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    Mean ± SD values of SAP (solid line), MAP (dotted line), and DAP (dashed line) for 13 adult nonpregnant female sheep anesthetized at various MAC multiples. Time points were before induction of anesthesia with desflurane (0 MACDES; Awake), immediately after intubation (etDES of 1.06 MACDES; After intubation), after a 30-minute equilibration period at an etDES of 10.5% (corresponding to 1.06 MACDES; Equilibration), during the first MACDES determination (1 MACDES; First MAC), during the second MACDES determination (1 MACDES; Second MAC), after a 15-minute equilibration period at 1.3 MACDES (1.3 MAC), after a 15-minute equilibration period at 1.6 MACDES (1.6 MAC), and immediately after discontinuation of desflurane administration (mean, 1.45 MACDES; End of procedures). *Value differs significantly (P < 0.05) from the value for Awake. Value differs significantly (P < 0.05) from the values for After intubation, Equilibration, First MAC, and Second MAC. Value differs significantly (P < 0.05) from the value for 1.3 MAC.

  • 1. Rampil IJ, Lockhart SH, Zwass MS, et al. Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429433.

    • Search Google Scholar
    • Export Citation
  • 2. Eger EI. Desflurane: a compendium and reference. Rutherford, NJ: Healthpress Publishing Group, 1993.

  • 3. Steffey EP, Mama KR, Brosnan RJ. Inhalation anesthetics. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;297331.

    • Search Google Scholar
    • Export Citation
  • 4. Keijzer C, Perez RSGM, De Lange JJ. Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 2005;5:6.

    • Search Google Scholar
    • Export Citation
  • 5. Quasha AL, Eger EI II, Tinker JH. Determinations and application of MAC. Anesthesiology 1980;53:315334.

  • 6. Sayre RS, Lepiz MA, Horsley KT, et al. Effects of oxymorphone hydrochloride or hydromorphone hydrochloride on minimal alveolar concentration of desflurane in sheep. Am J Vet Res 2015;76:583590.

    • Search Google Scholar
    • Export Citation
  • 7. Valverde A, Morey TE, Hernández J, et al. Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 2003;64:957962.

    • Search Google Scholar
    • Export Citation
  • 8. Dixon WJ, Massey FJ. The “up-and-down” method. In: Dixon WJ, Massey FJ, eds. Introduction to statistical analysis. 4th ed. New York: McGraw-Hill, 1983;428439.

    • Search Google Scholar
    • Export Citation
  • 9. Figueiró MR, Soares JH, Ascoli FO, et al. Isoflurane MAC determination in dogs using three intensities of constant-current electrical stimulation. Vet Anaesth Analg 2016;43:464471.

    • Search Google Scholar
    • Export Citation
  • 10. Doorley BM, Waters SJ, Terrell RC, et al. MAC of I 653 in Beagle dogs and New Zealand White rabbits. Anesthesiology 1988;69:8991.

  • 11. Hammond RA, Alibhai HIK, Walsh KP, et al. Desflurane in the dog: minimum alveolar concentration (MAC) alone and in combination with nitrous oxide. J Vet Anaesth 1994;21:2123.

    • Search Google Scholar
    • Export Citation
  • 12. Wang B, Tang J, White PF, et al. The effect of GP683, an adenosine kinase inhibitor, on the desflurane anesthetic requirement in dogs. Anesth Analg 1997;85:675680.

    • Search Google Scholar
    • Export Citation
  • 13. McMurphy RM, Hodgson DS. The minimum alveolar concentration of desflurane in cats. Vet Surg 1995;24:453455.

  • 14. Eger EI II, Johnson BH, Weiskopf RB, et al. Minimum alveolar concentration of 1,653 and isoflurane in pigs: definition of a supramaximal stimulus. Anesth Analg 1988;67:11741176.

    • Search Google Scholar
    • Export Citation
  • 15. Tendillo FJ, Mascias A, Santos M, et al. Anesthetic potency of desflurane in the horse: determination of the minimum alveolar concentration. Vet Surg 1997;26:354357.

