In Pigs Anaesthetized with A—Chloralose

Scand, J. Lahl Anim. Sci. No. 3. 1990 . Vol, 17

Acid-base status and cardiovascular function in pigs anaesthetized with a—chloralose

by Per Svendsenl), Mark A insworthQ) and Anthony Carter”, 1) Biomedical Laboratory, Odense University, 2) Clinical Institute, Department of Internal Medicine, Odense University Hospital, 3) Institute of Medical Biology, Department of Physiology, Odense Univer— sity, 55, Campusvej, DK-5230 Odense M, Denmark.

INTRODUCTION sthetic in studies on chemoreceptor and ba- Blood gas tensions, acid—base status and car— roreceptor reflexes in this species (Booth er diovascular function have previously been a]. 1960, Bredeck el al. 1961 and Adams el examined in Gottingen mini-pigs anaesthe- al. 1987). In a comparison between halo- tized with halothane and methoxyflurane or thane, a-Chloralose, pentobarbitone and eto- intravenous metomidate hydrochloride midate anaesthesia on gastric function, (Svendsen & Carter 1989). Neither of the a-chloralose was found to increase gastric methods was fully acceptable for experi- acid secretion following stimulation with ments that required stable blood pressure pentagastrin (Stadkilde—Jargensen el al and acid-base balance within a narrow nor- 1985). mal range. The aim of the present study was to examine a-Chloralose has been used extensively as an the effects of a-chloralose anaesthesia on the anaesthetic in physiological experiments cardiovascular and respiratory systems in since it was first reported by Vincent & pigs during in an experimental study of acid Thompson 1928 that the arterial blood pres- neutralization in the duodenum. sure remained stable during anaesthesia in cats. Examinations in dogs have confirmed MA. TERIALS AND METHODS that arterial blood pressure and heart rate The study involved 47 female Danish Land- are higher and reflexes more active than race pigs weighing between 23 and 34 kg. under other anaesthetics (Brown & Hilton The animals originated from an SPF breed- 1955 & 1956 and Bass & Buckley 1966). ing unit, and were kept in the laboratory for In a study of the effects of different anaesthe- at least 48 hours prior to anaesthesia. The tics on the balance between central and animals were treated initially with azape- chemoreceptor control of respiration in rone (Sedaperone vet. 4 %) at 2 mg/kg (i.m.), dogs, it was demonstrated that the central and were after 30 min anaesthetized with response to CO; was considerably dimin- metomidate hydrochloride (Hypnodil vet. ished and the sensitivity of the chemorecep- 5 %) at 4 mg/kg (i.v.), intubated and main- tors increased during a-Chloralose anaesthe- tained at a surgicaI level with 1 % halothane sia. a-chloralose thus seems to cause a shift in 100% oxygen (group 1) or 60 % oxygen in the balance between two factors involved and 40 % air (group 2) for approximately 90 in respiratory control, so that the part min. During this period the surgical inter— played by direct chemical stimulation of the ventions were completed and the animals respiratory centre is diminished and the part prepared for the experiment. The halothane played by the chemoreceptor reflexes is was removed and anaesthesia was main— augmented (Dripps & Dunke 1943). tained by intravenous infusion of a-chlora— The side effects of a-chloralose on respira- lose 0.25 0/o (100 mg/kg). Two thirds of the tory and circulatory parameters in pigs dose was given as a bolus, and one third as have never been thoroughly investigated, al— continuous infusion throughout the remain- though the drug has been used as an anae- ing experimental period. The animals were

