CLINICAL EXPERIENCES WITH DIALLYL-NORTOXIFERINE IN CHILDREN

Transcription

1 Brit. J. Anaesth. (1964), 36, 787 CLINICAL EXPERIENCES WITH DIALLYL-NORTOXIFERINE IN CHILDREN BY G. H. BUSH Department of Anaesthesia, Alder Hey Children's Hospital, Liverpool, England SUMMARY Diallyl-nortoxiferine has been used as a muscle relaxant in 321 neonates and children up to 15 years. The neonates appeared to be more sensitive to this relaxant than infants under 1 year, both in regard to the initial dose and the consumption rate. Using a dose of 140 (ig/lb (300 ng/kg) body weight, the onset of relaxation was rapid and intubation was easily performed after only 1 minute. No evidence of local histamine release was found. The average interval between the initial and subsequent dose was 54 minutes in the neonate, 37 minutes in infants under 1 year, 39 minutes in children between 1 and 5 years, 43 minutes in children of 5 to 10 years, and 55 minutes in children over 10 years of age. The reversal of the myoneural block following neostigmine was excellent provided the interval between the administration of the relaxant and neostigmine exceeded 20 minutes. The heart rate was raised in two-thirds of cases following diallylnortoxiferine, but this may not be a specific effect of the drug. Diallyl-nortoxiferine is a synthetic antidepolarizing relaxant derived from C-toxiferine, first used clinically by Hiigin and Kissling (1961) and subsequently given a number of clinical trials. This relaxant seemed to possess a number of advantages over well established antidepolarizing relaxants and a trial was therefore undertaken to assess the clinical use of diallyl-nortoxiferine in children. The properties of the drug that seemed to warrant further investigation included rapid onset of neuromuscular block (Seeger, Ahnefeld and Hauenschild, 1962; Lund and Stovner, 1962a), good conditions for intubation (Lund and Stovner, 1962b), lack of histamine release (Waser and Harbeck, 1962), little alteration in pulse rate and blood pressure with doses up to 200 mg/kg (Waser and Harbeck, 1962; Foldes et al., 1963; Alder, 1963), and excellent reversal of the myoneural block following neostigmine administration (Lund and Stovner, 1962b; Seeger, Ahnefeld and Hauenschild, 1962). METHOD Diallyl-nortoxiferine has been administered to 321 children of all ages ranging from newborn babies to children of 15 years, undergoing a variety of routine and emergency operations. Because of variation in drugs used in premedication, however, this report is concerned with only 205 patients. The age distribution is shown in table I. TABLE I Age distribution of 205 patients. Neonates 1 year 1-5 years 5-10 years >10 years Neonates were intubated while conscious and pulmonary ventilation started using a mixture of nitrous oxide and oxygen, with muscle relaxation provided by diallyl-nortoxiferine. An initial dose of 0.5 mg in full term and 0.25 mg in premature babies was injected intravenously and incremental doses of mg used to produce adequate control of ventilation and operating conditions. In infants under 1 year premedication was limited to atropine 0.3 mg intramuscularly preoperatively. Older children received trimeprazine tartrate 0.75 mg/lb. (1.65 mg/kg) body weight, up to a maximum of 30 mg, usually 4 hours pre-operatively, followed 1 hour before operation by morphine 0.1 mg/lb. (0.22 mg/kg) and atropine 0.45 mg in the 1-5 year age group or 0.6 mg in children over 5 years old. Anaesthesia 787