    • Search Google Scholar
    • Export Citation
  • 16. Steffey EP, Woliner MJ, Puschner B, et al. Effects of desflurane and mode of ventilation on cardiovascular and respiratory functions and clinicopathologic variables in horses. Am J Vet Res 2005;66:669677.

    • Search Google Scholar
    • Export Citation
  • 17. Hedenqvist P, Roughan JV, Antunes L, et al. Induction of anaesthesia with desflurane and isoflurane in the rabbit. Lab Anim 2001;35:172179.

    • Search Google Scholar
    • Export Citation
  • 18. Weiskopf RB, Holmes MA, Eger EI II, et al. Cardiovascular effects of I, 653 in swine. Anesthesiology 1988;69:303309.

  • 19. Weiskopf RB, Holmes MA, Rampil IJ, et al. Cardiovascular safety and actions of high concentrations of I 653 and isoflurane in swine. Anesthesiology 1989;70:793798.

    • Search Google Scholar
    • Export Citation
  • 20. Tranquilli WJ, Grimm KA. Introduction: use, definitions, history, concepts, classification, and considerations for anesthesia and analgesia. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;297331.

    • Search Google Scholar
    • Export Citation
  • 21. Weiskopf RB. Cardiovascular effects of desflurane in experimental animals and volunteers. Anaesthesia 1995;50(suppl):1417.

  • 22. Wilson DV, Evans AT, Carpenter RA, et al. The effect of four anesthetic protocols on splenic size in dogs. Vet Anaesth Analg 2004;31:102108.

    • Search Google Scholar
    • Export Citation
  • 23. Zlateva N, Marinov G. Effect of three anesthetic protocols on the haematological indices in cats during ovariohysterectomy. MedInform 2015;2:184193.

    • Search Google Scholar
    • Export Citation

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Determination of minimum alveolar concentration and cardiovascular effects of desflurane in positive-pressure ventilated sheep

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  • 1 Dipartimento di Medicina Veterinaria, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 2 Centro di Ricerca di Chirurgia Comparata, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 3 Department of Clinical Studies–New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.
  • | 4 Dipartimento di Medicina Veterinaria, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 5 Dipartimento di Medicina Veterinaria, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 6 Dipartimento di Medicina clinica e sperimentale, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 7 Dipartimento di Medicina clinica e sperimentale, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 8 Department of Clinical Studies–New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.
  • | 9 Dipartimento di Medicina Veterinaria, Università degli Studi di Sassari, 07100 Sassari, Italy.
  • | 10 Centro di Ricerca di Chirurgia Comparata, Università degli Studi di Sassari, 07100 Sassari, Italy.

Abstract

OBJECTIVE To determine the minimum alveolar concentration of desflurane (MACDES) and effects on cardiovascular variables in positive-pressure ventilated sheep.

ANIMALS 13 adult female sheep.

PROCEDURES Anesthesia was induced with desflurane. After a 30-minute equilibration at an end-tidal concentration of desflurane (etDES) of 10.5%, an electrical stimulus (5 Hz/ms and 50 mA) was applied for 1 minute or until gross purposeful movement occurred. The etDES was then changed by 0.5% (modified up-down method), depending on whether a positive motor response had been elicited, and stimulation was repeated. The MACDES was the etDES midway between a positive and negative response. After MACDES was determined, etDES was increased to 1.3 and 1.6 MACDES. Animals were allowed to equilibrate for 15 minutes, and cardiovascular, blood gas, acid-base, and hematologic variables were measured. Times to induction of anesthesia, extubation, attainment of sternal position, and standing and duration of anesthesia were recorded.

RESULTS Mean ± SD MACDES was 9.81 ± 0.79%. Times to intubation, extubation, and standing were 4.81 ± 2.21 minutes, 14.09 ± 4.05 minutes, and 32.4 ± 12.5 minutes, respectively. Duration of anesthesia was 226 ± 22 minutes. Heart rate increased significantly at induction of anesthesia but otherwise remained at preanesthetic rates. Arterial blood pressures progressively decreased with increasing etDES; pressures increased slightly only in response to noxious stimulation.