89 Scand. J. Lab Anim, Sci. No. 3 . 1990‘ V01. 17

divided into two groups, one maintained on RESULTS spontaneous respiration using 100 0/o 02 Azaperone produced sedation sufficient to (Komesarotf Small Animal Anaesthetic perform intravenous injection within 10—30 Machine) (n = 22), and the other (n = 25) in min. However, intravenous injection into an which respiration was supported by an arti- ear vein of metomidate hydrochloride fre- ficial ventilator (Servo ventilator 900. Elema quently caused a reaction involving violent Schonander, Sweden). The respiratory fre— head shaking. This could be prevented by quency was 20 breaths per min with an in- giving part of the metomidate hydrochloride spiratory time of 25 0/o, a pause time of 10 % intraperitoneally at the same time as aza- and a deep sigh function. The 02 level was perone. 60 %. The minute volume was adjusted ac- Tracheal intubation was easily performed cording to the arterial blood gas measure- after induction with metomidate hydrochlo- ments. ride. Respiratory arrest was never observed. The femoral artery was exposed and cathe- Values for arterial blood gas tension, acid- terized. Arterial blood pressure was mea— base status, blood pressure and heart rate in sured with a pressure transducer and ampli- unanaesthetized Gottingen mini—pigs fier (Simonsen & Weel, Denmark) at 15 min (Svendsen & Carter 1989) are used as refer- intervals, beginning 60 min after withdrawal ence values in this study. of halothane. Heart rate was measured with Fig. 1 shows the mean arterial blood pres- a pulse monitor placed on a front leg, or sure from 60 to 180 min after withdrawal from the electrocardiogram. Two m1 of he- of halothane inhalation. A stable pressure parinized blood was drawn from the femoral of about 85 mm Hg was obtained in pigs artery at 45 min intervals, beginning 45 min breathing spontaneously. These values were before halothane was removed, and analyzed significantly below reference values, whereas at 37°C for pH and pCOz (BMS 2 MK B1ood in pigs ventilated artificially, mean blood Micro System, Radiometer, Denmark). pressure was significantly higher and within The experiments lasted for 5—6 hours from the reference range. initial preanaesthetic medication until the Heart rates during the same period are anima1 was euthanized. Homeostasis was shown i Fig. 2. Spontaneously breathing pigs affected by removal of pancreatic and hepa- showed heart rates similar to reference va- tic secretions and by perfusion of the iso1a- lues, whereas the artificially ventilated ani- ted duodenum with solutions of varying pH. mals had a higher heart rate, but not signifi- During the entire experiment isotonic saline cantly above the reference values. was given by intravenous infusion. The product of systolic arterial blood pres- The following commercial preparations sure and heart rate, the rate pressure pro- were used: azaperone (Sedaperone vet. 4 “/0, duct (Kilamura et a1. 1972), is shown in Fig. Janssen Pharmaceutica, Beerse, Belgium); 3. Values were higher in artificially ventila- metomidate hydrochloride (Hypnodil vet. ted pigs than during spontaneous respira- 5 “/0, Janssen Pharmaceutica, Beerse, Bel— tion. gium); a-chloralose with 10 0/o B-isomer (Sig- Figs. 4 and 5 show arterial pC02 and arte- ma, St. Louis, NO., U.S.A.) in which the rial pH. Spontaneously breathing animals solution was prepared immediately before had significantly elevated pCO2 and con- use by dissolving 2.5 gram of a-Chloralose in sequently developed acidosis. Using the ven- 1 1 isotonic NaCl at 60°C; and halothane tilator, it was possible to adjust respiration (Halocarbon Laboratories Inc., Hackensach, and normalize arterial pC02 and pH. The N.J., U.S.A.). respiratory minute volume necessary to nor-

9] Scand. J, Lab. Anim. Sci. No. 3 , 1990. Vol. 17

Mean arterial blood pressure (mmHg) Heart rate (beufs/min) 120 1

6041 I 1 I 1 I 1 | 1 ['0 J I I l I I I I I I 60 90 120 150 180 60 90 120 150 130 Time (min) Time (min) Figure 1. Effect of a-chloralose on mean arterial Figure 2. Effect of a-chloralose on heart rate in blood pressure in pigs. Horizontal lines delineate pigs. Horizontal lines delineate reference values reference values for conscious animals. Spon- for conscious animals. Spontaneous respiration taneous respiration (O), artificial respiration (O). (O), artificial respiration (O). (+) indicates signifi- (*) indicates significant difference from reference cant difference between the two groups. Values values, (+) indicates significant difference between are means i- S.E.M. the two groups. Values are means i S.E.M.

