POST-TETANIC COUNT AND INTENSE NEUROMUSCULAR BLOCKADE WITH VECURONIUM IN CHILDREN

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1 Br. J. Anaesth. (988), 6, POST-TETANIC COUNT AND INTENSE NEUROMUSCULAR BLOCKADE WITH VECURONIUM IN CHILDREN S. A. RIDLEY AND N. BRAUDE Monitoring of profound neuromuscular blockade may be based on post-tetanic facilitation because it persists at a greater depth of neuromuscular blockade than the train-of-four (TOF) or single twitch response []. However, individual neuromuscular blocking drugs may be associated with varying degrees of fade (tetanic and TOF) and hence the presence or absence of the fourth twitch of the TOF may be associated with different absolute degrees of block, depending on the drug used []. In addition, the TOF response is difficult to quantify accurately by simple visual means without complex monitoring equipment [3]. The post-tetanic count (PTC) has been used to assess the level of profound neuromuscular blockade with atracurium [4]. As post-tetanic facilitation is a presynaptic phenomenon [5] and as neuromuscular blocking drugs have different presynaptic effects [6], PTC is unlikely to relate precisely to intensity of paralysis for all agents. Vecuronium is a medium acting neuromuscular blocking drug which may be used by infusion. After a bolus dose, once recovery of neuromuscular function has started it proceeds quickly [7]. Therefore, to provide adequate paralysis over longer periods, profound neuromuscular blockade may be required. The aim of this study was to examine how the PTC varied with intense neuromuscular blockade induced with a vecuronium infusion and to identify if the return of the TOF may be predicted from the PTC. PATIENTS AND METHODS The study was approved by the hospital Ethics Advisory Committee but, as neuromuscular func- S. A. RIDLEY*, M.B., B.S., F.F.A.R.C.S.; N. BRAUDE, M.B., CH.B., M.R.C.P., F.F.A.R.C.S. ; The Hospitals For Sick Children, Great Ormond Street, London WCN 3JH. Accepted for Publication: March, 988. *Present address for correspondence: Clinical Shock Study Team, Western Infirmary, Glasgow Gil 6NT. SUMMARY Sixty children undergoing surgery were allocated, according to weight, to three equal groups. Each child received a loading dose of vecuronium 80 ng kg~ followed immediately by an infusion set initially at.4 ng kg min~'. The subsequent intense neuromuscular blockade was assessed using the post-tetanic count (PTC). Maintaining the PTC between 5 and 5 ensured adequate paralysis which was antagonized easily 6-8 min after stopping the infusion. However, the duration of the initial intense block was unpredictable and the use of a peripheral nerve stimulator is advisable, particularly in smaller infants (<5kg). The results suggest that vecuronium accumulated after 3 h infusion and that has less presynaptic effect than atracurium. tion is monitored frequently, parental consent was not requested. Sixty patients undergoing a variety of surgical procedures requiring mechanical ventilation of the lungs were studied. The patients were allocated to one of three equal groups according to body weight (group = < 5 kg; group =5-5 kg; group 3 = > 5 kg). All patients were free from hepatic or neuromuscular disease, and none was receiving any drugs that could interfere with neuromuscular function. Patients younger than 8 months of age and all neurosurgical patients received atropine 0.0 mg kg" i.m. 45 min before anaesthesia. Older children who weighed less than 5 kg were premedicated with Pethidine Compound ml kg" ( ml contains pethidine 5 mg, promethazine 6.5 mg and chlorpromazine 6.5 mg). Children heavier than 5 kg received papaveretum 0.4 mg kg" and hyoscine mg kg" 90 min before induction of anaesthesia.

