ORAL PREMEDICATION IN CHILDREN WITH TRIMEPRAZINE

Transcription

1 Brit. J. Anaesth. (1966), 38, 878 ORAL PREMEDICATION IN CHILDREN WITH TRIMEPRAZINE The Effect of varying Dosage and Timing BY D. R. DA VIES AND ANDREW DOUGHTY Department of Anaesthetics, Kingston Group of Hospitals, England SUMMARY In the belief that both dosage and timing of premedication may be important, a double blind trial was carried out on 484 children undergoing adenotonsillectomy receiving trimeprazine with hyoscine according to four differing methods within the limits suggested by the manufacturers' instructions. Thus trimeprazine was given in doses of 1 or 2 mg/lb. (2.2 or 4.4 mg/kg), 1 or 2 hours pre-operatively. The most intense action of the drug was evident when the stronger dose was given 2 hours before operation. However, this was associated with a comparative deterioration in behaviour of the children in the anaesthetic room and a higher frequency of undue postoperative pallor. Possible advantages of the more intense action of trimeprazine are salivary suppression and amnesia. Postoperative vomiting was infrequent with all four methods of premedication. A plea is made for the more critical evaluation of premedicant drugs. Trimeprazine tartrate (Vallergan) was introduced into clinical practice as an oral premedicant for children by Cope and Glover (1959) to induce a state "between sedation and basal narcosis". Its use is associated with salivary suppression, antiemesis, marked postoperative pallor and amnesia (Doughty, 1962). Although trimeprazine has found general acceptance among those hitherto accustomed to using the oral barbiturates, some doubt has been cast on its efficacy and freedom from undesirable sideactions. Gunner and Fox (1960) reported a progressive improvement in behaviour of children in the anaesthetic room as the dose of trimeprazine premedication was reduced, while Doughty (1962) showed that children premedicated with trimeprazine were less co-operative and less satisfactorily sedated than those who had received a control solution. There is a wide divergence of opinion as to the ideal method of use of the drug and its proponents have attributed inadequacy of sedation to incorrect dosage and riming of administration. The manufacturers' original instructions that trimeprazine should be given in a dose of 1 to 2 mg/lb., 1 to 2 hours before operation suggest at least four methods of use which might usefully be compared in a trial. The purpose of this investigation was to examine the effects of varying the dosage and riming of administration of the drug in an attempt to find the best method of use. METHOD Combined with hyoscine 0.2 mg/stone (0.03 mg/ kg), trimeprazine was given by mouth in a "Strong" (2 mg/lb.; 4.4 mg/kg) or a "Weak" (1 mg/lb.; 2.2 mg/kg) solution. Each solution was given either 1 hour (Strongj or ) or 2 hours ( or Weak a ) before induction of anaesthesia to 484 children undergoing adenotonsillectomy (table I). The interval between premedication and induction was within 5 minutes of that intended and patients induced outside this narrow limit of punctuality were excluded from the trial. Trimeprazine 28 mg/stone (4.4 mg/kg) 28 mg/stone (4.4 mg/kg) 14 mg/stone (2.2 mg/kg) 14 mg/stone (2.2 mg/kg) TABLE I Methods of premedication. Hyoscine 0.2 mg/stone (0.03 mg/kg) 0.2 mg/stone (0.03 mg/kg) 0.2 mg/stone (0.03 mg/kg) 0.2 mg/stone (0.03 mg/kg) Timing (pre-op.) Symbol 1 hour 2 hours 1 hour 2 hours

2 ORAL PREMEDICATION EN CHILDREN WITH TRIMEPRA2INE 879 All the children received an intravenous injection in the back of the hand of thiopentone 50 mg/stone (7.9 mg/kg) and suxamethonium 5 mg/ stone (0.8 mg/kg). After intubation anaesthesia was maintained with nitrous oxide, oxygen and 1 per cent halothane by spontaneous respiration. The conditions under which the children were anaesthetized and the methods of evaluation of the premedication were essentially similar to those used in previous trials (Doughty, 1959, 1962). Observations were made in the anaesthetic room of the child's demeanour up to the time of the intravenous injection, the response to the injection and the presence or absence of hand-withdrawal following the venepuncture. The antisalivary effect of the premedication was assessed following induction of anaesthesia. Postoperative observations were made of vomiting, restlessness and pallor, and the following day each child was questioned regarding memory of the injection in order to test for amnesia or any resentment of the method of induction. RESULTS Demeanour in the