CONCLUSIONS AND CLINICAL RELEVANCE The MACDES determined here compared favorably with that determined for other sheep populations and indicated similar anesthetic potency as in other species. Desflurane caused dose-dependent arterial hypotension, which indicated the need for careful blood pressure monitoring.

Abstract

OBJECTIVE To determine the minimum alveolar concentration of desflurane (MACDES) and effects on cardiovascular variables in positive-pressure ventilated sheep.

ANIMALS 13 adult female sheep.

PROCEDURES Anesthesia was induced with desflurane. After a 30-minute equilibration at an end-tidal concentration of desflurane (etDES) of 10.5%, an electrical stimulus (5 Hz/ms and 50 mA) was applied for 1 minute or until gross purposeful movement occurred. The etDES was then changed by 0.5% (modified up-down method), depending on whether a positive motor response had been elicited, and stimulation was repeated. The MACDES was the etDES midway between a positive and negative response. After MACDES was determined, etDES was increased to 1.3 and 1.6 MACDES. Animals were allowed to equilibrate for 15 minutes, and cardiovascular, blood gas, acid-base, and hematologic variables were measured. Times to induction of anesthesia, extubation, attainment of sternal position, and standing and duration of anesthesia were recorded.

RESULTS Mean ± SD MACDES was 9.81 ± 0.79%. Times to intubation, extubation, and standing were 4.81 ± 2.21 minutes, 14.09 ± 4.05 minutes, and 32.4 ± 12.5 minutes, respectively. Duration of anesthesia was 226 ± 22 minutes. Heart rate increased significantly at induction of anesthesia but otherwise remained at preanesthetic rates. Arterial blood pressures progressively decreased with increasing etDES; pressures increased slightly only in response to noxious stimulation.

CONCLUSIONS AND CLINICAL RELEVANCE The MACDES determined here compared favorably with that determined for other sheep populations and indicated similar anesthetic potency as in other species. Desflurane caused dose-dependent arterial hypotension, which indicated the need for careful blood pressure monitoring.

Desflurane is 1 of 3 contemporary ether-derived volatile anesthetics that was developed in the 1960s. However, it was not used in clinical practice throughout North America and Europe until the 1990s. In contrast to the other volatile anesthetics, desflurane is characterized by a boiling point close to room temperature; thus, it requires a specially designed and electrically heated vaporizer for safe use in both clinical practice and research settings.1–3 This requisite and the higher cost per milliliter of agent (compared with the cost for isoflurane) have curtailed the widespread use of desflurane in veterinary practice and for larger research animals (eg, sheep and pigs). However, patent protection for desflurane has expired, and drug costs are likely to decrease soon; thus, use of desflurane will probably increase.

The overall pharmacodynamic profile of desflurane is similar to those of isoflurane and sevoflurane, the other 2 ether-derived anesthetics used in clinical practice.1–3 However, desflurane is characterized by relatively unique properties that may offer advantages for its use in certain clinical and research situations. It has the lowest rate of biodegradation (< 0.02% vs 0.2% for isoflurane and 2% to 3% for sevoflurane) among all volatile anesthetics, which explains the reason that the increase in serum inorganic fluoride concentration is much smaller with desflurane than with isoflurane and sevoflurane.3 In contrast, desflurane may result in higher amounts of CO, compared with the amounts of CO when isoflurane or sevoflurane are used, when the anesthetic agent is in contact with dry CO2 absorbents, with higher amounts of CO formed in calcium hydroxide–barium hydroxide compounds than in soda lime, which favors use of desflurane under low-flow anesthesia conditions that result in much less desiccation of CO2 absorbents.4 The extremely low solubility of desflurane in blood (blood gas partition coefficient, 0.424 at 37°C) and tissues allows for rapid induction and emergence from anesthesia as well as precise control over anesthetic depth and other clinical drug effects.2,3 Thus, desflurane may offer important advantages over the use of isoflurane and sevoflurane for induction and maintenance of anesthesia, particularly when clinical or research circumstances restrict the use of injectable anesthetics or anesthetic adjuvants.