2 788 BRITISH JOURNAL OF ANAESTHESIA was induced with thiopentone 1.8 mg/lb. (4 m g/kg) body weight intravenously using a 26 SWG needle, followed by diallyl-nortoxiferine 140 [Ag/lb. (300 (jlg/kg) body weight. The lungs were then passively hyperventilated with a mixture of nitrous oxide and oxygen, and any movements of the limbs noted. Gross movements requiring restraint were classified as severe (+ + +), movements of forearm and lower legs as moderate (+ +), and movements limited to fingers and toes as ( + ). One minute after the start of the injection of diallyl-nortoxiferine, which was made as rapidly as possible and usually completed within 5 seconds, laryngoscopy and intubation were performed. Conditions for intubation were described as excellent when the jaw was well relaxed and the cords immobile and abducted, fair when the larynx was easily visualized but the cords were moving or adducted, and poor when the larynx could not be visualized because of inadequate relaxation. Evidence of local histamine-like action, such as reddening of the vein and weal formation in the lower arm, was sought by observing the arm proximal to the site of injection. Pulse rates were determined before and 5 minutes after the intravenous injection of diallylnortoxiferine in 56 children. Anaesthesia was maintained with nitrous oxide and oxygen with pulmonary hyperventdlation, and incremental doses of diallyl-nortoxiferine of one quarter to one sixth of the initial dose given as required to produce satisfactory operation conditions and adequate control of pulmonary ventilation. At the termination of the operation, the residual myoneural block was reversed with neostigmine mg/lb. (0.08 mg/kg) body weight preceded by atropine 0.01 mg/lb. (0.022 mg/kg) body weight Five minutes after the administration of neostigmine the older patients were asked to raise their heads. The reversal was deemed excellent when adequate clinical restoration of pulmonary ventilation and the ability to sustain the raised head was achieved; inability to raise the head in the presence of adequate pulmonary ventilation was described as fair. Dose requirement. This was calculated for all age groups by dividing the total dose of relaxant given by the weight of the patient and the duration of operation in minutes. Duration of action. The duration of action of the relaxant was assessed by determining the average length of operation when no incremental dose was required and in those instances where an incremental dose was given, by determining the interval between the initial and incremental doses. RESULTS Movements after relaxant. The results in percentages and related to the different age groups are shown in table IL TABLE II Movements of the limbs noted in 123 patients during passive hyperventilation immediately after induction of anaesthesia with thiopentone followed by diallylnortoxiferine. Age (yrs) Less than Over 10 Nil No. of cases Conditions for intubation. The results related to the different age groups are shown as percentages in table m. TABIX III Classification of intubating conditions. Age (yrs) Excellent Fair No. of cases Less than Over Histamine release. No evidence of local histamine-like action was found in any case. Duration of action. The results are shown in table IV. Because of suspected variation in sensitivity only neonates less than 10 days old are included in this analysis. The initial dose for these patients

3 CLINICAL EXPERIENCES WITH DIALLYL-NORTOXIFERINE IN CHILDREN 789 Neonates under 10 days old X Infants between 3 and 12 months old X! 3 * 2 X» X X* X Time (mln) Fio. 1 Comparison of the dose requirements of diallyl-nortoxiferine in /ig/lb./min in neonates under 10 days old and infants between 3 and 12 months old in relation to the duration of operation. 8 7 In) 1. c V EV ' y req uir u o Q 3 2 r :* * * f * * * ** r. - * '* 1 * Time (mln) Fio. 2 The consumption of diallyl-nortoxiferine in ^g/lb./min in 117 children between 1 and 15 years in relation to duration of operation.

