FLUNITRAZEPAM AS AN INDUCTION AGENT IN CHILDREN

FLUNITRAZEPAM AS AN INDUCTION AGENT IN CHILDREN

Br. J. Anaath. (1984), 56, 899 FLUNITRAZEPAM AS AN INDUCTION AGENT IN CHILDREN A clinical and pharmacokinetic study E. IlSALO, J. KANTO, L. AALTONEN ...

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Br. J. Anaath. (1984), 56, 899

FLUNITRAZEPAM AS AN INDUCTION AGENT IN CHILDREN A clinical and pharmacokinetic study E. IlSALO, J. KANTO, L. AALTONEN AND J. M A K E L A SUMMARY

pethidine 1 mgkg~' were administered i.m. as premedication about 60min before the beginning of anaesthesia. Flunitrazepam 0.03 mg kg"1 (n= 4), or 0.04 mgkg"1 (n=6) was injected in 20-30s, and venous blood samples were drawn from a contralateral antecubital vein at the time of administration and subsequently at the intervals given in figure 1. The largest dose (0.03 mg kg"1) recommended for adult patients by the manufacturer was used initially, but because of an inadequate response the dose was increased later to 0.04 mg kg"1. The other components of the anaesthetic were 70% nitrous oxide in oxygen and pethidine 0.8-2.8 mgkg"1. Suxamethonium 0.8-1.8mgkg" 1 , and pancuronium O.lO-O.SOmgkg"1 were administered to provide appropriate neuromuscular blockade. Atropine 0.02 mg kg"1 and neostigmine 0.04-0.05 mgkg"1 were used to reverse the neuromuscular blockade. Anaesthesia lasted for 0.75-3.0 h (mean 1.62h). Systolic and diastolic arterial pressures and heart rate were recorded frequently before and during anaesthesia (at 3 - 5-min intervals) and in the recovery room (at 5-10-min intervals). The degree of PATIENTS AND METHODS postoperative sedation was determined by an anaesAnaesthesia was induced with flunitrazepam in 10 thetist (E.I.) 5, 30, 60 and 90min after the end of children (ASA 1 or 2) about to undergo major anaesthesia (asleep, very sedated, moderately sesurgical procedures. Their ages, weights and dated, alert). On the day following the operation the heights ranged from 3 to 10yr(mean4.8yr), 12.6 to patients were questioned by the anaesthetist as to 28.0kg (mean 21.4kg), and 89 to 135cm (mean their memory for being taken to the operating 113.2cm), respectively. Atropine 0.01 ing kg"1 and theatre, the induction of anaesthesia, recovery from anaesthesia, time spent in the recovery room, return to the ward, or the evening of the day of operation at the ward. The use of analgesics after operation was EILA IISALO, M.D.; Jusa KANTO, M.D.; JARKXO MAKELA, M.D.; Department of Anaesthesiology, Turku University Central Hosrecorded. In addition, the possible retrograde ampital,. Kiinamylrynkatu 4 - 8 , SF-20520 Turku 52, Finland. nesic effect of flunitrazepam was assessed. Just beLEENA AALTONEN, M.SC, Department of Pharmacology, Turku fore the induction of anaesthesia the patients were University, Turku, Finland. shown two pictures (a horse and a car). On the first Correspondence to J. K. Flunitrazepam has proved to be a satisfactory premedicant in children older than S yr when administered by oral or parenteral routes (Lindgren, Saarnivaara and Himberg, 1979, 1980; Richardson and Manford, 1979; Kanto, 1981). However, its usefulness as an induction agent has not been studied widely in children. Generally, flunitrazepam, like other benzodiazepines, has been regarded as a slower acting sedative rather than as a short-acting induction agent (Dundee, 1979a, b; Kanto and Klotz, 1982). This is mainly because flunitrazepam fails to produce an acceptable depth of anaesthesia in one arm-brain circulation time, leading to great individual variation in drug response. However, because flunitrazepam has been considered a satisfactory induction agent in adult patients (Stovner, Endresen and Osterud, 1973; Freuchen, 0stergaard and Mikkelsen, 1976), we have studied its properties in children. In addition, pharmacokinetic parameters were calculated to determine the possible relationship between kinetic and clinical indices (Klotz, Kangas and Kanto, 1980).

