max (%)t E1max (%)t90
I0.110 ± 2.65 min 50 s ± 36 s-
II0.259 ± 10.54 min 40 s ± 18 s-
III0.391 ± 3.14 min 40 s ± 24 s -
IV0.493 ± 1.54 min 20 s ± 18 s3 min 30 s ± 1 min 55 s
V0.596 ± 1.43 min 00 s ± 24 s2 min 28 s ± 1 min 23 s
The action of the initial dose of atracurium (E1max) and the time interval from its administration to the maximal effect of the drug (tE1 max) and the time interval to reach 90% of T1 block (t90). All results are presented as mean ± SD values.

The response to the first stimulation in the TOF test diminished to less than 10% of the baseline in all patients from groups 4 and 5 and in 4 patients from group 3. The mean time interval to diminish the EMG response from the hand muscles by 90% (t90) was 4min 35s in 4 out of 5 patients from this group. In the fifth child, the minimal observed value equalled 26% as compared with the baseline. The increase of atracurium dose to 0.4 mg/kg shortened t90 to 3min 30s(± 1' 55"), and to 0.5 mg/kg - to 2min 28s(p<0.25).
The dynamics of neuromuscular blockade in children from groups 4 and 5 is presented in Fig. 3.
Fig. 3. Comparison of neuromuscular block course following administration of 0.4 mg/kg (Group 4) and 0.5 mg/kg (group 5) of atracurium.
The calculated value of ED50 was 189 mg/kg/ of body weight.
A maintenance dose of atracurium 0.1 mg/kg, after the spontaneous return of T1 value to 25% of the baseline (in TOF demonstrated by a single twitch) intensified the neuromuscular block by 92 ± 2.3% T1 after the first dose, and by 94 ± 4.8% after the third one. The differences between the action of repeated doses of the drug were not statistically significant. The same was observed for the duration of "clinical muscle relaxation" (T1<25%), which equalled 14 min 20 s ± 3 min 54 s and 13 min 20 s ± 1 min 48 s respectively. No accumulation of the repeated maintenance doses of the drug was noted. The mean time of muscle relaxation equalled 14 minutes (± 2 min 8 s).
RI25-75value was 10 min 46 s ± 1 min 38 s and the time from the last maintenance dose administration to the return of neuromuscular function (T1>=90% and TR?70%) was 30 min 20 s (± 2 min 56 s).
DISCUSSION
The action of atracurium is weaker action in children than in adults, which is demonstrated by higher values of ED50 (Tab. III).
Table III. ED50 value in children and adults
 ChildrenAdults* (n=5)
ED500.179 ± 0.01 (20)
0.169 (21)
0.189 **
0.12 (0.08 - 0.15)
ED50 value reflects the dose of atracurium causing the diminishing of T1 by 50% from the baseline at its peak of action
** ED50 is presented here as a median and range of values on the basis of results from different reports [22]; n=number of the publication cited
** own results from the present study

This phenomenon is related to the chemical structure of nondepolarising muscle relaxants. Their highly polarised molecules do not cross the cellular membranes, which causes that their volume of distribution is the extracellular water volume which is greater in children (per kg of body weight) than in adults.
Administration of muscle relaxant drugs causes neuromuscular block in the masticators [23], laryngeal muscles [24] and diaphragm [25] earlier than in the muscles of the hand. That is why laryngoscopy and atraumatic tracheal intubation can be smoothly performed at the 90% level reduction of neuromuscular transmission in the hand and do not require complete blockade.
The increase in initial dose shortens the time of neuromuscular block (T1) development (Fig. 3), 90% shortening of T1 block in the muscles of the hand and reduction of time to the maximal relaxation (Tab. I). Higher doses, however, prolong the duration of muscle relaxation [26] and, as with atracurium and other benzylisochinolinic compounds, may increase the rate of untoward effects related to histamine release.
Clinical observations in children [27] demonstrated significant differences in the duration of action of maintenance doses, as compared with adult patients. Multicentre trials performed in adults demonstrated that after a maintenance dose of 0.1 mg/kg, resulting in 91.5 ± 0.9% T1 block, the mean time of "clinical relaxation" equals 22.3 min ± 1.0 [28], which is 50% longer than in children.
The repeated doses of atracurium accumulate only minimally. The comparison of duration of "clinical relaxation" (T1<25%) after the first and the third maintenance doses did not demonstrate prolongation of action. In his report, however, Ali [28] found that in adults, anaesthetised with N2O and fentanyl, the return of T1 from 5 to 25% is significantly prolonged after the fifth maintenance dose, as compared with an intubation dose (9.7min ± 0.8 and 7.6 min ± 0.5 respectively). The same was noted for the relaxation duration (13.2 min ± 0.6 and 11.8 min ± 0.5). The differences were statistically significant, but the absolute values difference did not exceed 15%.
In the present study, RI value for spontaneous return of neuromuscular function was 10 min 49s ± 1 min 38s. In the paper by Goudsouzian et al. [20] this value in children ranged from 9.2 to 11.1 min. and was lower than in adults (19.1 min.) [28].
In children anaesthetised with N2O/O2 and fentanyl, the interval from the administration of the last maintenance dose of atracurium to the spontaneous return of neuromuscular function enabling safe extubation (T1>=90% and TR>=70%) equals about 30 min 20 s(± 2 min 56 s).
CONCLUSIONS
1. The pharmacological effect of atracurium is weaker in children than in adults; ED50 averaging 189 mg/kg b.w.
2. Safe atraumatic tracheal intubation in children may be performed after 2.5-3.5 minutes from administration of atracurium at a dose 0.4-0.5 mg/kg.
3. In children under N2O/O2 and fentanyl anaesthesia, "clinical" muscle relaxation (T1<25%) persists about 14 minutes after a maintenance dose of atracurium 0.1 mg/kg.
4. Repeated maintenance doses do not cause prolonged action of atracurium.
5. The time interval from the administration of the last maintenance dose of atracurium to the spontaneous return of neuromuscular function (T1>=90% and TR>=70%) is about 30 minutes.

Originally published in Anestezjologia Intensywna Terapia 31; (3), 161-166, 1999.
Piśmiennictwo
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Adres do korespondencji:
Al. Dzieci Polskich 20; 04-736 WARSAW, Poland

Anaesthesiology Intensive Therapy 1/2001