J . vet. Ptmrnuzcol. 7'hrrcip. 16,488493, 1993

Propofol as an induction agent in the goat: a pharmacokinetic study I . REID, A . M . NOLAN* & E. WELSH*

Departments of Veterinary Surgery and *Veterinary Pharmacology, University of Glasgow, Veterinary School, Bearsden Road, Glasgow

Reid, J., Nolan, A.M., Welsh, E. Propofol as an induction agent in the goat: a pharmacokinetic study. J . uet. Phar7nacol. Therap. 16, 488-493.

The pharmacokinetics of propofol, 4 nig/kg, administered as a bolus dose intravenously (i.v.) prior to the maintenance of anaesthesia with halothane in oxygen, were determined in five goats, and a clinical impression of its use as an induction agent was made. Induction of anaesthesia was rapid and smooth, providing satisfactory conditions for intubation in all animals. Post-induction apnoea occurred in one goat and minimal regurgitation of' ruminal contents was recorded in two animals. Recovery times were rapid with a mean time to standing after halothane inhalation ceased of 13.7 min. The blood propofol concentration time profile was best described by a bi-exponential decline in all five goats. The mean elimination half-life was short (15.5 min), the volume of distribution at steady state large (2.56 I/kg) and the clearance rapid (275 ml/min.kg). Propofol was shown to be a very satisfactory induction agent in the goat. J . Kezd, Department of Veterinaiy Surgery, UriiverJily of Glusgow Veterinary School, Beursden Road, Gla~gow G61 IQH, UK.

I N TRO D U C T I 0 N

Goats represent a very small part of the agricultural population in the British Isles. They are kept as a hobby, for showing, milk production and, niore recently, for mohair and cashmere production. Consequently, the economics of goat farming are very different from those of the sheep. In addition to routine surgical procedures such as disbucl- ding and castration, goats are often presented to the veterinary surgeon for the types of surgery which we associate more with com- panion animals, e.g. t'racture repair. In the goat, minor procedures are frequently carried out electively in young animals under general anaesthesia and this is essential for major surgical procedures. In the majority of these cases the maintenance of anaesthesia is best pel-formed using inhalational agents with the ;ininial intul)ated, but injectable agents have a

place in induction of anaesthesia and for anaesthetic maintenance under certain cir- cumstances.

Propofol (Rapiiiovet, Pitman-Moore), an intravenous agent licensed for use in the dog and cat, is an alkyl phenol which is poorly soluble in water and is therefore presented as an emulsion containing soya bean oil and egg phosphatide. Work carried out in small ani- mals indicated a quick onset of action, short duration of effect and rapid recovery (Wat- kins et al., 1987). Reports of the use of propofol in ruminants have been limited to a clinical study undertaken by Waterman (1988), who described its use as an induction agent in sheep prior to gaseous niainteriarice o f anaesthesia with halothane and nitrous oxide. Pharmacokinetic studies in dogs (Nolan & Reid, 1991) have shown that recovery from anaesthesia is due to distribution and rapid metabolism of the drug.

4xx

Propofol in the goat 489

This study was designed to investigate the use of propofol as an induction agent in goats and to evaluate its pharmacokinetics in this species. Part of this work has been reported in abstract form (Nolan el al., 1991). Flunixin was administered to all goats to provide peri- operative analgesia.

MATERIALS AND METHODS

Five goats, four male and one female pre- sented for surgery, were used in this study. They were aged between 6 and 18 months and weighed between 11 and 63 kg (mean 29.8 kg). All were free from clinical signs of cardiorespiratory disease and were graded as ASA (American Society of Anesthesiologists) 1 (nos 1-4) or ASA 2 (no. 5 ) . Goats 1 - 4 were presented for castration and goat 5 for repair of a tibial fracture. All animals were fasted overnight and were not premedicated. Propo- fol, 4 mg/kg, was administered i.v. by bolus injection into a cephalic vein and, once the goats became recumbent, endotracheal in- tubation was carried out. Intubation was assessed subjectively and recorded as good, fair, difficult or failed. Following intubation, anaesthesia was maintained by the administra- tion of halothane in oxygen delivered via a circle system with carbon dioxide absorption. Once the halothane was turned off, the times to extubation, sternal recumbency and stand- ing were recorded.

