Cardiovascular effects of doxacurium chloride in isoflurane-anaesthetised dogs

Cardiovascular effects of doxacurium chloride in isofluraneanaesthetised dogs E. A. Martinez, A. A. Wooldridge, D. E. Mercer, M. R. Slater and S. M. Hartsfield Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4474, USA

SUMMARY

effects and/or histamine release (Faulds and Clissold 1991). A long-acting neuromuscular blocking agent without significant cardiovascular effects would be desirable for long surgical procedures requiring muscle relaxation and cardiovascular stability. Doxacurium has been reported to have little or no cardiovascular effects in humans and halothane or pentobarbitone-anaesthetised dogs (Savarese et al. 1983; Basta et al. 1988; Murray et al. 1988; Faulds and Clissold 1991). Since no studies have been performed in dogs anaesthetised with isoflurane, the purpose of this study was to determine the cardiovascular effects of doxacurium chloride in isoflurane-anaesthetised dogs.

The cardiovascular effects of doxacurium were studied in 6 isoflurane-anaesthetised dogs. Each dog was anaesthetised twice, receiving doxacurium (0.008 mg/kg bwt) or placebo iv. Dogs were ventilated to normocapnia. Heart rate, cardiac index, systolic, diastolic, and mean arterial blood pressures, stroke volume, pulmonary vascular resistance, pulmonary artery wedge pressure, systemic vascular resistance, and pulmonary arterial pressure were determined. Neuromuscular blockade was assessed using the train-of-four technique. After recording baseline values, dogs randomly received either doxacurium or placebo iv, and data were recorded at 5 , 10,15,30,45,60,75,90,105 and 120 min. At 120 min, dogs treated with doxacurium received edrophonium (0.5 mg/kg bwt iv) to antagonise neuromuscular blockade; dogs treated with placebos received saline iv. No statistically significant differences were detected after doxacurium compared to placebo. In both the doxacurium and placebo groups, significant increases in systolic arterial blood pressure, cardiac index, and stroke volume and a significant decrease in systemic vascular resistance occurred with time. Doxacurium depressed twitch tension 100% in all dogs (time to maximal twitch depression, 11 f 7 min). First twitch tension was less than 10% of baseline values in all dogs at the time (120 min) of edrophonium administration. Additional edrophonium (1 .O f 0.4 mg/kg iv) was required to obtain a fourth twitch to first twitch ratio of greater than 0.70. In conclusion, doxacurium is a long-acting neuromuscular blocking agent with no significant cardiovascular effects in isoflurane-anesthetised dogs. In dogs, doxacurium is indicated primarily for long surgical procedures requiring neuromuscular blockade and cardiovascular stability.

MATERIALS AND

METHODS

Animal preparation The experimental protocol was approved by the institutional animal care and use committee. Six adult mixed-breed dogs (2 males, 4 females) with a mean f sd bwt of 23.7 f 3.6 kg were studied. Dogs were healthy based on results of physical examinations, complete blood counts and serum biochemical profiles. The dogs served as their own controls and were randomly assigned to receive either doxacurium (Nuromax, Burroughs Wellcome Co, North Carolina, USA), 0,008 mg/kg bwt, or an isovolumetric, saline placebo (0.9% Sodium Chloride Injection USP, Baxter Healthcare Corporation, Illinois, USA) iv. A minimum of 7 days elapsed between studies in each dog. Anaesthesia was induced with 5% isoflurane (Aerrane, Anaquest, New Jersey, USA) in 0, ( 5 l/min) via face mask. Following endotracheal intubation, anaesthesia was maintained with a circle system using a precision vaporiser (Isotec I11 Vaporiser, Ohmeda, West Yorkshire, UK) and an end-tidal isoflurane concentration of 1.5 MAC (1.9%), as measured by an infrared gas analyser (Puritan Bennett 254 Airway Gas Monitor, Datex Instrumentation Corporation, Helsinki, Finland). The MAC value is defined as the minimum alveolar concentration of an anaesthetic that prevents gross purposeful movement in 50% of subjects in response to a painful stimulus (Steffey 1996). The value for MAC of isoflurane used in this study was 1.28% (Steffey 1996). Ventilation was controlled, using a small animal

INTRODUCTION Doxacurium chloride is a nondepolarising neuromuscular blocking agent with a slow onset and long duration of action. It is the most potent neuromuscular blocking agent available (Mirakhur 1992). Intravenous administration of commonly used neuromuscular blocking agents have been associated with clinically significant cardiovascular effects including hypotension, bradycardia, and tachycardia due to autonomic 10

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ventilator (Small Animal Ventilator, North American Drager, Pennsylvania, USA) attached to the circle system. End-tidal carbon dioxide tension, measured by the gas analyser, was maintained between 35 and 45 mm Hg. Dogs were placed on a circulating warm water blanket to maintain body temperature at 37-39°C.

on the tongue. Cardiac index, stroke volume, systemic vascular resistance, pulmonary vascular resistance, and arterial bicarbonate concentration were calculated using standard formulas (Schwenzer 1990). A lead I1 electrocardiogram was monitored continuously (Tram Critical Care Monitor, Marquette Electronics Inc, Wisconsin, USA).