Rute—pressure product (x 1000 mm Hg/min) Arterial pC02 (mmHg) 60 ~

l 30 — I I I I I I 60 90 120 150 180 -1.5 0 1.5 90 135 180 Time (min) Time (min) Figure 3. Effect of u-chloralose on the product of Figure 4. Effect of u—chloralose on arterial pCOz. systolic arterial blood pressure and heart rate. Ho- Horizontal lines delineate reference values for rizontal lines delineate reference values for con- conscious animals. Spontaneous respiration (O), scious animals. Spontaneous respiration (O), arti- artificial respiration (O). (*) indicates values sign- ficial respiration (O). (*) indicates significant dif- ificantly above reference values, (**) indicates ference from reference values, (+) indicates signifi- values significantly below reference values, (+) cant difference between the two groups. Values indicates significant difference between the two are means : S.E.M. groups. Va1ues are means : S.E.M.

Scand. J. Lab. Anim. Sci. No. 3 . 1990. Vol. 17

Arterial pH Base excess (mmol/l) 7.5 — 3 —

7.2 ~ I I I I 1 j l | I I I | -1+5 0 1+5 90 135 180 4.5 0 AS 90 135 180 Time (min) TimeImin) Figure 5. Effect of a-chloralose on arterial pH. Figure 6. Effect of a—chloralose 0n calculated base Horizontal lines delineate reference values for excess. Horizontal lines delineate reference values conscious animals. Spontaneous respiration (O), for conscious animals. Spontaneous respiration artificial respiration (O). (*) indicates values sign- (O), artificial respiration (O). (*) indicates values ificantly below reference values, (+) indicates sign- significantly below reference values, (+) indicates ificant difference between the two groups. Values significant difference between the two groups. Va— are means : S.E.M. lues are means : S.E.M. malize arterial blood pCOz and pH was 0.15 cardiac performance, as there was an in- 1 per kg body weight in the weight range 23 crease in heart rate and in the rate-pressure to 34 kg (instrument dead space 45 m1). product. Fig. 6 shows the calculated base excess. A Respiratory depression was demonstrated by significant deficit was recorded in spon- arterial blood gas measurements. During taneously breathing animals, whereas the spontaneous respiration pC02 was elevated artificially ventilated group was only below and respiratory acidosis developed. This the reference value before removal of halo- condition was reversed by artificial ventila- thane and in the last sample. tion. The observation by Dripps & Dunke 1943 that C02 stimulation of the respiratory DISCUSSION centre was diminished during a-chloralose The observation by Vincent & Thompson anaesthesia in dogs could thus be confirmed 1928 that arterial blood pressure in cats re- in pigs. mained stable during a-chloralose anaesthe- The metabolic acidosis in the artificially sia was confirmed for pigs, whereas the hy— ventilated animals at the end of the experi- pertension described by Brown & Hilton ment could be explained by the experimen- 1916 and Bass & Buckley 1966 in dogs an- tal procedure involving removal of HC03_ aesthetized with u—chloralose could not be from hepatic and pancreatic secretions. confirmed. In our experiment spontaneously It is concluded that a-chloralose is a useful breathing pigs were hypotensive, presum- anaesthetic in terminal physiological experi- ably due to peripheral vasodilatation, as ments in pigs, provided the animals are intu- heart rate remained within the normal ran- bated and ventilated artificially. Otherwise ge. Artificial ventilation, however, normal— the animals will develop hypotension and ized blood pressure, probably by improving respiratory acidosis. Compared with two 93 Scand. J. Lab. Anim. Sci. No. 3 . 1990. Vol. 17