Flunixin meglumine (Finadyne, Schering- Plough Animal Health, Mildenhall, UK), 1 mg/kg, was injected i.v. between 18 and 22 rnin after induction of anaesthesia. Venous blood samples, (1 ml), were taken through a pre-placed jugular cannula (Intraflon; Vygon) 1, 2, 4, 6, 8, 10, 15, 20, 30, 45, 60, 90, 120 and 240 rnin after propofol administra- tion. The blood was placed in tubes containing fluoride oxalate (Sarstedt; Germany) and stored at 4°C for a maximum of 3 weeks until analysed. Blood stored in this way retains in excess of 98% propofol for up to 4 weeks. Blood propofol was analysed by high per- formance liquid chromatography (HPLC) using fluorescence detection according to the method described by Plummer (1987). The limit of detection of propofol using this method was 5 ng/ml and the interassay coeffi-

cient of variation was less than 8%. The blood disposition of propofol was analysed with the curve stripping programme CSTRIP (Sed- man & Wagner, 1976). The coefficients and exponents of the equations best describing the data were confirmed using Aikakes informa- tion criterion (Yamaoka et al., 1978). These were subsequently used to calculate the dis- position pharmacokinetics of propofol in each individual animal using standard methods (Baggot, 1977). Results are reported as means k standard error of the mean (SEM) with the exception of the distribution and terminal elimination half-lives which are expressed as harmonic mean.

RESULTS

Induction of anaesthesia was rapid and smooth in all goats and clinical details re- corded are shown in Table I. Intubating conditions were good in all goats with the exception of goat 3, in which anaesthesia from the propofol seemed exceptionally short- lived. Nevertheless intubation was possible in this animal and no cases of failed intubation were recorded. Following intubation, the transition to gaseous anaesthesia was smooth. Regurgitation of ruminal contents occurred at 5 min post-induction in goat 2 and goat 1 had two incidents of slight regurgitation 19 min after the halothane was switched off. Duration of anaesthesia and recovery times from the time at which the halothane was switched off are shown in Table I . For surgical reasons goat 5 (tibial fracture) was unable to stand after surgery.

Each individual blood concentration-time curve was best fitted by a hi-exponential equa- tion. The mean blood concentrations of propofol k SEM following i.v. injection of 4 mg/kg bodyweight, are shown in Fig. I . Blood propofol concentration declined rapidly fol- lowing i.v. injection to a level of 0.1 Kgirnl at approximately 20 min. In all goats secondary blood propofol peaks were evident at a variety of time points; goat 5 at 10 min, goat 4 at 15 rnin and goats 1, 2 and 3 at 20 min. There- after, there was a steady decline in concentra- tion with propofol still detectable in the blood of two goats at 90 min and in none of the goats at I20 min. Table I1 shows the principal

490 A. M. Nolan et al.

T A B L E I . Anaesthetic duration, clinical observations and times to recovery in five goats where anaesthesia was induced with a single i.v. bolus of propofol(4 mg/kg) and maintained with halothane in oxygen. Recovery times are from the time of cessation of halothane administration

Goat number 1 2 3 4 5 Mean k SEM

Duration of anaesthesia (min) 15 27 45 30 220 67.4 rt 43 Time to extubation (min) +3 +6 +4 +5.5 +5 4.7 k 0.6 Time to sternal recumbency (min) + 1 1 +6 +8 12.5 +9 9.3 2 1.3 Time to standing (rnin) +14 +7 +18 +16 - 13.7 +_ 2.8 Post induction apnoea (min) no no yes* no no Intubating conditions (min) good good fair good good

*1 rnin duration.

pharmacokinetic parameters for individual DISCUSSION goats along with the mean values k SEM. The distribution half-life (tlria) was very rapid, Various anaesthetic regimes have been sug- mean 0.7 min. However, since the first sam- gested as being suitable for use in small pling point was at 1 min, this exponential has ruminants (Taylor, 1991). Induction and been based on a small number of points and maintenance of anaesthesia with a volatile so its value may not be accurate. agent such as halothane is associated with

0 1 5 30 4 5 6 0 75 90

Time (min)

FIG. 1 . Semilogarithmic plot of mean blood propofol concentrations (pg/rnl) f SEM against time (min) for a group of' five goats after a bolus injection of 4 nig/kg, i.v. where anaesthesia was maintained with halothane in oxygen.