The MAC of a volatile anesthetic is the concentration that prevents gross purposeful movement in response to a defined supramaximal noxious stimulus in 50% of subjects, and it determines the potency of an inhalation anesthetic.3,5 The MACDES has been determined in humans and various other species, including cats, dogs, horses, mice, pigs, rats, and rabbits3 as well as sheep.6,a In most of the studies that involved domestic animals, noxious stimulation involved a mechanical stimulus (eg, forceps clamping).

The purposes of the study reported here were to determine the MACDES in sheep by applying a train of electrical impulses instead of mechanical stimulation as the supramaximal nociceptive stimulus and to describe the effects of various doses of desflurane (ie, MAC multiples) on hemodynamic variables. We hypothesized that desflurane would have similar anesthetic potency and cardiovascular effects of similar magnitude in sheep as has been reported for other animal species.

Materials and Methods

Animals

Thirteen healthy adult nonpregnant female Sardinian sheep were included in the study. The sheep were 5 to 7 years old and had a mean ± SD body weight of 35.3 ± 2.7 kg. All sheep were deemed to be healthy on the basis of results of physical examination, hematologic assessment, and serum biochemical assay. The study was performed in Sassari, Italy, which is located at 225 m above sea level. Atmospheric pressure during the period of MACDES determinations was between 101 and 102 kPa. The study protocol was approved by the Institutional Animal Care and Use Committee at the University of Sassari (protocol No. 132/11) in accordance with Italian legislation.

Study protocol

Food was withheld for 12 hours prior to anesthesia, but animals had unlimited access to water. On the day of the procedure, body weight, heart rate, respiratory rate, and rectal temperature were recorded for each animal while at rest. Sheep then were positioned in right lateral recumbency on a preparation table. The subcutaneous tissues over a rostral auricular artery were infiltrated with lidocaine 2% solution, and a 20-gauge, 3.1-cm catheterb was aseptically inserted in the artery; that catheter was used to obtain invasive arterial blood pressure measurements and for collection of blood samples. Wool was clipped over the lateral surface of a saphenous vein, and the region was aseptically prepared. An 18-gauge, 4.5-cm catheterb was inserted into the vein and used for administration of lactated Ringer solution (5 mL/kg/h) to maintain normovolemia during anesthesia.

Sheep then were moved onto a surgery table and gently physically restrained. Sheep were not given premedicants but were preoxygenated (3 L/min) for at least 3 minutes by use of a tight-fitting face mask connected to a standard rebreathing system. The rebreathing system was connected to an anesthesia workstationc that included soda limed and a desflurane vaporizere and was equipped with an electrically driven and electronically controlled turbo ventilator.f Baseline measurements (including invasively measured blood pressures, heart rate, and arterial oxygenation) and an ECG were continuously recorded.

Anesthesia was induced with desfluraneg (vaporizer dial setting, 14%) administered in O2 (flow rate, 3 L/min) by use of a face mask, which allowed a rapid arrival at an etDES that resulted in an adequate depth of anesthesia as determined by lack of a palpebral reflex, decreased jaw tone, and cessation of swallowing. Once an adequate depth of anesthesia was achieved, a cuffed 9.0-mm (internal diameter) Murphy endotracheal tube was placed and the animal connected to the rebreathing circuit. Sheep received volume-limited positive-pressure ventilation and were maintained at a Petco2 of 35 to 45 mm Hg throughout the remainder of the study.

The ECG; heart rate; invasively measured SAP, DAP, and MAP; Sao2; and esophageal body temperature were continuously monitored by use of a multiparameter vital monitor.h Respiratory rate, tidal volume, and O2 flow rate were monitored via the anesthesia workstation screen.i The O2 flow rate was maintained at 3 L/min throughout the experiment to ensure the fraction of inspired O2 remined > 0.96. The fraction of inspired O2, etDES, and Petco2 were continuously monitored via the workstation integrated gas modulej as a side-stream analyzer (250 mL/min) through a nylon catheter positioned in the distal end of the endotracheal tube. The gas module was calibrated before each experiment with gas standardsk (5% desflurane, 5.5 % C O2, 43% N2O, and 46.5% O2).