Cardiovascular instrumentation

Measurement of neuromuscular function

An arterial catheter (20 g, 31 mm, Jelco I.V. Catheter, Criticon, Florida, USA) was placed percutaneously into a dorsal pedal artery for collection of blood samples for bloodgas and pH analysis and for direct measurement of arterial blood pressures (Transpac-I1 Disposable Transducer, Abbott Laboratories, Illinois, USA). A 7-F, balloon-tipped, thermodilution catheter (Swan-Ganz 93A- 131-7F, American Edwards Division, AHS del Caribe, Anasco, Puerto Rico) was placed percutaneously into the pulmonary artery via an introducer placed in the right jugular vein. Correct positioning of the catheter was determined by observation of the characteristic pressure waveform. A thermistor in the tip of the pulmonary arterial catheter allowed measurement of core body temperature. Cardiac output was determined by thermodilution [5 ml of iced (0-5°C) 5% dextrose] and use of a cardiac output computer (Tram Critical Care Monitor, Marquette Electronics Inc, Wisconsin, USA). The mean value of 3 measurements was determined for each cardiac output value. Mean pulmonary arterial pressure, pulmonary artery wedge pressure, and central venous pressure were determined by use of a calibrated pressure transducer (Transpac-I1 Disposable Transducer, Abbott Laboratories, Illinois, USA). Arterial pH, P,O, and PaCO, were determined using an acidbase, blood-gas analyser (Model 280 Blood Gas System, Ciba-Corning, Massachusetts, USA). Oxygen saturation of haemoglobin was determined by pulse oximetry (Model N200 Pulse Oximeter, Nellcor Inc, California, USA) with the probe (Model VSC-S, Vetstat Oxygen Transducer and Veterinary Sensor Clip, Nellcor Inc, California, USA) placed

Each dog was placed in left lateral recumbency with the left hind limb immobilised from femur to tarsus in a padded cradle attached to a fixed vertical pole. The tip of the paw was attached to a force displacement transducer (Microdisplacement Myograph Transducer F- 1000, Narco Bio-Systems Inc, Texas, USA) using a loop of wire sutured to the paw at the level of the metatarsal heads. Supramaximal train-of-four stimuli at 2 Hz for a duration of 0.25 milliseconds were applied to the superficial peroneal nerve every 20 s by a square-wave stimulator (Model NS-2CA, Professional Instruments Dual Stimulator Plus, Life-Tech Inc, Texas, USA), and the evoked digital extensor tension was recorded on a physiographic tracing (Physiograph Desk Model DMP-4B, Narco Bio-Systems Inc, Texas, USA). In dogs receiving doxacurium, first twitch tension at maximal depression compared to the baseline value, onset (time from injection to maximal depression of first twitch tension), and first twitch tension at the time of edrophonium administration were recorded. Fourth twitch to first twitch ratio of the train-of-four was monitored until adequate reversal with edrophonium was achieved. A ratio greater than 0.70 correlates well with adequate reversal of neuromuscular blockade (Ali and Savarese 1976).

Experimental protocol Once the dogs were instrumented and in a stable condition, as determined by end-tidal isoflurane concentration, P,CO,

TABLE 1: Effect of doxacurium, 0.008 mglkg iv, or placebo on cardiovascular variables in 6 isoflurane-anaesthetised dogs ~~

Value

Baseline

HR (bpm) D 114+16 P 107f20 MAP (mmHg) D 66f5 P 69f7 DAP (mmHg) D 58+7 P 58f8 PVR (dynes-s/cm5) D 232f72 P 260f67 PWP (mrnHg) D 13+3 P 12+2 PAP (mmHg) D 19f1 P 18f2

Time after treatment (min)