4 790 BRITISH JOURNAL OF ANAESTHESIA Age (yrs) TABLE Assessment of the duration of action of diallyl-nortoxiferine. Duration of operation (min) IV Interval between initial and incremental dose (min) Range Average Range Average Neonates Less than Over varied between 55 [xg/lb. (120 fxg/kg) and 150 ng/lb. (330 [j.g/kg) body weight but for the other age groups the initial dose was constant at 140 p.g/lb. (300 [xg/kg) body weight. Dose requirements. The dose requirement in xg/lb./min is shown in figures 1 and 2. In figure 1 the requirement in neonates is compared with infants less than 1 year old. Because of the closely similar sensitivities neonates over 10 days old and infants less than 3 months are excluded from this analysis. The requirement for neonates would appear to approximate to 9 [ig/lb./min (19.8 [xg/kg/min) but accurate estimation of the consumption of the other age group is not possible because of the small number of cases but appears to be definitely higher than in the neonate. Because of the method of calculation of dose requirements and the high initial dose of relaxant used, the dose requirement will be lower the longer the operating time, which accounts for the shape of the curve in figures 1 and 2. When the flat part of the curve is reached presumably an equilibrium exists between the consumption, that is the rate of destruction and elimination of the relaxant, and the requirements, that is the dose required to maintain satisfactory operating conditions and control of pulmonary ventilation. Reversal. In all neonates reversal was excellent. In the older age groups using the standard initial dose, attempts at reversal at 15 minutes only resulted in a fair recovery of muscle movements. In one patient in the over 10-years group reversal at 20 minutes was only fair whilst in all other cases lasting over 30 minutes reversal was excellent. No case of recurarization was encountered. Heart rates. Thr effect on the heart rate is shown in table V. TABLE V Changes in heart rate in 56 children determined before and 5 minutes after intravenous injection of diallylnortoxiferine. Percentage change + > < 10 nil -< Total No. of cases DISCUSSION The small amount of muscle movement and the excellent conditions for intubation in over 90 per cent of cases only 1 minute after the intravenous injection of diallyl-nortoxiferine shows that this drug produces a fairly rapid action at the myoneural junction. As might be expected, muscle movements and conditions for intubation were less favourable in children than in infants because of the increased circulation time. The lack of evidence of a histamine-like action confirms the findings of Waser and Harbeck (1962) who showed that following diallyl-nortoxiferine 10 mg in adults the histamine blood level remained within normal limits, This drug has the important advantage, therefore, of not being contraindicated in patients known to have an increased sensitivity to histamine as in asthma. Furthermore no fall in blood pressure should occur due to release of histamine; and because of its increased specificity, Le., ratio of ganglion-blocking dose to the dose that paralyses the motor end plate (50 for diallyl-nortoxiferine compared with 11 for tubocurarine (Waser and Harbeck, 1962)), little alteration should be produced in the heart rate or blood pressure. Blood pressure studies were only undertaken in a few cases but this aspect is under investigation in a further series. Although the heart rate increased in approximately two-thirds of the cases this may not be a specific effect of diallyl-nortoxiferine since thiopentone administration, the institution of intermittent Percentage