<£) The Macmillan Press Ltd 1984

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Flunitrazepam was studied as an induction agent in paediatric patients. The onset of action was slow and its efficacy uncertain following single doses of 0.03 mg kg"1 (n —4), or 0.04 mg kg"1 (n = 6) i.v. Long-lasting sedative effects were observed following operation. A strong anterograde but not retrograde nmnr«ir effect was obtained, and a possible analgesic sparing property. Flunitrazepam has a faster and more extensive tissue distribution and a more rapid elimination (half-life about 12 h) in children thpn in adults.

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day after operation these two pictures were mixed with eight others (presenting four different flowers, and four different butterflies) and the patients were asked to recognize the two pictures shown to them before anaesthesia. Serum concentrations of flunitrazepam were determined according to Kangas (1977) and the pnarmacokinetic parameters for the agent calculated as described previously (Kanto et al.,1981).

4

5 6 Time (h)

FIG. 1. Hunitrazepam concentrations (mean ±SD) in the sera of children after a single 0.03-mgkg"1 ( n - 4 ) (O O) or 0.04mgkg-' (n = 6) ( • • ) injection i.v. At 72 h after drug administration, flunitrazepam was not detectable in the serum (lower limit of sensitivity of the method - 0.2 ng ml"1)-

recovery room for up to 90 min. The four patients who had received flunitrazepam 0.03mgkg"1 i.v. were either asleep (n = 2), or very sedated (n = 2) for up to 60 min after the end of anaesthesia. At 90 min the anaesthetist's assessment was: asleep ( n = l ) , moderately sedated (ft = 2), alert (n= 1). Three of the six patients receiving flunitrazepam 0.04mgkg" 1 i.v. were asleep in the recovery room for up to 30 min, very sedated at 60 min, and moderately sedated at 90 min. The remainder were either moderately sedated (n = 2), or alert (n = 1) although they had experienced the longest anaesthetics (2.1, 2.5 and 3 h). The nursing staff in the recovery room

TABLE I. Pharmacokinetic parameters (meaniSD) derived from the serum concentrations of flunitraxepam after a single 0.03mgkg~'(n'm 4) or 0.04-mgkg~' (h— 6) injection i.v. Tj*= half-life of the initial rapid exponential term; V— apparent volume of distribution during a phase; T|r ~ half-life of the second rapid exponential term (— second distribution phase); V*•» apparent volume of distribution during r phase; T / = elimination phase half-Hfe; v* = apparent volume of distribution duringfiphase; Cl — total serum clearance, AUC- ana under curve (litre kg"1)

7V (h)

(litre kg"1)

(h)

Flunitrazepam 0.03 mg kg"1 1.24 Mean 0.05 0.90 SD 0.02

0.57 0.32

4.13 1.46

11.77 3.65

Flunitrazepam 0.04 mg kg' 1 0.93 Mean 0.06 SD 0.06 0.88

0.72 0.41

9.52 3.66

11.99 4.40

(h)

O (ml min"1 kg- 1 )

AUC (fig litre"1 h"1)