______

~

5

10

15

30

45

60

75

90

105

120

1 15+20 107f19

113+19 104+18

113+18 106218

119+19 108+17

115216 109217

1 19f20 111216

117f16 111f13

118f15 112+13

112f11 107f16

112f9 108f15

67f9 70+7

67f9 67+7

65f9 67+8

65f6 71 21 1

67f5 69f9

68+5 69+8

67+5 70flO

68f6 69+9

70+7 69f10

69f7 69210

54f5 59f7

55f6 58f7

54f7 56f7

54f5 60f10

55f4 59+9

58+5 59+7

56+5 58flO

56+5 58+9

58+6 59f10

57f5 58f9

188+62 251 f71

172288 241 +67

163+64 220+90

155+64 241 283

157+64 245+65

177f57 238f70

21 9f83 21 7+47

227f74 234+55

21 4f65 186f53

227+78 194f71

13f3 12f2

14f3 13f2

14f2 13+3

14f2 13+3

14f1 14f2

14f2 14f3

13f3 13f2

12f3 12f3

13f3 14f2

12f3 13+2

1921 1922

19f2 19f2

18f1 19f2

18+1 19f2

19f2 20f1

19+2 20f2

19f2 20*2

20f3 20f2

19f2 20+2

19f2 19+1

Data are expressed as mean f sd; D = doxacurium; P = placebo; HR = heart rate; MAP = mean arterial pressure; DAP = diastolic arterial blood pressure; PVR = pulmonary vascular resistance; PWP = pulmonary artery wedge pressure; PAP = pulmonary arterial blood pressure. No significant differences exist between groups (P>0.05).

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Fig 3: Mean (f sd) stroke volume values in isofluraneanaesthetised dogs ( n = 6). Values without superscripts in common are signijicantly different from each other ( P 4 . 0 5 ) . There were no differences due to treatment, only differences related to time.

Fig 4: Mean (? sd) systemic vascular resistance values in isofluraneanaesthetised dogs (n = 6). Values without superscripts in common are signijicantly different from each other (P<0.05). There were no differences due to treatment, only differences related to time.

values and a stable twitch response, baseline data were collected. The dogs were then given either doxacurium or placebo. Variables were measured and recorded at 5, 10, 15, 30, 45, 60, 75, 90, 105 and 120 min following drug administration. Edrophonium (Tensilon, ICN Pharmaceuticals Inc, California, USA), 0.5 mg/kg bwt iv, was then given to reverse residual blockade. Additional edrophonium was administered, 0.25 mg/kg iv at 15 min intervals, until the fourth twitch to first twitch ratio was greater than 0.70. Anaesthesia was discontinued and positive pressure

ventilation was stopped when spontaneous ventilation began. Dogs were then allowed to recover from anaesthesia.

Statistical analysis An analysis of variance for repeated measures with a Bonferroni adjustment for multiple comparisons was used to test statistical significance of treatment and time on cardiovascular variables in dogs receiving doxacurium or placebo. At each time point, end-tidal isoflurane concentration, 12

.I. vet. Anaesth. Vol. 24(1) (1997) ~

pH, Pa02, PaC02, HCO,, oxygen saturation of haemoglobin, and body temperature for each treatment group were analysed, using a paired Student's t-test. Statistical significance was set at P<0.05. All data are reported as mean f: sd.

observed, but all 4 twitches in the train-of-four were abolished in all dogs. The dose chosen for this study was based on the EDloo of doxacurium in pentobarbitoneanaesthetised dogs (Savarese et al. 1983). Inhalational anaesthetics have been shown to potentiate the neuromuscular effects of doxacurium (Katz et al. 1989). The duration of blockade was not quantified for the dose used in this study because first twitch tension in all dogs was less than 10% of baseline values at the end of the study period. Further doseresponse studies are needed to determine the neuromuscular effects of doxacurium in isoflurane-anaesthetiseddogs. Antagonism of doxacurium-induced neuromuscular blockade by neostigmine and edrophonium has been reported to be satisfactory (Mirakhur 1992). It is recommended that spontaneous recovery of first twitch tension should be greater than 25% of the baseline value before administration of a reversal agent (Mirakhur 1992). Neostigmine may be more effective than edrophonium at antagonising moderate to deep levels of neuromuscular blockade (Faulds and Clissold 1991). Edrophonium was chosen for this study because its cardiovascular effects are less than those of neostigmine, and it does not require the concommittant use of an anticholinergic drug (Cronnelly and Morris 1982). In conclusion, doxacurium is an excellent choice for neuromuscular blockade when a long duration of action with minimal cardiovascular effects is desirable. Doses should be adjusted to provide an acceptable duration of neuromuscular blockade depending on the length of the surgical procedure requiring relaxation.