anaesthetic room (table II). Demeanour was recorded in one of seven categories: comatose, sleepy, cheerful, serious, apprehensive, tearful, and noisy. Those cases falling in any of the first four categories were regarded as showing satisfactory demeanour and those in the latter three categories as showing unsatisfactory demeanour. TABLE II Demeanour in the anaesthetic room following premedication. Comatose Sleepy 27(35) 40(53) 16(19) 35(37) Cheerful Serious Apprehensive Tearful Noisy This broad classification seems to correspond with that used in previously published trials in which the demeanour of the children was described as "calm", "disturbed" or "turbulent" (Goulding et al., 1957; Rollason, 1959) and at first sight there appears to be little difference between the four methods of premedication. However, the umbrella term "calm" conceals important differences between groups. The action of trimeprazine in producing coma and somnolence is most marked with Strong;,. Even so, as only 44 per cent of children in this group showed this effect, trimeprazine cannot be regarded as reliably producing its intended action by this method of use. It is worth noting that all children who were comatose following trimeprazine given by any of the four methods used in the trial were under the age of 7, suggesting an increased sensitivity to the drug in younger children. The weaker dose of trimeprazine, as long as it was given 2 hours before operation (Wealc,), was associated widi a fairly high incidence of somnolence and a low frequency of coma. With both the weak and strong solutions a more marked soporific effect was seen when premedication was given 2 hours rather than 1 hour before induction. Previous authors agree that oral trimeprazine should be given at least H hours pre-operatively (Bhattacharjee, 1960; Gillett and Keil, 1960; Binning and associates, 1962; Kalle and associates, 1962). With Strong 2, which was associated with the highest incidence of somnolence, there was also a greater tendency to noisy delirium, while the lowest frequency of serious disturbance was seen with Weak^ that is to say the smaller dose given at a time at which trimeprazine cannot exert its full effect before induction. It should also be noted that with Weak L there were 20 children with a cheerful demeanour but that with the more intense action of trimeprazine cheerfulness is almost eliminated. Response to venepuncture and incidence of reflex hand-withdrawal following venepuncture (tables III and IV). The response to the induction venepuncture was classified in one of five categories: no response, winced, whimpered, cried, and violent response. Those children in the first three groups

3 880 BRITISH JOURNAL OF ANAESTHESIA No response Winced Whimpered Cried Violent response, venepuncture abandoned TABLE III Response to injection were judged satisfactory- and those in the last two groups unsatisfactory. In table IV the results are classified according to whether or not the children held their hands still following venepuncture after having been asked to do so. Those classified as "no hand-withdrawal" were regarded as satisfactory. The figures from both these tables argue against the suitability of trimeprazine as a sedative before an intravenous induction. When the drug was given 2 hours pre-operatdvely some form of response to the injection was more frequent and crying more frequently followed the venepuncture. Similarly, the children receiving the premedica- TABLE IV Incidence of reflex hand-withdrawal following venepuncture. No handwididrawal Hand-withdrawal Classification as satisfactory or unsatisfactory (table V). It is now possible to classify the patients as satisfactory or unsatisfactory in relation to the four different methods of premedication. A child showing unsatisfactory behaviour in any one of three tests demeanour, response to venepuncture or hand-withdrawal was classified as unsatisfactory. Those classified as satisfactory showed satisfactory behaviour in all three tests. The results in table V reflect the findings in the three tests from which they are derived. There was a trend for the more intense action of trimeprazine to be associated with the less satisfactory behaviour in the anaesthetic room. The number of satisfactory children who had been given Weakj as premedication was significantly greater than the number of those who had received Strong.,. TABLE V Classification as satisfactory or unsatisfactory based on the results of the tests detailed in tables II, III and IV. 76(62.8%) 45 Strong x 