2 55 BRITISH JOURNAL OF ANAESTHESIA Anaesthesia was induced with 50% cyclopropane in oxygen or with thiopentone 5 mg kg". Neonates underwent tracheal intubation awake while all other patients received suxamethonium mg kg". Anaesthesia was maintained with 0.5 % halothane and 67 % nitrous oxide in oxygen delivered by a paediatric T-piece. Electrocardiogram, arterial pressure (Dinamap), and praecordial heart and breath sounds were monitored in all patients. After the suxamethoniuminduced paralysis had worn off, a constant current peripheral nerve stimulator (Bard Biomedical) provided supramaximal stimuli for all measurements, using adult surface electrodes placed over the posterior tibial nerve behind the medial malleolus or the ulnar nerve at the wrist. Patients' lungs were ventilated with a Nufneld 00 ventilator (Penlon) using a paediatric valve which converted the machine to a pressure generator and enabled it to deliver smaller tidal volumes [8]. After clinical recovery from the suxamethonium-induced paralysis and when no further increase in visible twitch response ( Hz) was apparent with supramaximal stimulation, a loading dose of vecuronium 80 ug kg" was given. This was followed immediately by an infusion set initially at.4 ug kg" min". The intensity of neuromuscular blockade was monitored by assessing the visible twitches in response to the following standardized sequence of stimulation, modified from that described by Viby-Mogensen and others [9] and described previously [4]: (a) a train-of-four, repeated every s if necessary for reassessment (b) a 30-s delay (c) tetanic stimulation (50 Hz) for 5 s (d) a 3-s delay (e) single twitch stimulation at Hz lasting 60 s, counting the number of visible twitches. The neuromuscular blockade was assessed first 6 min after the bolus dose and then at 6-min intervals, so avoiding the effect of the tetanic stimulation on the subsequent cycle. The intensity of neuromuscular blockade was adjusted using the following regimen: (i) If the bolus dose had failed to obliterate the TOF, incremental doses of 0 ug kg" were given at 6-min intervals until this was achieved, (ii) If no post-tetanic twitches were visible after 4 min, the vecuronium infusion was discontinued until the PTC had reached 5, when the infusion was restarted at its previous rate, (iii) If the PTC was decreasing, the infusion rate was halved when the count reached 5. If the PTC was increasing, the infusion rate was doubled when it reached 5. (iv) If doubling the rate failed to bring the PTC below 5, additional boluses of vecuronium 0 ug kg" were given as before. Towards the end of surgery, the infusion was discontinued if the PTC was less than 5, to allow recovery from profound neuromuscular blockade. When at least one response was visible on the TOF, the anaesthetic drugs were discontinued and the residual neuromuscular blockade was antagonized with neostigmine 0.05 mg kg" given with atropine 0.0 mg kg". The time taken from injection of these drugs to the return of the fourth response on the TOF, and to the patient making an adequate clinical recovery (as assessed by adequate regular ventilation, good muscle tone and purposeful movements) were recorded. Student's t test and Wilcoxon rank sum test were used for comparing data from patient groups. P < 0.05 was considered significant. Results are expressed as mean (SEM). RESULTS Patients details are shown in table I. The three groups did not differ significantly with respect to the initial bolus dose or any additional doses. The mean initial dose used in all patients was 87 (.) ug kg". Eighteen patients (five from group, six from group and seven from group 3 required a total of 3 additional doses (mean 7 (.95) ug kg" ). In group, the duration of intense blockade after initial bolus (i.e. when the PTC was 0) was significantly longer in those 4 infants who were less than 44 weeks post-conception compared with the remainder of the group (P < 0.0). The mean duration of such blockade in these 4 infants was 3. (4.) min, whilst that for all the other children was 5. (.7) min. However, this period of intense blockade was extremely variable in group (range 0-60 min, 0th centile 6 min, 90th centile 48 min). The mean hourly infusion rates are illustrated in figure. Group (< 5 kg) required a significantly lower hourly mean rate over the first h (P < 0.0), whereas there was no significant difference between the other two groups. Overall, the mean infusion rate was.06 (0.07) ug kg" min" in group and.64 (0.07) ug kg" min" in groups and 3.

3 VECURONIUM IN CHILDREN 553 TABLE I. Details of patients studied Group (<5kg) Group (5-5 kg) Group 3 (> 5 kg) Age (yr) Mean SD 0th centile 90th centile Range Weight (kg) Mean SD 0th centile 90th centile Range Duration of anaesthesia (min) Mean SD 0th centile 90th centile Range Surgical procedures General Urological Ophthamological Neurosurgical Orthopaedic ENT Plastic ^ ^ Time (h) FIG.. Mean hourly infusion rates (±SEM) for group (O)> group ( ) and group 3 ( ). *P < SEM bars not shown if less than five values.

4 554 BRITISH JOURNAL OF ANAESTHESIA I ocj g CO tet % Time (min) FIG.. The recovery of neuromuscular function (mean (SEM) post-tetanic count) spontaneously at the end of surgery (A) and under the effect of an infusion (A). *P < Figure illustrates the recovery of neuromuscular transmission from intense block both spontaneously (towards the end of surgery) and under the influence of the infusion. There was no significant difference between any of the three groups studied. The spontaneous recovery rapidly reached a value where the PTC was greater than 5, whereas the infusion delayed the rate of recovery so that twice the time (36 min) was required to reach a similar PTC. The difference between recovery spontaneously and with an infusion became significant after 4 min. Following administration of neostigmine and atropine, the mean time to the return of the fourth response of the TOF was. (0.4) min, while that taken to clinical recovery was.9 (0.3) min. The recovery of function after antagonism was not significantly different between the groups. The relationship between the PTC and TOF response for all three groups is shown in figure 3. For a similar TOF value, group had a significantly lower PTC (P < 0.0) for the first two TOF responses. 0/0 /4 /4 TOF 3/4 4/4 FIG. 3. Mean (SEM) post-tetanic count varying with the number of TOF responses in group (O)J group ( ) and group 3 ( ). *Statistically significant difference between group and other two groups. DISCUSSION The mean initial loading dose given in this study is similar to that used by Goudsouzian and colleagues [0] who reported that, in a similar group of patients, vecuronium 80 ug kg" caused complete suppression of the TOF. The infusion rate of.4 ug kg" min" was based on that used in the study of adults []. In another adult study [], vecuronium was infused at a rate of.5 ug kg" min", but achieved only 87 % twitch depression. The mean infusion rate for groups and 3 in this study suggests that vecuronium may be infused at rates similar to those used in adults. All patients except those aged less than 44 weeks post-conception received a bolus of suxamethonium to facilitate intubation. Suxamethonium is known to prolong the duration of subsequent boluses of competitive neuromuscular blocking drugs. This will initially have increased the effect of the vecuronium. However, the shortest mean duration of anaesthesia was 75 min and no procedure was shorter than 34 min. Therefore, the majority of the data were collected when the effect of the suxamethonium was diminishing. The longer duration of intense neuromuscular blockade in neonates compared with the other infants and children reflects their greater sen-