8.64 4.42

7.98 2.08

67.13 22.35

12.57 11.02

11.93 8.15

83.96 58.98

(litre kg-

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RESULTS Flunitrazepam was found to be an unsatisfactory induction agent for general anaesthesia in children. After the 0.03mgkg" 1 i.v. dose, the eyes closed spontaneously in 40, 50 and 70s in three of four patients, and the palpebral reflex disappeared in 55, 90 and 180 s. However, all three reopened their eyes, and were given thiopentone 25-50 mg to deepen anaesthesia. The fourth patient, who received flunitrazepam 0.03 mg kg"1 i.v., did not close his eyes at all until 5 min after administration, and he then received thiopentone 50 mg. In two of the six patients receiving flunitrazepam 0.04mgkg"1 i.v. the eyes closed spontaneously in 30 and 35 s, and the palpebral reflex disappeared in 55 and 85 s. No additional thiopentone was needed. The other four patients receiving flunitrazepam 0.04mgkg"1 i.v. did not fall asleep until 5 min after administration, and they were given additional thiopentone 2 5 - 50 mg. Three of these four patients began to cry before the injection of thiopentone. Good cardiovascular stability was observed during and after anaesthesia. Immediately afterwards, two patients vomited, one complained of nausea and hypoventilation lasting 30 min was noted in one patient (flunitrazepam 0.04 mg kg"1 i.v.). In general, the patients were over sedated in the

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DISCUSSION

Our results suggest that flunitrazepam is not an ideal agent with which to induce anaesthesia in children. It produces marked anterograde but no retrograde, amnesia, and may have some analgesic sparing effect following operation. The pharmacokinetics of this nitrobenzodiazepine derivative in children differ substantially from those obtained in adults. Although the age range of our patients was wide (3 -10 yr) and the type of operation varied, there was no clear age dependency in the pharmacodynamic drug action of flunitrazepam as an induction agent, nor in its pharmacokinetics. The main disadvantages of flunitrazepam as an induction agent were its slow and varying onset of action, and the long lasting postoperative sedation. The latter property clearly increased the nursing time both in the recovery room and in the ward in comparison with that required by patients given thiopentone. Thus, flunitrazepam, like other benzodiazepine derivatives, is a basic hypnotic com-

pound rather than an orthodox induction agent (Dundee, 1979a, b; Kanto and Klotz, 1982). It appears to be more useful when used as an adjuvant to general or local anaesthesia (Dundee et al., 1976). The assessment of retrograde amnesia in this study might have been too simple for the older children. However, a more complicated test would be unsatisfactory in the younger ones. No retrograde amnesic effect was obtained, but the marked anterograde amnesia associated with flunitrazepam in children seems to equal that observed in adult (Dundee et al., 1976; Korttila and Linnoila, 1976; George and Dundee, 1977) and elderly (HoviViander et al., 1982) patients. However, this effect is not always desirable since the loss of self-control may be alarming for some patients (Conner et al., 1978). Consequently, these problems should be discussed with patients, especially with the more grown-up children, during the preoperative visit (Kanto and Klotz, 1982). The analgesic sparing effect of flunitrazepam has also been reported in earlier studies (Manila et al., 1979; Hovi-Viander et al., 1982). It is possible that our patients were so sleepy and amnesic that they were unable to ask for analgesics. However, they had undergone various surgical procedures such as herniorrhaphy (n=l), orchidopexy (n= 1), osteofixation (n = 2), ureteroplasty (n = 1), coxal osteotomy (n = 2) and circumcision (n = 3) and generally, after thiopentone-induced anaesthesia, opiates are required in the period after operation. In children, the pharmacokinetics of flunitrazepam appear to differ greatly from those determined in adult patients (Kanto et al., 1981; HoviViander et al., 1982; Kangas, Kanto and Pakkanen, 1982). The half-life of the elimination phase varies in adults from 23 to 29 h, and the respective volume of distribution between 3.57 and 6.58 litre kg"1. In this study, the half-life of the elimination phase was about 12 h, although the respective distribution volume was greater than that in adults (about 9-12 litre kg"1)- Thus, the shorter elimination phase half-life observed in children was caused by a total clearance value (approximately 8-12 ml min"1 kg"1) much greater than that in adult subjects (0.165 litre h"1 kg"1 or 106-135 ml min"1) (Kanto et al., 1981; Hovi-Viander et al., 1982; Kangas, Kanto and Pakkanen, 1982). This is in agreement with the fact that the metabolism of drugs is generally enhanced in children compared with adults (Morselli, Franco-Morselli and Bossi 1980).