66(54.5%) 55 Statistical observation: / x' = 3.90; 81(67%) 40 P< (59.5%) 49 tion only 1 hour before induction were able to co-operate better in keeping their hands still after venepuncture than those premedicated 2 hours pre-operatively. Nevertheless, it will be noted that of the 484 children in the whole trial only one responded so violently that the attempt at venepuncture had to be abandoned. Age in relation to behaviour (table VI). The data in the table confirm that the mean ages of children in each premedication group were reasonably comparable. In view of the commonly held belief that older children behave better than their juniors the mean ages of the satisfactory and unsatisfactory patients were compared. When

4 ORAL PREMEDICATION IN CHILDREN WITH TRIMEPRAZINE 881 All cases behaviour behaviour Age TABLE in relation VI to behaviour. Mean ages of children in the premedication groups Statistical observations Mean ages all cases / (widest discrepancy) t = 0.65; P<0.60 Mean ages / Difference 0.03 years t = 0.07; P<1.0 Difference 1.46 years t = 3.27; P<0.002 Difference 0.43 years t = 1.07; P<0.30 Difference 0.78 years t= 1.94; P< four Under 7 Over 7 55 (65%) Statistical observation: Under (58%) TABLE Age in relation Under 7 Over 7 39 (48%) /Over 7 VII to behaviour. (69%) Under 7 Over 7 54 (66%) 27 (69%) X' = 5.01; P< Under 7 Over 7 44 (55%) (68%) trimeprazine was given only 1 hour before operation there was little difference, but with the mean age of the unsatisfactory children was significantly lower than that of the satisfactory. A similar but lesser trend was observed with the children who received Weak 2. If the totals in each premedication group are divided into "Under 7" and "Over 7" sub-groups (table VII) it will be noted that the difference between groups is accounted for almost entirely by the children under 7 who behaved significantly worse when given Strong.,. Over the age of 7 there is little difference between the groups. It is worth recalling that it is for the younger children that trimeprazine has been particularly recommended as a premedication. Antisalivary effect of trimeprazine (table VIII). Observations were made after induction of anaesthesia to assess any drying effect of the premedication, each case being classified as dry, moist, wet, or very wet. The figures show the marked increase of salivary suppression following trimeprazine with the higher dosage and with the longer time between administration of premedication and induction of anaesthesia. As with other observations, the results associated with Strong! and Wealc, are very similar. TABLE VIII Antisalivary effect of premedication; amount of secretion in mouth following induction of anaesthesia. Dry Moist Wet Very wet Postoperative observations. Children on whom only adenoidectomy or antrum washout were performed and those who

5 882 BRITISH JOURNAL OF ANAESTHESIA No vomiting One vomit Repeated vomiting TABLE IX Postoperative vomiting. Strong! 75(84%) 72(88%) 67(84%) 75(84%) Not restless Moderately restless Violently restless TABLE X Postoperative restlessness Statistical observation Violent restlessness Strong/Weak x' = 5-31; P<0.05 were re-anaesthetized for post-tonsillectomy haemorrhage were excluded from the postoperative observations of vomiting, restlessness, pallor and memory of the intravenous injection. In addition, those who did not receive papaveretum as a postoperative analgesic were excluded from the observations of postoperative vomiting, and those giving an indefinite answer were excluded from the observations of the children's memory of the intravenous injection. Postoperative vomiting (table IX). Observations of vomiting extended only up to 4 hours after operation. The patients were put into three categories: no vomiting, one vomit, and repeated vomiting. The relative infrequency of postoperative vomiting following trimeprazine premedication has previously been noted. There is little difference in anti-emetic effect between the four premedication groups, suggesting that quite a small dose of the drug might confer immunity from vomiting when used in combination with other premedicants. Postoperative restlessness (table X). Assessment of postoperative restlessness divided the children's behaviour into three categories: not restless, moderately restless, and violently restless. Trimeprazine is included among the slightly analgesic phenothiazines by Dundee and Moore (1961). This opinion is reflected in the lower frequency of children recorded as being violently restless postoperatively among those who had received the stronger dose of the drug. That this effect is slight is suggested by the absence of a significantly higher frequency of such children recorded as being not resdess. Furthermore, the figures for response to injection and hand-withdrawal (tables III and IV) give no indication of any analgesic effect of trimeprazine whatever, although one might expect such an effect to modify the child's response to the needle-prick of an intravenous induction. Not pallid Pallid TABLE XI Undue postoperative pallor. Strongj 44(41%) Statistical observation Pallor Strong/Weak 32(32%) 57(54%) x' = 8.08; P< (48%)