Supramaximal noxious stimulation

Preliminary experiments conducted by one of the investigators (NC) revealed that repeated brief stimulations of the lateral palmar nerves with 60-second trains of constant-current electrical impulses caused motor responses without noticeable tissue damage and thus proved superior to repeatedly clamping a body part such as the tail, as has been commonly applied in other MAC studies.7 Therefore, disposable low-resistance silver–silver chloride electrodesl with an inter-electrode distance of 1 cm were applied on the lateral surface of the metacarpus midway between the carpal and metacarpophalangeal joints and secured in place with self-adhesive bandages. Stimuli were delivered by a 220-V constant-current stimulatorm triggered by a 9-V battery-powered digital timer.n Supramaximal noxious stimulation consisted of trains of square-wave impulses (1 millisecond in duration, 5 Hz, and constant current of 50 mA) delivered for 60 seconds or until a gross purposeful motor response was detected. A response was considered positive when major motor responses were observed in nonstimulated body areas (eg, flexion or extension of the contralateral hind limb or gross movement of the neck). Muscle tremors, occasional swallowing, nystagmus, and changes in cardiorespiratory variables were not considered a positive response. Because the maximum voltage delivered by the stimulator was 200 V, the electrical resistance between electrodes was measured with an ohmmetero before each stimulation to ensure resistance remained at < 3 kΩ to discharge a current of 50 mA. If resistance increased to > 3 kΩ, the electrodes were replaced. A 1-second train of electrical stimulation was applied once after placement of electrodes to verify appropriate function of the equipment.

Determination of MACDES

A modified protocol of the up-down method was used.8 Anesthetized sheep were allowed a 30-minute equilibration period at an etDES of 10.5%; the previously described supramaximal noxious stimulation procedures were then applied. When gross purposeful movement (positive response) was elicited prior to the end of the 60-second stimulation cycle, noxious stimulation was immediately discontinued. When the noxious stimulation elicited a positive response, the etDES was increased by 0.5%; a 15-minute equilibration period was then allowed before the noxious stimulus was applied again. When noxious stimulation did not elicit gross purposeful movement (negative response), the etDES was decreased by 0.5%; a 15-minute equilibration period was allowed before the noxious stimulation was repeated. The MACDES for each sheep was calculated as the mean of 2 successive etDES values (1 that did not prevent gross purposeful movement and 1 that prevented gross purposeful movement) in response to the supramaximal electrical stimulation. Each determination of MACDES was performed in duplicate. The population MACDES was calculated as the arithmetic mean ± SD of the MACs of all 13 sheep.

Determination of dose-dependent effects of desflurane on body temperature and cardiovascular variables

After MACDES was determined for each sheep, etDES was adjusted to 1.3 MACDES for each animal. This etDES was then maintained for 15 minutes before variables were recorded. The etDES then was adjusted to 1.6 MACDES for each animal. This etDES was then maintained for 15 minutes before variables were again recorded. The sheep then were allowed to recover from anesthesia, and the interval until extubation, sternal recumbency, and standing were recorded.

Data collection

Body temperature, respiratory rate, Petco2, heart rate, SAP, DAP, and MAP were recorded in each awake sheep before administration of desflurane (awake), immediately after intubation (etDES, 10.5%), after intubation), at the end of the 30-minute equilibration period (equilibration), during the first MACDES determination (first MAC), during the second MACDES determination (second MAC), at the end of the 15-minute equilibration period when sheep received an etDES of 1.3 times MACDES (1.3 MAC), at the end of the 15-minute equilibration period when sheep received an etDES of 1.6 times MACDES (1.6 MAC), and immediately before discontinuation of desflurane administration (etDES corresponded to 1.45 ± 0.43 MACDES; end of procedures). The etDES was also recorded at all those time points, except for awake.

At various time points, an arterial blood sample (1 mL) was collected from each sheep into a heparin-coated syringe and immediately analyzed by use of a blood gas analyzer.p Samples were collected at the awake, equilibration, and end of procedures time points.