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and in the ward considered the patients over sedated and this required more nursing supervision. Surprisingly, five of 10 patients did not need any analgesia after operation, and the other five patients only required analgesia at 60 min, 90min, 5.5h,6h and 7 h after anaesthesia. No retrograde amnesia was observed: all the patients remembered the two pictures the following day, and they all remembered being taken to the operating theatre. However, strong anterograde amnesia was reported. No patient had any recollection of the induction of anaesthesia or of the subsequent awakening, and only one patient remembered the period in the recovery room. Three had no recollection of returning to the ward, but all remembered being in the ward on the evening of the day of operation. The youngest patient (3yr), however, was not able to report this drug effect very reliably. The serum concentrations of flunitrazepam are presented in figure 1 and the pharmacokinetic parameters derived from these are shown in table I. There was no correlation between any of these parameters and the observations obtained during the induction and maintenance of anaesthesia, or in the period after operation. The sole finding was that the three patients with the lowest degree of postoperative sedation woke up from anaesthesia during the flunitrazepam elimination phase when there were no longer any great alterations in the serum concentrations.

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REFERENCES

Conner, J. T., Katz, R. L., Bcllville, J. W., Graham,C, Pagano, R., Dorey, F. (1978). Diazepam and lorazepam for intravenous premedication. / . Clin. Pharmacol, 18,285. Dundee, J. W. (1979a). New i.v. anaesthetics. Br. J. Anatsth., 51,641. (1979b). Benzodiazepine sedation-amnesia; in Currtnt Topia in Anatsthtsia Stria 1: Intravenous Anattthttic Agtnts. London: Edward Arnold (Publishers) Ltd. George, K. A., Varadarajan, C. R., Clarke, R. S. J., and Nair, S. K. G. (1976). Anaesthesia and amnesia with flunitrazepam. Br. J. Anatsth., 48, 266. Freuchen, I., 0stergaard, J., and Mikkelsen, B. O. (1976). Flunitrazepam (Rohypnol) compared with enibomal (Narcodorm) as an anaesthetic induction agent: a controlled clinical trial. Curr. Thtr. Rts., 20, 36. George, K. A., and Dundee, J. W. (1977). Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man Br. J. Clin. Pharmacol, 4, 45. Hovi-Viander, M., Aaltonen, L., Kangas, L., and Kanto, J. (1982). Flunitrazepam as an induction agent in elderly, poorrisk patients. Aha Anatsthtsiol. Scand., 26, 507. Kangas, L. (1977). Comparison of two gas-liquid chromatographic methods for plasma nitrazepam determination. / . Chromatogr., 136, 259. Kanto, J., and Pakkanen, A. (1982). Phannacokinetic and pharmacodynamic study of flunitrazepam. Int. J. Clin. Pharmacol. Thtr. Toxicol.y 20, 585. Kanto, J. (1981). Benzodiazepines as oral premedicants. Br. J. Anatsth., Si, 1179. Kangas, L., Aaltonen, L., and HOke.H. (1981). Effect of age on the pharmacokinetics and sedative effect of flunitrazepam. Int. J. Clin. Pharmacol Thtr. TaxicoL, 19,400. Klotz, U. (1982). Intravenous benzodiazepines as anaesthetic agents: pharmacokinetics arid clinkr^ consequences. Ada Anaesthtsiol. Scand., 26, 554. Klotz, U., Kangas, L., and Kanto, J. (1980). Clinical pharmacokinetics of benzodiazepines; in Progrta in Pharmacology, Vol. 3, No. 3. Stuttgart and New York: Gustav Fischer Verlag. Korttila, K., and Linnoila, M. (1976). Amnwir action and skills related to driving after intravenous flunitrazepam. Ada Anaesthtsiol. Scand., 20, 160. Lindgren, L., Saamivaara, L., and Himberg, J.-J. (1979). Comparison of i.m. pethidine, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery. Br. J. Anatsth., 51, 321. Lindgren, L., Saamivaara L., and Himberg, J.-J. (1980). Comparison of oral triclofos, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery. Br. J. Anaesth., 52, 283.