5 CLINICAL EXPERIENCES WITH DIALLYL-NORTOXIFERINE IN CHILDREN 791 >- positive pressure respiration and tracheal intubation all occurred between the times of recording the pulse rate. Tracheal intubation with relaxation produced by 200 ng/kg body weight of diallyl-nortoxiferine produced an increase in cardiac rate of beats/min in 7 out of 10 patients described by Lund and Stovner (1962a). Similar sinus tachycardia has been observed following intubation using tubocurarine (Rosner, Newman and Burstein, 1953). The duration of action of the initial dose varied according to the age of the patient and, as might have been anticipated, the neonate under 10 days showed an increased sensitivity to this antidepolarizing relaxant. This finding is in keeping with previous experience with tubocurarine (Stead, 1955; Bush and Stead, 1962). The greater sensitivity with increasing age accords with the belief that young children and infants are more resistant to antidepolarizing relaxants (Bush, 1963). In adults previous workers (Waser and Harbeck, 1962; Foldes et al., 1963; Alder, 1963) found that a dose of ng/kg lasted for minutes whilst a dose of 200 (Ag/kg lasted minutes (Seeger, Ahnefeld and Hauenschild, 1962). These estimates were based on an anaesthetic technique which included either halothane, ether, or pethidine. Lund and Stovner (1962a) found that for 3-hour operations a total dose of 348 [Ag/kg was required for upper abdominal surgery, whilst a total dose of 308 ng/kg was required for the lower abdomen. This means that the consumption rate varies between 19 and 17 ng/kg/min (9[j.g/lb./ min and 8.4 (j.g/lb./min), but is probably a low estimate because of the supplementary agents used during anaesthesia. In the series reported here, no supplementary agents were used although passive pulmonary hyperventilation was achieved, and the duration of action of 300 [ig/kg is probably fairly accurate in view of the close agreement of the two methods of determining the duration of action. The consumption in neonates seems to be approximately 9 (Ag/lb./min (19 [Ag/kg/min), and slightly higher in infants and older children. The consumption rate of the case marked with an arrow in figure 2 was that of a feverish toxic child who was undergoing a cortical mastoidectomy for an acute infection and this may suggest that a raised metabolic rate increases the utilization. Increased consumption rates have also been noted in cases undergoing operation for acute appendicitis. Reversal of the myoneural block with neostigmine has been considered necessary in all cases in view of the prolonged period of partial paresis likely to occur following such a high dose of diallyl-nortoxiferine, and also because of the inability to determine the degree of block still present at the myoneural junction at the termination of operation. Although a number of reports (Seeger et al, 1962; Waser and Harbeck, 1962; Foldes et al., 1963) have stressed the "respiratory sparing action" of diallyl-nortoxiferine and suggested that anticholinesterases are unnecessary, considerably lower doses were given than were used in this study. Complete clinical reversal following neostigmine was noted in children under 10 years when the interval between the administration of the relaxant and reversal exceeded 20 minutes, but any reduction in this time interval was associated with only a fair reversal of the neuromuscular block. This finding stresses the importance of reversing the myoneural block when high doses of diallyl-nortoxiferine are administered. No adverse effects of neostigmine administration were noted. The duration of action of diallyl-nortoxiferine is only about one-tenth of that of toxiferine (Waser and Harbeck, 1962) and a greater degree of control can therefore be achieved. In a "blind" study Lund and Stovner (1962b) found using the criteria of satisfactory conditions for intubation and relaxation for abdominal surgery, that diallylnortoxiferine was 1.7 times more potent than tubocurarine. The cumulative effect for equipotent doses and neostigmine requirements were similar for both relaxants. No comparison has been made between the side effects of these two relaxants and such an investigation using a blind study is at present in progress. In view of the little difference in the neuromuscular effects demonstrated between equipotent doses of tubocurarine and diallyl-nortoxiferine (Lund and Stovner, 1962), it may well be that the comparison of side effects will be the deciding factor in determining the superiority of one of these relaxants.