Arterial blood gas variables (Pao2, Paco2, and Sao2), arterial acid-base variables (pH, HCO3−- concentration, base excess, and lactate concentration), electrolytes (concentrations of Na+, K+, Ca2+, and Cl−-), anion gap, Hct, hemoglobin content, glucose concentration, and creatinine concentration were recorded at the awake, equilibration, and end of procedures time points. Intervals from mask induction with desflurane to intubation and from cessation of positive-pressure ventilation after discontinuation of desflurane administration to spontaneous ventilation were recorded. Times to sternal recumbency and to standing without ataxia as well as total anesthesia time were also recorded.

Statistical analysis

An ad hoc electronic data setq was used for all variables. Continuous data were summarized as mean ± SD or median and IQR on the basis of their parametric distribution. To reduce variability, cardiovascular variables were logarithmically transformed. Student t or Wilcoxon rank tests were performed for normally and nonnormally distributed quantitative variables, respectively. A repeated-measures ANOVA was used to assess significant differences among time points for normally distributed quantitative variables. Values of P < 0.05 (2-tailed test) were considered significant.

Results

Animals

Mean ± SD time to induce anesthesia with desflurane administered via face mask was 4.81 ± 2.21 minutes. Ten of 13 sheep were apneic immediately after intubation (etDES was 10.5%, which corresponded to 1.06 ± 0.15 MACDES). Mean total anesthesia time was 226 ± 22 minutes. Mean time to extubation was 14.09 ± 4.05 minutes after discontinuation of desflurane administration and cessation of positive-pressure ventilation. Median time to sternal recumbency was 17.1 minutes (IQR, 15.9 to 18.8 minutes), and mean ± SD time to standing without ataxia was 32.4 ± 12.5 minutes.

MACDES

Mean ± SD M ACDES for the 13 adult nonpregnant female Sardinian sheep was 9.81 ± 0.79%. There was no significant difference in MACDES between the first MAC (mean ± SD, 9.89 ± 0.87%) and second MAC (mean ± SD, 9.73 ± 0.83%) determination.

Dose-dependent effects of desflurane on body temperature and cardiovascular variables

Body temperature decreased steadily during the experimental procedures, and all temperature values recorded during anesthesia were significantly (all P < 0.01) lower than values measured in the awake sheep (Table 1). Because positive-pressure ventilation was used, respiratory rate and Petco2 did not change with increasing etDES. Heart rate increased significantly at induction of anesthesia and intubation, but it then returned to values not significantly different from the heart rate in awake sheep. Arterial blood pressures (SAP, MAP, and DAP) began to significantly decrease from the values in awake animals by 25% to 30% as soon as desflurane was administered. Arterial blood pressures increased for a short period during and after noxious stimulation as part of the MAC determination procedure before they decreased again to prestimulation values. When etDES was increased to 1.3 and 1.6 MACDES without further noxious stimulations, arterial blood pressures decreased significantly with increasing etDES (Figure 1).

Table 1—

Mean ± SD values for body temperature and heart rate in 13 adult nonpregnant female sheep anesthetized with desflurane at various MAC multiples.

VariableAwakeAfter intubationEquilibrationFirst MACSecond MAC1.3 MAC1.6 MACEnd of procedures
etdes01.06 ± 0.151.06 ± 0.10111.31.61.45 ± 0.43
Body temperature (°C)39.1 ± 0.638.9 ± 0.5*38.4 ± 0.7*38.0 ± 0.8*37.4 ± 0.8*37.2 ± 0.7*36.9 ± 1.0*36.9 ± 1.0*
Heart rate (beats/min)79 ± 16103 ± 28*85 ± 1887 ± 1588 ± 1381 ± 1077 ± 675 ± 8

Value for etDES is the MACDES multiple. Time points were before induction of anesthesia with desflurane (0 MACDES; Awake), immediately after intubation (etDES of 1.06 MACDES; After intubation), after a 30-minute equilibration period at an etDES of 10.5% (corresponding to 1.06 MACDES; Equilibration), during the first MACDES determination (1 MACDES; First MAC), during the second MACDES determination (1 MACDES; Second MAC), after a 15-minute equilibration period at 1.3 MACDES (1.3 MAC), after a 15-minute equilibration period at 1.6 MACDES (1.6 MAC), and immediately after discontinuation of desflurane administration (mean, 1.45 MACDES; End of procedures).

Value differs significantly (P < 0.05) from the value for Awake.