RESULTS In both groups, mean end-tidal isoflurane concentration was 1.9 f 0.1% and all dogs recovered without complications following anaesthesia. There were no significant differences between treatment groups for end-tidal isoflurane concentration, pH, Pa02, PaC02, HCO,, oxygen saturation of haemoglobin, and body temperature. In the placebo and doxacurium groups, respectively, mean arterial pH was 7.34 f: 0.03 and 7.35 f: 0.02, mean PaC02 values were 40 f 2 and 40 f 3 mmHg, mean Pa02values were 569 f: 35 and 573 f 41 mmHg, mean oxygen saturation of hemoglobin was 99.7 f 0.6 and 98.9 f 0.7% and mean rectal temperature was 37.6 f 0.7 and 37.8 f 0.7"C. After administration of doxacurium, there were no significant changes in the measured cardiovascular variables that were attributable to treatment (Table 1). A temporal effect was observed in both groups, with a significant increase in systolic arterial blood pressure (P=0.006), cardiac index (P=O.OOl), and stroke volume (P=0.001), and a significant decrease (P=0.004) in systemic vascular resistance (Figs 1-4). There were no significant differences between the doxacurium and placebo groups. Doxacurium administration caused a 100% depression of twitch tension compared to baseline values. Time to maximal depression was 11 f: 7 (range: 5-22) min. First twitch tension was less than 10% of the baseline values in all dogs at the time of edrophonium administration. Additional edrophonium (1.O f 0.4 mg/kg iv) was required in all dogs to obtain a fourth twitch to first twitch ratio greater than 0.70.

REFERENCES Ali, H.H. and Savarese, J.J. (1976) Monitoring of neuromuscular function. Anesthesiol. 45,216-249. Basta, S.J., Savarese, J.J., Ah, H.H., Embree, B.B., Schwartz, A.F., Rudd, G.D. and Wastila, W.B. (1988) Clinical pharmacology of doxacurium chloride, a new long-acting nondepolarising muscle relaxant. Anesthesiol. 69, 478-486. Cronnelly, R. and Morris, R.B. (1982) Antagonism of neuromuscular blockade. Brit. J . Anaesth. 54, 183-194. Fdulds, D. and Clissold, S.P. (1991) Doxacurium: a review of its pharmacology and clinical potential in anesthesia. Drugs 42, 673-689. Katz, J.A., Fragen, R.J., Shanks, C.A., Dunn, K., McNulty, V. and Rudd, G.D. (1989) Dose-response relationships of doxacurium chloride in humans during anesthesia with nitrous oxide and fentanyl, entlurane, isoflurane or halothane. Anesthesiol. 70,432-436. Mirakhur, R.K. (1992) Newer neuromuscular blocking drugs: an overview of their clinical pharmacology and therapeutic use. Drugs 44, 182- 199. Murray, D.J., Mehta, M.P., Choi, W., Forbes, R.B., Sokoll, M.D.. Gergis, S.D., Rudd, G.D. and Abou-Donia, M.M. (1988) The neuromuscular and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide-narcotic anesthesia. Anesthesiol. 69,472-477. Savarese, J.J., Wastila, W.B., Basta, S.J., Beemer, G.H. and Sunder, N. (1983) Pharmacology of BW A938U. Anesthesiol. 59, A274. Schwenzer, K.J. (1990) Venous and pulmonary pressures. In: Clinical Monitoring. Ed: C.L. Lake, Philadelphia, WB Saunders, pp 147.196. Steffey, E.P. and Howland, D. Jr. (1977) Isoflurane potency in the dog and cat. Am. J . vet. Res. 38, 1833-1836. Steffey, E.P. and Howland, D. Jr. (1978) Potency of enflurane in dogs: comparison with halothane and isoflurane. Am. J . vet. Res. 39, 573-577. Steffey, E.P. (1996) Inhalation Anesthetics. In: Lumh & Jonrs Vrterinay Anesthesia, 3rd edn. Eds: J. C. Thurmon, W.J.Tranquilli, J. G. Benson, Baltimore: Williams & Wilkins, pp 297-329.

DISCUSSION Doxacurium chloride is a long-acting non-depolarising neuromuscular blocking agent that has been reported to have minimal cardiovascular effects at therapeutic doses and a wide autonomic safety margin (Savarese et al. 1983; Faulds and Clissold 1991; Mirakhur 1992). It is also noncumulative, reversible, and more potent than pancuronium (Savarese et al. 1983; Murray et al. 1988). In our study, doxacurium did not cause significant cardiovascular effects and provided a long duration of neuromuscular blockade. The significant decrease in systemic vascular resistance observed can be explained by a temporal effect of isoflurane administration and is similar to changes reported in previous studies in dogs (Steffey and Howland 1977; Steffey and Howland 1978). The increases in systolic arterial blood pressure, stroke volume, and cardiac index are most likely to be due to an autonomic response to the periodic application of supramaximal peripheral nerve stimuli. Interpatient variability for both onset and duration of neuromuscular blockade with doxacurium has been reported in human patients (Faulds and Clissold 1991). In our study, a wide range for onset of action of neuromuscular blockade was I3