Propofol in the goat 491

T A B L E I I . Pharmacokinetic parameters for five goats following a single i.v. dose of propofol, 4 mg/kg

Goat 1 1.936 17.35 0.904 5.723 2.319 228.6 Goat 2 1.704 20.63 0.939 7.291 3.219 244.9 Goat 3 1.205 16.04 0.842 8.360 2.753 361.3 Goat 4 0.249 11.05 0.254 5.603 2.939 351.3 Goat 5 0.875 15.40 0.353 4.198 1.599 189.0 Mean 0.705* 15.46* 0.658 6.235 2.560 275.0 f SEM 0.147 0.810 0.320 38.5

*Harmonic mean; tlFia = distribution half-life; t,j2P = elimination half-life; V, = volume of the central compartment; VdCnrca) = apparent volume of distribution; Vd,, = volume of distribution at steady state; Cl, = whole body clearance.

rapid return to consciousness, but the time available for intubation is minimal and, unless well fasted, animals are prone to regurgitation at induction. Of the various injectable agents described for use in small ruminants, the barbiturates such as pentobarbitone tend to prolong recovery from anaesthesia. Combina- tions of the a-2 agonist xylazine and the dissociative anaesthetic ketamine have been reported as satisfactory for use in the goat by Kumar et al. (1976) and this method has gained popularity in some countries. How- ever, such a method does not allow for the fine control of the depth of anaesthesia which can be achieved by an inhalational agent. Waterman (1988) reported that a mean dose of 3.5 mg/kg propofol was satisfactory for the induction of anaesthesia prior to gaseous maintenance in sheep. A bolus of 4 mgikg proved very satisfactory for the induction of anaesthesia in this series of five goats, with rapid induction, good intubating conditions and smooth transition to gaseous mainte- nance. This dose rate compares with that in the sheep, is lower than that used in dogs and cats (mean 5.8 nig/kg Watkins et al., 1987), but higher than that required to induce anaesthe- sia in man (2.0-2.5 nig/kg, data sheet: ICI).

Regurgitation of ruminal contents with the subsequent risk of aspiration pneumonia is a well-documented hazard of' general anaesthe- sia in the ruminant (Hall & Clarke, 1991). In this series, two of the five goats regurgitated, at 5 min and 34 min post-induction. Neither of these incidents was significant since in-

tubation had already been carried out under the optimum intubating conditions provided by propofol.

Waterman (1988) found that recovery times in sheep given propofol prior to gaseous maintenance were almost identical to those of sheep anaesthetized with halothane alone. However, goats differ from sheep in their reaction to various drugs used for anaesthe- sia; an example being the increased sensitivity of the goat to the effects of xylazine (Hall & Clarke, 1991). The mean recovery times of the goats in this study were slightly longer than those of the sheep reported by Water- man (4.7; 9.3; 13.7 min compared with 1.8; 6.0; 8.0 min for extubation, sternal and standing times in goats and sheep, respective- ly). The duration of anaesthesia in the goats was variable, with goat 5 having surgery for 220 min. I t is interesting to note, however, that in this animal recovery time from halothane was similar to the others, which bears out Waterman's findings in the sheep.

The bi-exponential decline of propofol concentration in the blood of goats differs from the tri-exponential decline in four of seven dogs (Nolan & Reid, 1991) and in humans'(Kay et al., 1986). There is evidence to suggest from human studies that the length of sampling time has an influence on the charac- teristics of the disposition curve (Campbell et al., 1988). Early work in humans, in which the decline of propofol in blood best fitted a bi- exponential curve, may have been misleading because of a short sampling time (Schuttler et

492 A . M . Noluri et al.

d., 1985). In this study samples were taken up to 240 min post-in.jection, but no propofol was detected in any goat after 120 min and this would tend to suggest that the bi-exponential decline was correct. However, the limit of tletectioti for the assay was 5 ng/ml and therefore any third exponential may have been undetectable.