6 ORAL PREMEDICATION IN CHILDREN WITH TRIMEPRAZINE 883 Undue postoperative pallor (table XI). The occurrence of pallor after operation in children following trimeprazine premedication has been reported previously (Doughty, 1962). The table shows the numbers of children in this trial who displayed undue postoperative pallor and indicates a tendency for the incidence of pallor to increase with the higher dosage of trimeprazine. The child's memory of the intravenous injection (tabu XII). On the day after the operation each child was asked if he remembered the prick in the back of the hand and if it hurt. The answers were classified as: "amnesia", "no", "a little", "yes", and "indefinite answer". The table gives these results excluding those of "indefinite answer". TABLE XII Children's memory oj the intravenous induction. Answers to the question "Did the prick in the back oj the hand hurt}" Amnesia No A little Yes Statistical observations Amnesia: Dosage 2 mg per pound/1 mg per pound x' = 1.63; P<0.30 Timing 2 hours pre-op./l hour pre-op. x' = 6.07; P<0.02 memory of induction / x' = 3.92; P<0.05 The table shows that the increased frequency of amnesia is more a function of the lapse of time beween premedication and induction of anaesthesia rather than of dosage. With Strong.,, however, there were significantly fewer children who remembered the injection as an unpleasant experience. DISCUSSION The purpose of this investigation was to attempt to determine the optimum method of use of trimeprazine as a pre-operative sedative for children by varying the dosage and riming of administration. As might have been expected, increasing the dose of the drug increased its intensity of action as did increasing the interval between premedication and induction of anaesthesia. Certainly a 1-hour interval is insufficient for an oral dose of trimeprazine to exert its full effect. Strongj, although providing the greatest intensity of action of trimeprazine, did not appear to improve co-operation with the anaesthetist; in fact a reverse tendency was observed in that Wea^ was associated with significantly better preoperative behaviour. However, Strong 3 was associated with a high incidence of amnesia for the induction injection and among those whose memory was unimpaired few remembered the injection as an unpleasant experience. The marked salivary suppression associated with the more intense action of trimeprazine may facilitate the accurate placement of the Boyle-Davis gag for tonsillectomy but, on the other hand, may increase the patient's discomfort. It is possible that with strong doses of trimeprazine adequate salivary suppression might be achieved without the inclusion of hyoscine or atropine in the premedication. All four methods of administering trimeprazine showed unreliability of sedative effect, the demeanour of the patient in the anaesthetic room varying from coma through full consciousness to noisy delirium. The variability in effect was most marked with Strong 2. If a more reliable incidence of coma or somnolence were desired a dose higher than 2 mg/lb. (4.4 mg/kg) would be indicated though possibly at a cost of unacceptable circulatory depression. The main advantages of trimeprazine are suppression of postoperative vomiting and the production of amnesia. It might be argued that, whatever the child's behaviour in the anaesthetic room, amnesia for, or lack of resentment of, the induction is sufficient justification for using trimeprazine in a dosage scheme which provides a maximum intensity of action of the drug. The anti-emetic effect is similar with all dosage schemes so that the choice of dosage must be that which is most frequently associated with amnesia, or lack of resentment of induction, namely 2 mg/lb. (4.4 mg/kg), 2 hours before operation. However, in using this dosage one must accept poor behaviour in the anaesthetic room and a high incidence of undue pallor postoperativcly.