5 VECURONIUM IN CHILDREN 555 sitivity to vecuronium. The lower hourly infusion rates for group supports this further. These findings are in broad agreement with those of Fisher and Miller [3] who showed that the ED 50 for vecuronium was 6.5 ug kg" for infants, compared with 9 ug kg" for older children. However, the variability in the duration of block after the initial dose in these smaller infants would make the drug difficult to use without a peripheral nerve stimulator. Group had a lower PTC for a given TOF compared with larger patients, reflecting their tendency to post-tetanic exhaustion (rather than facilitation) demonstrated previously [4]. This phenomenon is more pronounced in neonates and may render the PTC an unreliable method of monitoring profound blockade in such patients. If the PTC is kept between 5 and 5, there is at most one response to TOF and adequate paralysis can be ensured (fig. 3). The spontaneous recovery of neuromuscular function illustrated in figure shows that the PTC increased from 5 to 5 in 6-8 min if the infusion was discontinued. Once the PTC was greater than 5, there was one response on the TOF and so the residual neuromuscular blockade could be antagonized easily. The methods and patient groups were similar to those used in a previous study [4]. A comparison of the two studies reveals that the relationships between the PTC and TOF for atracurium and for vecuronium are different- (for the same TOF response, vecuronium has a similar or higher PTC). Atracurium causes more fade of the TOF response than vecuronium [5] and Bowman [6] suggested that such fade may be an expression of prejunctional receptor binding impairing transmitter release during rapid stimulation. Our results reinforce the view that vecuronium has less presynaptic inhibitory effect than atracurium Vecuronium has a short duration of action after bolus injection and it may have little cumulative effect when given repeatedly or by infusion [7]. However, in our study, the required mean hourly infusion rate decreased after 3 h of continuous infusion. Also the PTC decreased after 48 min from the start of recovery when an infusion was used. Although these results are not significant statistically, perhaps because of the small number of patients in whom anaesthesia exceeded 80 min, they suggest that vecuronium may start to accumulate after this time in children. This may be anticipated because the action of vecuronium is terminated by distribution and it has a long elimination half-life (compared with that of atracurium). Indeed, Fahey and others [8] showed in adults that, after repeated boluses, the duration of action of subsequent doses increased. In conclusion, the results suggest that, in children heavier than 5 kg after an initial bolus of 90 ug kg" and an infusion set at.6 ug kg" min", satisfactory paralysis may be obtained if the PTC is kept between 5 and 5 during anaesthesia. From this level of neuromuscular blockade, the spontaneous recovery of function is such that the paralysis may be reversed easily 6-8 min after stopping the infusion. The variability of response to the bolus and infusion makes the use of a peripheral nerve stimulator important and may indeed render this agent or method of administration unsatisfactory for such patients. The results also suggest that vecuronium has less presynaptic effect than atracurium and that vecuronium may accumulate after 3 h of infusion. REFERENCES. Heisterkamp DV, Stansted P, Cohen PT. The effect of incremental doses of d-tubocurine on neuromuscular transmission in anesthesized man. Aneslhesiology 969; 30: Jones RM. Neuromuscular transmission and its blockade. Anaesthesia 985; 40: Viby-Mogensen J, Jensen NH, Engbaek J, 0rding H, Skorgaard LT, Chraemmer-Jorgensen B. Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology 985; 63: Ridley SA, Hatch DJ. Post-tetanic count and profound neuromuscular blockade with atracurium infusion in paediatric patients. British Journal of Anaesthesia 988; 60: Feldman S. Muscle relaxant seminar 8 9 December 975. Anaesthesia 976; 3: Williams NE, Webb SN, Calvey TN. Differential effects of myoneural blocking drugs on neuromuscular transmission. British Journal of Anaesthesia 980; 5: Gramstad L, Lilleaasen P, Minsaas B. A comparative study of atracurium and vecuronium. British Journal of Anaesthesia 983; 55: 95S-96S. 8. Newton NI, Hillman KM, Varley JG. Automatic ventilation with Ayre's T piece. Anaesthesia 98; 36: Viby-Mogensen J, Howardy-Hansen P, Chraemmer- Jorgensen B. Post-Tetanic Count (PTC); a new method of evaluating an intense non-depolarizing neuromuscular blockade. Anesthesiology 98; 55: Goudsouzian NG, Jeevandra JA, Martyn MD, Letty MP, Lui MD, Gionfriddo BA. Safety and efficacy of vecuronium in adolescents and children. Anesthesia and Analgesia 983; 6: Mirakhur RK, Ferres CJ, Pandit SK. Muscle relaxation with an infusion of vecuronium. Anesthesiology 984; 6: A93.

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