Studies in women, where anaesthesia was induced with propofol and subsequently maintained with halothane in nitrous oxide/ oxygen, indicated that the terminal elimina- tion half-life was 184 f 15 min (Cockshott et al., 1987). Dogs given a bolus of propofol prior t o a similar maintenance regime had a mean terminal elimination half-life of 75.2 min (range 59.6-88.8) (Nolan et nl., submitted for publication). In contrast, the eliniination half-life in the goat was consistently short, mean 15.46 min. The high values for both Vd,, and Vc~(2,,-c,aJ (mean values 2.56 Vkg and 6 . 2 3 I/kg respectively), indicate that ptopofol is extensively distributed from blood to the tissues and correlates well with results in humans (Cockshott et ul., 1987). Compared with values for body clearance in humans (mean 31 nil/min x kg) reported by Cockshott r l ul. (1987), clearance values in all goats were extremely high (mean 275 m h i n x kg). Hepatic blood f low in the sheep is of the order of YO ml/kg X min (Runciman el ul., 1990) and while this value may not be directly applicable to the goat, it is likely to be similar given the simi1arit.y of the two species. The value for propofol clearance of 275 ml/min x kg is therefore likely to be far in excess of liver liloocl flow in the goat. This suggests either the involvement of an extrahepatic site of metabolism for propofol and/or that the drug is concentrated in tissues as yet undetermined. The possiliility of extrahepatic metabolism, involving a well-perfusetl tissue such as kidney or lung, has also been suggested in humans and additional evidence in support of this was provided by a study carried out during the anhepatic phase of orthotopic liver transplan- tation when a propofol metabolite was de- tected in the urine (Veroli et al., 1992).

Propofol is highly bound (99%) to plasma proteins (Russell et al., 1989) and consequent- ly any alteration in binding, such as might occur in hypoproteinaemia or competitive displacement by other highly protein bound

drugs, could be expected to have profound el'lects on its pharmacokinetics. Alteration in plasma binding may affect drug distribution, elimination half-life and organ clearance (Wood, 1986). All f ive goats were given flunixin by i.v. injection within 22 min of induction of anaesthesia. Flunixin, a coninion- ly used analgesic in veterinary medicine, is a potent non-steroidal anti-inflammatory drug which is highly protein bound arid thus would have the potential to alter the kinetics of propofol by displacing it from binding sites (Lees et nl., 1991). Secondary peaks in blood propofol concentration such as those seen in all five goats have been described in humans, where they are often associated with awaken- ing, and it has been suggested that this niay be related to the haeniodyriamic changes which occur in the body at this time (Elfstrom, 1979). Only in goat I , however, could awakening be implicated in the developmenr. of the secon- dary peak since in all the others anaesthesia continued beyond the time of the peak. Many drugs affect regional 1)lood flow through altetations in peripheral vascular resistarice and although this has not been described for flunixin, such effects cannot be ruled out. However, in three 01' the five goats the injection of' iluriixiri was made after the secondary peak in blood propofol concentra- tion had occurrecl. Consequently, the increase in propofol concentration in these goats c:ould not be attributed to flunixin administration. This could be confirmed in a g ro~ ip of goats anaestl-ietized under the same conditions with- out flunixin administration, although in this event alternative drug therapy woii ld be required as a meails of supplying post- operative an;ilgesia.

I n conclusion, i t was foimd that propofol at a close rate of 4 mg/kg was ;I good induction agent in the goat anti furthermore its pharma- cokinetic profile, with rapid metabolism and high body clearance, would make it a suitable agent for total i.v. anaesthesia i n this species, either by incremental dosing or continuous i.v. infusion. Such techniques have much to com- mend them including smooth induction arid stable niaintenance of anaesthesia, the depth of which can be easily altered. Lack of atmospheric pollution and avoidance of the possible harm- ful effects of waste anaesthetic gases on theatre personnel are also important considerations.

Pvopofol in the goat 493

AC KN 0 W LEDG M ENTS

We wish to thank Peter Baxter for his techni- cal assistance.

REFERENCES

Baggot, J .D. (1977) in Principles of Drug Disposition in Domestic Animals. W. B. Saunders Company, pp. 144-183.