Figure 1—
Figure 1—

Mean ± SD values of SAP (solid line), MAP (dotted line), and DAP (dashed line) for 13 adult nonpregnant female sheep anesthetized at various MAC multiples. Time points were before induction of anesthesia with desflurane (0 MACDES; Awake), immediately after intubation (etDES of 1.06 MACDES; After intubation), after a 30-minute equilibration period at an etDES of 10.5% (corresponding to 1.06 MACDES; Equilibration), during the first MACDES determination (1 MACDES; First MAC), during the second MACDES determination (1 MACDES; Second MAC), after a 15-minute equilibration period at 1.3 MACDES (1.3 MAC), after a 15-minute equilibration period at 1.6 MACDES (1.6 MAC), and immediately after discontinuation of desflurane administration (mean, 1.45 MACDES; End of procedures). *Value differs significantly (P < 0.05) from the value for Awake. Value differs significantly (P < 0.05) from the values for After intubation, Equilibration, First MAC, and Second MAC. Value differs significantly (P < 0.05) from the value for 1.3 MAC.

Citation: American Journal of Veterinary Research 79, 7; 10.2460/ajvr.79.7.727

Ten of 13 sheep remained apneic for 5.25 ± 1.43 minutes after desflurane administration and positive-pressure ventilation was discontinued. At that time point, mean ± SD etDES was 15.40 ± 1.53% (1.56 ± 0.10 MACDES), median Sao2 was 100% (IQR, 100% to 100%), and mean ± SD Paco2 was 47.3 ± 5.7 mm Hg. The mean etDES and Paco2 in the 3 sheep that immediately resumed spontaneous breathing after discontinuation of desflurane administration and positive-pressure ventilation were 14.80% and 50.5 ± 5.5 mm Hg, respectively; these values did not differ significantly (etDES, P = 0.60; Paco2, P = 0.49) from values measured in the other 10 sheep.

Changes in values for arterial blood gas measurements (Pao2, Paco2, and Sao2), acid-base variables (pH, HCO3 concentration, base excess, and lactate concentration), electrolytes (concentrations of Na+, K+, Ca2+, and Cl), and other hematologic variables at 3 time points during the study (awake, equilibration, and end of procedures) were summarized (Table 2). Some values differed significantly from values for awake animals.

Table 2—

Values for arterial blood gas variables, electrolyte concentrations, and hematologic variables for 13 adult nonpregnant female sheep anesthetized with desflurane at various MAC multiples.

VariableAwakeEquilibrationEnd of procedures
pH7.50 ± 0.047.43 ± 0.06*7.41 ± 0.06*
Paco2 (mm Hg)33.8 ± 2.344.7 ± 4.6*47.9 ± 5.5*
Pao2 (mm Hg)74.1 ± 11.7424.4 ± 156.6*409.9 ± 105.5*
HCO3 (mmol/L)28.0 ± 3.729.9 ± 2.8*30.2 ± 3.4
Base excess (mmol/L)0.74 ± 0.551.22 ± 1.151.14 ± 1.22
Sao2 (%)96.3 (95.2–97.1)100 (99.9–100)*100 (100–100)*
Na+ (mmol/L)145 ± 2144 ± 2145 ± 2
K+ (mmol/L)4.0 ± 0.54.1 ± 0.73.9 ± 0.6
Ca2+ (mmol/L)1.15 ± 0.091.08 ± 0.121.08 ± 0.15
Cl (mmol/L)104 (102–105)105 (103–107)105 (101–108)
Anion gap (mmol/L)19 ± 215 ± 2*14 ± 2*
Hct (%)23 ± 318 ± 2*16 ± 3*
Hemoglobin (g/dL)7.7 ± 0.85.9 ± 0.8*5.4 ± 1.0*
Lactate (mmol/L)2.34 (1.84–2.73)1.20 (1.02–1.76)*0.96 (0.82–1.37)*
Glucose (mg/dL)103 ± 3494 ± 3084 ± 16
Creatinine (mg/dL)1.14 ± 0.201.04 ± 0.270.96 ± 0.21

Values reported are mean ± SD or median (IQR).