previously described anaesthetic methods in tys oli heikentynyt, joka aiheutti kohonneen hiili- pigs using either halothane and methoxyflu- dioksidipitoisuuden ja respiratorisen asidoosin. Hengityskoneen kaytto (0.15 l/kg min) normalisoi rane or metomidate hydrochloride (Svend- sekéi verenkierto- etta hengitysmuuttujat. sen & Carter 1989), the present method re- Yhteenvetona todetaan, etta hengityskonetta ka'y- sults in more stable respiratory and cardio- tettaessa' alfa—kloraloosi on kayttokelpoinen nu- vascular conditions. kutusaine sioille akuuteissa kokeissa, joista elai- men ei tarvitse herata, kun halutaan pitaa verenkierto- ja hengitysvaikutukset mahdollisimman Acknowledgements pienina. We wish to thank Mrs. Karin Sejersen, Mrs. Lis Teusch and Mrs. Hanne Thayssen for skilled tech- References nical assistance. The project was financially sup- Adams, L., D. A. Schneider, E. R. Schertel, E. B. ported by Novo Foundation, Ib Henriksen’s Strong & J. F. Green: Respiratory reflexes in Foundation and P. Carl Petersen’s Foundation. anesthetized miniature swine, Respir. Physiol. 1987, 70, 343—357. Summary Bass, B. G. & N. M. Buckley: Chloralose anesthe- Respiratory and cardiovascular parameters were sia in the dog: a study of drug action and ana- examined in 47 pigs anaesthetized with a-chlo- lytical methodology. Am. J. Physiol. 1966, ralose 0.25% (100 mg/kg i.v.). Animals main- 210, 854—862. tained under spontaneous respiration had a stable Booth, N. H., H. E. Bredeck & R. A. Herin: Baro- but subnormal arterial blood pressure. Heart rate ceptor reflex mechanisms in swine. Am. J. was within the normal range. Respiration was de— Physiol.. 1960,199, 1189—1191. pressed, causing elevated pCOz and respiratory Bredeck, H. E., R. A. Herin & N. H. Brooth: Che— acidosis. moceptor reflexes in swine. Am. J. Physiol. Artificial ventilation with a minute volume of 1961, 201, 89—91. 0.15 1 per kg body weight normalized both cardio- Brown, R. V. & J. G. Hilton: Baroreceptor re- vascular and respiratory parameters. flexes in dogs under chloralosane anaesthesia. In conclusion a-chloralose can be considered Am. J. Physiol. 1955,143,433—437. valuable for maintaining anaesthesia in pigs dur- Brown, R. V. & J. G. Hilton: The effectiveness of ing acute, non-survival experiments demanding baroreceptor reflexes under different anesthe— minimal cardiovascular and pulmonary disturban- tics. J. Pharmacol. Exptl. Therap. 1956, 118, ce, but only where artificial ventilation is used. 198—203. Dripps, R. D. & P. R. Dunke: The effect of narco- Sammendrag tics on the balance between central and che— Der foreligger en undersagelse af respirations- og moreceptor control of respiration. J. Pharma- kredslzbsparametre hos 47 grise under a-chlora- col. Exptl. Therap. 1943, 77, 290—300. lose anastesi. Under spontan respiration havde Kitamura, K, C. R. Jorgensen, F. L. Gabe], H. L., dyrene stabilt men subnormalt arterielt blodtryk. Taylor & Y. Wang: Hemodynamic correlates Hjertefrekvensen var indenfor normalomradet. of myocardial oxygen consumption during up- Respirationsdepression forarsagede forhajet pC02 right exercise: J. Appl. Physiol. 1972, 32, 516— 0g respiratorisk acidose. 522. Bade respirations- 0g kredslabsparametre kunne Smdkilde-Jargensen, H, B. Sarensen, K. Kruge— normaliseres ved artificiel respiration med et lund & J. C. Djurhuus.’ Gastric acid secretion minutvolumen p5 0.15 1 pr. minut. during halothane, chloralose, pentobarbital Det kan konkluderes, at a—chloralose er velegnet and etornidate anaesthesia in the pig. Eur. Sur. til vedligeholdelse af anaestesi af grise under Res. 1985,17, 33—37. akutte, terminale forsag under forudsaatning af, at Svendsen, P. & A. M. Carter: Blood gas tensions, der anvendes artificiel ventilation. acid-base status and cardiovascular function in miniature swine anaesthetized with halo— Y hteenveto / K. Pelkonen thane and methoxyflurane or intravenous me— Alfa-kloraloosilla nukutetusta (100 mg/kg laski- tomidate hydrochloride. Pharmacol. Toxicol. monsisaisesti) 47 siasta tutkittiin hengitys- ja 1989, 64, 88—93. verenkiertomuuttujia. Luonnollisesti hengittavilla Vincent, S. & J. H. Thompson: The pharmacody— oli tasainen mutta normaalia alempi valtimo- namical action of chloralose. J. Physiol. paine. Syketaajuus oli normaalin rajoissa. Hengi- (Lond) 1928,65, 449—455.