6 792 BRITISH JOURNAL OF ANAESTHESIA ACKNOWLEDGMENT I am most grateful to Roche Products Ltd, Welwyn Garden City, Herts., for generous supplies of diallylnortoxiferine. REFERENCES Alder, A. (1963). Praktiscbe Erfahrungen mit Diallylnortoxiferine. Der Anaesthesist, 12, 172. Bush, G. H., and Stead, A. L. (1962). The use of d-tubocurarine in neonatal anaesthesia. Brit. i. Anaesth., 34, 721. Bush, G. H. (1963). The use of muscle relaxants in infants and children. Brit. J. Anaesth., 35, 552. Foldes, F. F., Brown, L M., Lunn, J. N., Moore, J., and Duncalf, D. (1963). The neuromuscular effects of diallyl-nortoxiferine in anesthetized subjects. A nest h. Analg. Curr. Res., 42, 177. HUgin, W., and Kissling, P. (1961). Vorlaufige Mitteilungen uber ein neues Kurwirkendes Relaxans vom depolarisation shindernden Typus das RO Schweiz. med. Wschr., 91, 445. Lund, I., and Stovner, J. (1962a). Experimental and clinical experiences with a new muscle relaxant RO , diallyl-nortoxiferine. Ada anaesth. Scand., 6, 85. (1962b). Potency and reversibility by prostigmine of RO and d-tubocurarine. Acta anaesth. Scand., 6, 161. Rosner, S., Newman, W., and Burstein, C L. (1953). Electrocardiographic studies during endotracheal intubation. VI: Effects during anesthesia with thiopental sodium combined with a muscle relaxant. Anesthesiology, 14, 591. Seeger, R., Ahnefeld, F., and Hauenschild, E. (1962). Erfahrungen mit dem nauer synthetischen Muskelrelaxans RO , einen Derivat das Calebassen alkaloides toxiferin. Der Anaesthesist., 11, 37. Stead, A. L. (1955). The response of the newborn infant to muscle relaxants. Brit. J. Anaesth., 21, 124. Waser, P. G., and Harbeck, P. (1962). Pharmakologie und Klinische Anwendung das Kurdauernden Muskelrelaxans Diallylnortoxiferine. Der Anaesthesist, 11, 33. EXPERIENCES CLINIQUES AVEC LA DIALLYL- NORTOXIFERINE CHEZ L'ENFANT SOMMAIRE La diallyl-nortoxife'rine a i.xit utilisee comme relaxant musculaire chez 321 nouveaux-nes et enfants jusqu'a l'age de 15 ans. Les nouveaux-nes semblaient 6tre plus sensibles a ce relaxant que les enfants de moins d'un an, cela valant autant pour la dose initiale que pour le rythme de relnjection. Avec des doses 140 /*g/lb (300 Mg/kg) de poids corporel le d but du relachement dtait rapide et l'intubation a pu gtre pratiquee aislment apres une minute seulement. On n'a pas constate de signes en faveur de la liwration locale d'histaminc. L'intervalle moyen entre la dose initiale et les doses subsequentes 6tait de 54 minutes chez le nouveau-ne', de 37 minutes chez l'enfant de moins d'un an, de 39 minutes chez l'enfant entre 5 et 10 ans et de 55 minutes chez l'enfant de plus de dix ans. La reversibility du blocage musculo-nerveux itait excellente apres injection de prostigmine a condition que l'intervalle entre l'administration du relaxant et la prostigmine d^passe 20 minutes. Le rythme cardiaque dtait acc^mrd chez deux tiers des malades apres administration de diallyl-nortoxife'rine, mais il se peut que cela ne soit pas un effet sp^cifique de la drogue en question. KLINISCHE ERFAHRUNGEN MIT DIALLYL- NORTOXIFERINE BEI KINDERN ZUSAMMENFASSUNG Diallyl-Nortoxiferine wurde bei 321 Neugeborenen und Kindern bis zu 15 Jahren als Muskelrelaxans angewandt. Die Neugeborenen schienen auf dieses Relaxans empfindlicher zu sein als Kleinkinder unter einem Jahr, sowohl in bezug auf die Anfangsdosis als auch auf die Ausnutzungsrate. Bei Verwendung einer Dosis von 140 mg/engl./pfund (300 mk/kg) K8rpergewicht, setzte die Relaxierung rasch ein und die Intubation konnte nach nur einer Minute leicht ausgeflihrt werden. Es fand sich kein Hinweis fur eine lokale Freiwerdung von Histamin. Das durchschnittliche Interval zwischen der ersten und der nachfolgenden Dosis betrug beim Neugeborenen 54 Minuten, bei Kleinkindern unter einem Jahr 37 Minuten, bei Kindern zwischen 1 bis 5 Jahren 39 Minuten, bei Kindem von 5-10 Jahren 43 Minuten und bei Kindern Uber 10 Jahren 55 Minuten. Die Umkehr des myoneuralen Blockes war durch Neostigmin ausgezeicb.net moglich, vorausgesetzt dass das Interval zwischen der Verabfolgung des Relaxans und Neostigmin 20 Minuten Uberstieg. Bei zwei Dritteln der Falle stieg die Herzrate nach Verabfolgung von Diallyl-Nortoxiferine an, aber dies ist msglicherweise keine spezifische Wirkung der Droge.