Manila, M. A. K., Slila, K., Kokko, T., and Karkkainen, T. (1979). Comparison of diazepam andflunitrazepamas adjuncts to general anaesthesia in j»i wilting arousal following surgical stimuli. Br. J. Anatsth., 51, 229. Morselli, P. L., Franco-Morselli, R., and Bossi, L. (1980). f^lipinol pharmacokinetics in newborns and infants. Agerelated differences and therapeutic implication!. Clin. Pharmaeokin.,5,485. Richardson, F. J., and Manford, M. L. M. (1979). Comparison of flunitrazepam and diazepam for oral premedication in older children. Br. J. Anatsth., 51, 313. Stovner, J., Endresen, R., and Orterud, A. (1973). Intravenous anaesthesia with a new benzodiazepine, Ro 5-4200. Acta Anatsthtsiol. Scand., 17,163. LE FLUNITRAZEPAM COMME AGENT DTNDUCTION CHEZ L'ENFANT Etudt cliniqut tt pharmacodnttiqut RESUME

Le flunitrazepam a etc etudie comme agent d'induction chez l'enfant. Le debut d'action etait lent et son efficarite incerrainr apres des injections intraveineuses uniques de 0 J 03mgkg- 1 (B-4)ou0,004mgkg- 1 (»-6). Des effets sedatifs prolonges ont etc observes apres la fin de rintervention. Une QTTiTifTir ant£rograde puissante a et£ obtenue ainsi qu'une £conomie possible d'analgesiquc, mais sans amncsie retrograde. Le flunitrazepam a, chez l'enfant, une distributiontissulaireplus rapide et plus importante que chez l'adulte, ainsi q'une elimination plus precoce (demi-vie d'environ 12 h). FLUNITRAZEPAM ALS EINLETTUNGSMEDIKAMENT BEI KINDERN Eint klmischt und pharmakokinttischt Studit ZUSAMMENFASSUNO

Flunitrazepam wurde als Fini^itungmrHylilfgTTi^nt bci padiatrischen Patienten untersucht. Der Wirkungseintritt erfolgte langsam, und nach Einzddosen von 0,03 mg kg"1 (n=»4) oder 0,04mgkg" 1 (n = 6) war die Wirksamkeit unntcher. Nach der Operation wurden lange andauernde sedative Effekte beobachtet. Es wurde ein starker anterograder, jedoch kein retrograder anamnestischer Effekt und cine moglkhe Analgetika-sparende Eigenschaft gefunden. Flunitrazepam hat bei Kindern cine schnellere und ausgedehntere Gewebeverteilung und eine schndlere Elimination (Halbwertszeit nur 12 Stunden) als bei Erwachsenen. EL FLUNITRAZEPAN COMO AGENTE DE INDUCCION EN NINOS Un atudio clinico y farmacodniaco SUMARIO

Se estudid elflunitrazepancomo agente de inducdon en pacientes pediitricos. El principio de la accion era lenta y tu * « r i « incierta despues de dosis unicas de 0,03 mg kg~' (n = 4) 6 de 0,04 mg kg~' (n = 6) por via i.v. Se observaron efectos sedativos de larga duracion despues de la operation. Se obtuvo un efecto amnesico fuerte anterogrado pero no retrogrado y una propiedad probable de economia analgesics. El flunitrazepan posee una distribucion en los tejidos mas rapida y mas extensa y una eliminacion mas rapida (media vida de 12 h aprootimadamente) en los ninos que en lew adultos.

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The two distribution phase half-lives of flunitrazepam were shorter in children than in adults (0.05-0.06h v. 0.08-1.02 h, and 0.57-0.72 h v. 1.37-1.90 h) and the respective distribution volumes greater (0.93-1.24 litre kg"1 v. 0.58-0.97 litre kg" and 4.13-9.52 litre kg"1 v. 1.43-2.401itrekg- 1 ) (Kanto et al., 1981, HoviViander et al., 1982; Kangas, Kanto and Pakkanen, 1982). Thus the tissue distribution of this agent was faster and more extensive in the paediatric patients.