Campbell, G.A., Morgan, D.J. , Kumar, K. & Crank- shaw, D.P. (1988) Extended blood collection period required to define distribution and elimina- tion kinetics of propofol. British Journal of Clinical Pharmacology, 26, 187-190.

Cockshott, I.D., Briggs, L.P., Douglas, E.J. & White, M. (1987) Pharmacokinetics of propofol in female patients: studies using single bolus injec- tion. British Journal of Anaesthesia, 59, 1 103-1 110.

Elfstrom, J . (1979) Drug pharmacokinetics in the postoperative period. Clinical Phannncokinetirs, 4, 16-22.

Hall, L.W. & Clarke, K.W. (1991) Veterinary Anaesthesia, 9th Edition, Bailliere Tindall, Lon- don.

Kay, N.H. , Uppington,]., Sear, J.W., Douglas, E. & Cockshott, I . (1986) T h e pharmacokinetics of propofol in patients undergoing surgery. A com- parison in men and women. British Journal uf Anaesthesia, 58, 1075-1079.

Kumar, A,, Thurmon, ,J.C. & Hardenbrook, H.J. (1976) Clinical studies of ketamine HCI and xylazine HCI in domestic goats. Veteiz’mzry MedicinelSmall Animal Clinician, 71, 1707-1713.

Lees, P., May, S.A. & McKellar, Q.A. (1991) Pharmacology and therapeutics of non-steroidal anti-inflammatory drugs in the dog and cat: 1 General pharmacology. Journal of Small Aninzal Practice, 32, 183-193.

Nolan, A.M. & Reid, J. (1991) A pharmacokinetic study of propofol in the dog. Proceedings of the 4th International Congress of Viterinary Anaesthesia, Utrecht, p. 40.

Nolan, A.M., Reid, J. & Welsh, E. (1991) T h e use of propofol as an induction agent in goats.Journa1 of Veterinary Anaesthesia, 18, 53.

Plummer, G.F. (1987) Improved method for the determination of propofol in blood by high performance liquid Chromatography with fluorescence detection. Journal of Chromatography, 421, 171-176.

Runciman, W.B., Mather, L.E. & Selby, D.G. ( 1990) Cardiovascular effects of propofol and of thiopentone anaesthesia in the sheep. British Joumal of Anaesthesia, 65, 353-359.

Russell, G.N., Wright, E.L., Fox, M.A., Douglas, E.J. & Cockshott, I.D. (1989) Propofol-fentanyl anaesthesia for coronary artery surgery and cardiopulmonary bypass. Anaesthesia, 44, 205- 208.

Schuttler, J., Stoeckel, H. & Schwilden, H . (1985) Pharmacokinetic and pharmacodynamic model- ling of propofol (Diprivan) in volunteers arid surgical patients. Postgraduate Medical Journal, 61, 53-54.

Sedman, A.J. & Wagner, J.G. (1976) CSTRIP, a Fortran iv computer programme for obtaining initial polyexponential parameter estimates. Jour- nal of Pharniaceutical Sciencr, 65, 10OCi1010.

Taylor, P.M. (1991) Anaesthesia in sheep and goats. I n Practice, 13(1), 31-36.

Veroh, P., OKelly, B., Bertrand, F., Trouvien, J.H., Farinotti, R. & Ecoffey, C . (1992) Extrahepatic metabolism of propofol in man during the an- hepatic phase of orthotopic liver transplantation. British Journal of Anaesthesia, 68, 183-186.

Waterman, A.E. (1988) Use of propofol in sheep. Veterinary Record, 122, 26.

Watkins, S.B., Hall, L.W. & Clarke, K.W. (1987) Propofol as an intravenous anaesthetic agent in dogs. Veterinary Record, 120, 326-329.

Wood, M. (1986) Plasma drug binding: Implica- tions for anesthesiologists. Anesthesia and Analge- sia, 65, 786-804.

Yamaoka, K., Nakagawa, T . & Uno, T. (1978) Application of Aikakes information criterion (AIC) in evaluation of linear pharmacokinetic equations. Journal of Pharniacokinetics and Biophar- maceutics, 6, 165-175.