Thiopentone, pentobarbitone, diazepam and alphaxolone-alphadolone were evaluated as anaesthetic agents in pregnant mice. Incidence of mortality was: Thiopentone 15%, pentobarbitone 13%, diazepam 8%, and alphaxolone-alphadolone 0%. Besides the low mortality, alphaxolone-alphadolone also distinguished by showing no side-effeets at all, neither to the dams nor to the fetuses, and it is recommended as an excellent anaesthetic in pregnant mice

Jensen, A. G.

Rank, J.

English

Journals from University of Tartu

Scand.J1Lab.Anim. Sci. No. 3. 198‘) 1V01. 16The value of anaesthetic steroids alphaxolone-alphadolone in pregnant miceJ, Rank and A.—G. Jensen, Department of Environment, Technology and Social Studies, Roskilde University,Roskilde, Denmark.Mortality in mice, during or as a result ofanaesthesia, is a well known problem (Green,1982) and this wastage entails an unnecessaryincrease in the number of laboratory animalsused in an experiment.During the last few years, we have carried outexperiments in order to elucidate the genotoxieeffect of diagnostic ultrasound in pregnantmice, for which it was necessary to anaesthetizethe animals, with a low risk of failure in boththe dams and fetuses.Pregnant mice (NMRl—Bom), at day 15-18 ofgestation, were anaesthetized i.V. and placed ina 36°C waterbath, where the ultrasound scan-ning took place. The scanning—time was from15 to 45 minutes, whereafter the mice wereallowed to recover. The next day the animalswere sacrified, the fetuses taken out and blood-cells from the fetal liver were further processedin the transplacental micronucleus test as desc—ribed by Cole et a1. (1981).Until now, we have evaluated four differentanaesthetic agents in the following order: Thio-pentone (Leopental®), pentobarbitone (Nem—butal®), diazepam (Apozepam®) and alphaxo—lone-alphadolone (Saffan®). Thiopentone andpentobarbitone are barbiturates, which areamong the most commonly used anaestheticsin mice. From other studies (Au et a1. 1982 andO’Brien 1976), where mice have been ultra-sound scanned, it appears that barbiturates ha-ve been used without side—effects, and this wasthe reason why we also from the beginning de—cided to use them. The benzodiazepine, diaze—pam, was used only because we had easy accessto it, and because we thought it was a mildagent. Saffan®, a mixture of alphaxolone(0.9% w/v) and alphadolone acetate (0.3%w/v), is the most recent anaesthetic we havetried.Table 1. Incidence of mortality in pregnant mice usingdifferent kind of anaesthetics, i.V. Anaesthetic dose number of number ofmg/kg mice dead miceThiopentone 75—100 60 9 (15 07o)Pentobarbitone 50-60 60 8 (13 070)Diazepam 25-35 12 1 (8%)*Alphaxolone 25—** l l l Oalphadolone *) In 6 of the pregnant mice all fetuses were dead 20hours after injection, and in one of the mice 5 outof 13 fetuses had died.**) Initial dose.Table 1 shows the mortalities in mice within 20hours of i.V. injection of the four differentanaesthetics. The incidence of mortality washighest for the two barbiturates, thiopentone15%, pentobarbitone 13070. The mortality ofthe dams was less using diazepam (8 070) but thisdrug had a disastrous effect in the fetuses.With alphaxolone—alphadolone we have neverseen any dead mice until now, and neither havewe observed any side-effects as we have withthe other three agents. Besides the high morta—lity, the barbiturates gave rise to a slow awake-ning with the mice in a bad condition duringthis process, which in our opinion causes unne-cessary suffering to the animals. Even worsewere the sideeffects of diazepam. The awake-ning was slower than for the barbiturate anaes—thetized mice, and the condition of the animalscan only be described as terrible. It is not possi-ble to say whether the suffering was due to theapozepam itself or was a consequence of the to-xic effect on the fetuses, which all died in 6 outof 12 mice.With alphaxolone—alphadolone we have seenno side—effects. Shortly after termination of theanaesthesia, the mice awoke and appeared torecover completely within minutes. A single[15dose of alphaxolone-alphadolone (25 mg/kg,i.V.) will anaesthetize the mice for about 10 mi-nutes, and for a longer duration it is merely ne-cessary to inject more anaesthetic. For this pur-pose we have, without any problems, used awinged infusion set inserted i.V. into a lateraltail vein and this allowed