7 884 BRITISH JOURNAL OF ANAESTHESIA The dosage schemes producing the lesser intensity of action of trimeprazine are associated with a lower incidence of amnesia and lack of resentment of the intravenous induction although behaviour in the anaesthetic room and co-operation with the anaesthetist is improved. Indeed a previous trial suggests that behaviour may be best if trimeprazine is omitted altogether (Doughty, 1962). It is realized that the criteria in this trial for assessing the children's behaviour in the anaesthetic room were stringent. An intravenous induction was used in all cases and a deliberate attempt was made to awaken all the sleeping children in order to distinguish those who were comatose from those who were merely somnolent. This action must have caused a number of children to appear fretful at the time of induction. An inhalational induction avoiding the arousal of the somnolent children would not only have increased the frequency of amnesia for the induction but would also have resulted in better behaviour in the anaesthetic room (Binning et al., 1962). When an intravenous induction is intended it is difficult to recommend trimeprazine as the ideal premedicant for young children although it must be conceded that anaesthetists would normally adapt the method of induction to the child's demeanour at the time. The results of this trial underline the need for a more critical evaluation of premedicant drugs. This must take into account not only the dosage and riming of administration but also the clinical background of their use. ACKNOWLEDGEMENTS Our thanks are due to our surgical colleagues, Mr. K. G. Rotter and Mr. A. C. Riley, and to the operating theatre staff at Surbiton Hospital for their interest and ready co-operation; to Sister Bowen, in charge of the Children's Ward, for observing and recording the postoperative behaviour of the patients; and to Miss B. Davies and Miss B. McNeill for secretarial assistance. We are also indebted to Miss Down, Deputy Chief Pharmacist at Kingston Hospital, for dispensing and coding the trimeprazinehyoscine solutions, and to Messrs. May and Baker Ltd. for generous supplies of trimeprazine. REFERENCES Bhattacharjee, B. (1960). Oral premedication in children (experience with trimeprazine tartrate). Antiseptic, 57, Binning, R., Watson, W. R., Samrah, M., and Martin, E. (1962). Premedication for adenotonsillectomy. Brit. J. Anaesth., 34, 812. Cope, R. W., and Glover, W. J. (1959). Trimeprazine tartrate for premedication of children. Lancet, 1, 858. Doughty, A. G. (1959). The evaluation of premedication in children. Proc. roy. Soc. Med., 52, 823. (1962). Oral premedication in children. Brit. J. Anaesth., 34, 80. Dundee, J. W., and Moore, J. (1961). The myth of phenothiazine potentiation. Anaesthesia, 16, 95. Gillert, G. B., and Keil, A. M. (1960). Trimeprazine tartrate in paediatric premedication. Anaesthesia, 15, 158. Goulding, R., Helliwell, P. J., Kerr, A. C., and Wilkin, E. M. (1957). The sedation of children as outpatients for dental operations under general anaesthesia. Brit. med. J., 1, 855. Gunner, B. W., nnd Fox, B. S. O. (1960). Oral premedication of children with trimeprazine tartrate. Med. J. Aust., Kalle, N. R., Mehta, S., Dhawan, S., and Thomas, M. (1962). Trimeprazine tartrate (Vallergan) as a premedicant in children. Indian J. Anesth., 9, 123. Rollason, W. N. (1959). The evaluation of premedication in children. Proc. roy. Soc. Med., 52, 407. LA PREMEDICATION ORALE CHEZ L'ENFANT PAR LA TRIMEPRAZINE: L'EFFET DE DIVERSES DOSES ET DU MOMENT SOMMAIRE Croyant que tant la dose que le moment de la premedication peuvent tre importants, on a fait une experience en double insu chez 484 enfants devant subir une adenoamygdalectomie et recevant de la trimdprazine avec hyoscine selon quatre mithodes differentes dans les limites suggdrees par les instructions des fabricants. La trim6prazine a done etc donnee aux doses de 4,4 ou 2J. mg/kg, 1 ou 2 heures avant l'operation. L'effet le plus intense de la drogue s'est manifeste quand la plus forte dose 6tait administrfe 2 heures avant l'operation. Pourtant, ceci 6tait associi a une certaine alteration du comportement des enfants dans la salle d'anesthesie et une frequence plus 61cvee de paleur post-operatoire excessive. Les avantages possibles de Faction plus intense de la trimeprazine sont la suppression de la salive et l'amnesie. Les vomissements post-operatoires ont eti rares avec les quatre methodes de preme<lication. On demande qu'il soit fait une evaluation plus critique des drogues de premedication. ORALE PRAMEDIKATION MIT TRIMEPRAZIN BEI KINDERN WIRKUNG VERSCHIEDENER DOSIERUNGEN UND APPLIKATIONSZEITPUNKTE ZUSAMMENFASSUNG In der Annahme, dab sowohl die Dosishohe der Prfimedikation als auch der Zeitpunkt ihrer Verabreichung wichtig sein konnten, wurde ein Doppelblindversuch bei 484 Kindern durchgefuhrt, die einer Tonsillektomie mit Adenotomie unterzogen werden sollten. Dabei erhielten die Kinder Trimeprazin mit Scopolamin nach vier verschiedenen Pramedikationsmethoden innerhalb der Grenzen der vom Hersteller angegebenen Dosierungsempfehlungen. Entsprechend wurde Trimeprazin