us to give further in-jections during the experiment whenever themice showed any sign of awakening. The totaldose for 30 minutes anaesthesia was about 50mg/kg.Our findings are in agreement with resultsfrom studies to determine the anaesthetic po-tency and acute toxicity of alphaxolone-alpha-dolone. AI-Khawashki et a1. (1979) found thatan i.V. dose of these steroids ranging from 2—24mg/kg induced immediate sleep in mice for pe-riods of 4-17 minutes in direct proportionalityto the dose level, and the therapeutic index wascalculated to be 22.7 (LD50 = 47 mg/kg andAD50 = 2.07 mg/kg). Child et al. (1971) foundthe therapeutic index of the steroids to be 30.6(LD50 = 54.7 mg/kg and ADSO = 1.7 mg/kg)in mice, when given i.V.. In another study,Green et al. (1978) reported the value of alpha—xolone-alphadolone if given i.V. to mice, rats,hamsters and neonatal pigs. Further, Green(1982) emphasizes that the wide therapeutic in-dex of alphaxolone-alphadolone anaestheticmakes it an excellent agent for mice. The shortperiod of anaesthesia can easily be extended byusing the winged infusion set as mentioned ear-lier, and making this extra effort is nothingcompared to the satisfaction of knowing thatthe animals, when anaesthetized with alphaxo-lone-alphadolone are completely unconscious,feel no pain, are fully relaxed and recover ra—pidly at the end of the experiment. Of particu«lar importance to us was the knowledge thatthe fetuses also survived the anaesthesia.SummaryThiopentone, pentobarbitone, diazepam and alpha-xolone—alphadolone were evaluated as anaestheticagents in pregnant mice. Incidence of mortality was:Thiopentone 15%, pentobarbitone 13%, diazepam8%, and alphaxolone—alphadolone 0%. Besides thelow mortality, alphaxolone—alphadolone also distin—Scand. J. Lab. Anim, Sci. No. 3 . 1989 . Vol. 16guished by showing no side-effeets at all, neither tothe dams nor to the fetuses, and it is recommended asan excellent anaesthetic in pregnant mice.SammendragThiopentone, pentobarbitone, diazepam 0g alpha—xolone—alphadolone er anvendt som anaestesimidler igravide mus. Forekomsten af dedsfald blandt dyrenevar: Thiopentone 15%, pentobarbitone 13%, diaze—pam 8% 0g alphaxolone-alphadolone 0%. Forudenat have den laveste forekomst af dadsfald, udmxr-kede alphaxolone—alphadolone sig desuden ved ikkeat vise tegn pa bivirkninger, hverken i moderdyr ellerfostre, og det anbefales som et glimrende anwsteti—cum til gravide mus.Yhteenveto / K. PelkonenTyossa arvioitiin tiopentonia, pentobarbitonia,diatsepaamia ja alphaxolone-alphadolonea nukutu—saineena kantaville hiirille. Kuolemantapauksia sat—tui tiopentonilla 15%, pentobarbitonilla 13°70, diats-epaamilla 8% ja alphaxolone-alphadolonella 0%.Viimemainitulla ei myoskaan havaittu mita‘an sivu-vaikutuksia, ei emoihin eika sikioihin. Tekijat suo—sittelevat alphaxolone—alphadolonea erinornaisenaanesteettina kantaville hiirille.ReferencesAI—Khawashki, M. 1., H. A. Caleb, N. El—Gawhary,M. K. Madkour, A. M. Radwan &A. M. El-Sher-biny: Pharmacological assessment of the anaes—thetic potency and acute toxicity of Althesin andits steroidal components in laboratory animals.J. Egypt. Med. Assoc, 1979, 62, 191—208.Au, W. W., N. Obergoenner, K. L. Goldenthal, P.M. Corry & V. Willingham: Sister-chromatid ex—changes in mouse embryos after exposure to ul—trasound in utero. Mut. Res., 1982, 103, 315-320.Child, K. J., J. P. Currie, B. Davis, M. G. Dodds, D.R. Pearce & D. J. Twissell: The pharmacologicalproperties in animals of CT1341 — a new steroidanaesthetic agent. Brit. J. Anaesth., 1971, 43, 2-13.Cole, R. J., N. Taylor, J. Cole & C. F. Arlett: Short—term tests for transplacental active carcinogens.I. Mieronucleus formation in fetal and maternalmouse erythroblasts. Mat. Res, 1981, 80, 141-157.Green, C. J., M. J. Halsey, S. Precious & B. Ward—ley-Smith: Alphaxolone—alphadolone anaesthe-sia in laboratory animals. Lab. Anim., 1978, 12,85—89.Green, C. J..' Animal Anaesthesia. Laboratory Ani—mal Handbooks 8. London, 1982, pp 147-154,O’Brien, W. D..' Ultrasound induced fetal weight re-duction in mice. Ultras. Med, 1976, 2, 531—532.[17

The value of anaesthetic steroids alphaxolonealphadolone in pregnant mice

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The value of anaesthetic steroids alphaxolonealphadolone in pregnant mice

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