8 ORAL PREMEDICATION EN CHILDREN WITH TRIMEPRAZINE 885 in Dosen von 2.2 oder 4.4 mg/kg Korpergewicht eine oder zwei Stunden vor der Operation verabfolgt. Die starkste Wirkung des Mittcls zeigte sich, wenn die hohere Dosis zwei Stunden vor dem Eingrifi gegeben wurde. Dies war jedoch von einem vergleichsweise ungiinstigeren Verhalten der Kinder im Narkoseraum sowie von einer starkeren Haufigkeit ubermafiiger Blasse nach der Operation begleitet. Evenruelle Vorteile dieser ausgepragteren Trimeprazin-Wirkung sind cine Unterdruckung des Speichelflusses und Amnesie. Postoperatives Erbrechen war bei alien vier Pramedikationsmethoden selten. Es wird eine kritischere Oberprufung der zur Pramedikation verwendeten Mittel empfohlen. CORRESPONDENCE MUSCLE PAINS ASSOCIATED WITH SUXAMETHONIUM Sir, The two papers on muscle pains after suxamethonium (Newnam and Loudon, 1966; Glauber, 1966) have served to rekindle interest in a subject of considerable importance to the clinical anaesthetist. Certainly there is no surer way of losing popularity with outpatients thnn to leave a large proportion of them feeling like the aftermath of a severe accident, whilst the operation site is relatively comfortable. Glauber's method of attempting to reduce the incidence of these pains has been used with some success in this area for two years, during which period the author has experienced only one patient with severe post-suxamethonium muscle pains after bronchoscopy (the bank manager's wife!). Fasciculation, and that slight, was observed on only one occasion in a muscular male, who complained of no muscle pains afterwards. On the other hand, in contradistinction to Glauber's findings, the degree of relaxation was found not to be comparable to that produced by equipotent doses of suxamethonium alone. In fact, on occasions a further increment of suxamethonium was required to produce satisfactory relaxation. The findings of Newnam and Loudon that the incidence of post-suxamethonium muscle pain is reduced in the physically fit confirms our findings here; but the apparent complete absence of muscle pains in the African (Coxon, 1962) has also been confirmed here. Coupsr, over three years, has failed to discover any typical post-suxamethonium muscle pains in an African patient (personal communication, 1966). Most of these Africans were of the Xhosa tribe and many are anything but physically fit, which discounted the suggestion that the majority of these patients, including the females, did bard physical labour. This absence of post-suxamethonium pains did not apply to the other races Indian, Malay or people of mixed parentage. Thus, the findings of Newnam and Loudon that 2 out of 11 Negroes developed pains after suxamethonium is interesting. A possible explanation could be that in the United Kingdom and the United States the term Negro is applied to pigmented persons who are, in fact, of mixed descent. It thus appears that the exact cause of suxamethonium muscle pains is still uncertain, but may well be due to a combination of factors, although Tammisto and Airaksinen (1966) may help to throw some more light on the subject. JOHN T. RUSSELL Port Elizabeth REFERENCES Couper, J. L. (1966). Personal communication. Approximately 3,000 patients receive suxamethonium at the Livingstone Hospital, Port Elizabeth, per annum. Coxon, J. D. (1962). Correspondence Muscle pains after suxamethonium. Brit. J. Anaesth., 34, 750. Glauber, D. (1966). The incidence and severity of muscle pains after suxamethonium when preceded by gallamine. Brit. J. Anaesth., 38, 541. Newnam, P. T. F., and Loudon, J. M. (1966). Muscle pain following administration of suxamethonium: the aetiological role of muscular fitness. Brit. J. Anaesth., 38, 533. Tammisto, T., and Airaksinen, M. (1966). Increase of creatine kinase activity in serum as sign of muscular injury caused by intermittently administered suxamethonium during halothane anaesthesia. Brit. J. Anaesth., 38, 510. CORRIGENDUM Sir, A mistake appeared in my article entitled "Heat clearance: a convenient method of estimating peripheral blood flow?" (Brit. J. Anaesth. (1966), 38, 572 (July).) Line 3 of the appendix should read CJi = 4in' k 6. In the subsequent rearranging of the formula, r should read r 1. WILLIAM J. THOMSON Glasgow