See Table 1 for remainder of key.

Discussion

Mean ± SD MACDES for the sheep of the present study was 981 ± 0.79%. This value is in accordance with the median MAC of 95% (range, 8.4% to 11.1%) reported for administration of desflurane to nonpregnant ewes (1 to 8 years of age) in one studya and the only slightly higher MAC of 8.6 ± 0.2% determined for 8 adult nulliparous sheep of another study6 Investigators in both of those studies6a applied mechanical stimulation (forceps clamping) instead of electrical stimulation, as was used in the study reported here, for supramaximal noxious stimulation. Because the MACDES results for the present study were similar to those previously reported, they confirmed the findings for dogs7,9 and rabbits7 that electrical stimulation with current intensities of 30 mA and 50 mA (independent of the location of electrical stimulation) and mechanical stimulation in the form of tail or paw clamping result in supramaximal noxious stimulation and lead to determination of comparable MAC values. In contrast for humans, in which skin incision and electrical stimulation are of similar nociceptive strength and yield similar MAC values,5 a study7 involving rabbits and dogs revealed that a skin incision results in a much lower MAC, compared with the MAC for mechanical clamping or electrical stimulation.

The MACDES data for sheep of the present study and other studies indicate an anesthetic potency of desflurane of similar magnitude to that reported for dogs,10–12 cats,13 rabbits,10 pigs,14 horses,15,16 and 18- to 30-year-old humans.1 Differences between the MACDES for sheep of the present study and values reported for other species are likely attributable to variability that is common among species and reflect primarily biological variation.3 However, differences in experimental methods and breed, age, body temperature, and circadian rhythm among subjects and among species may also account for some of the variability in results.5,7

All sheep received positive-pressure ventilation throughout the experimental period to prevent arterial CO2 retention. Therefore, it was not surprising that at the end of the experiment, when the administration of desflurane was discontinued and positive-pressure ventilation ceased, analysis of arterial blood gas samples revealed only mild hypercapnia. However, 10 of 13 sheep were apneic for several minutes. The etDES at that time was 1.45 ± 0.43 MACDES. Only as desflurane was washed out with fresh O2 (flow rate, 3 L/min) did animals resume spontaneous breathing. Progressive respiratory depression attributable to desflurane has also been observed in other species.3 In swine, which have a MACDES of 10% (almost identical to that of sheep), the apneic index for desflurane (ie, ratio of the etDES at apnea and MACDES) is reportedly 1.6.3 Also, rabbits rapidly became apneic during mask induction with desflurane once the vaporizer setting reached values ≥ 6%.17 In contrast, dogs have an apneic index of 2.4,3 which indicates less respiratory depressant effects in that species. However, desflurane has a strong respiratory depressant effect in horses.16

Results of studies of sheep,6 horses,16 and pigs18,19 and the sheep of the study reported here indicated no significant dose-dependent change in heart rate when the desflurane concentration increased from 1.0 to 1.6 MACDES. The only significant increase in heart rate was detected during the induction of anesthesia. This might have been related to stage 1 of inhalation anesthesia, which commonly is associated with CNS excitement and tachycardia,20 and possibly to stimulation associated with orotracheal intubation of the sheep. In contrast to heart rate, arterial blood pressures rapidly decreased (by 25% to 30%) from baseline values in awake animals as etDES began increasing to concentrations of approximately 1 MACDES and then remained relatively stable during the equilibration period. As expected, mild recovery of blood pressures was detected during the period of MAC determinations, most likely as a result of repetitive noxious stimulation and related activation of the sympathetic nervous system.3 Thereafter, arterial blood pressures decreased further in a concentration-dependent manner as etDES increased to 1.3 and 1.6 MAC, reaching a dangerously low mean MAP of 44 mm Hg. A similar concentration-dependent decrease in arterial blood pressures as a result of pronounced peripheral vasodilation has been recognized in previous studies of sheep,6 horses,16 pigs,18,19 and humans.21 It is important to mention the reduction (approx 30%) in the hemoglobin concentration by the end of the experimental procedures, which was potentially related to both constant administration of IV fluids and sequestration of erythrocytes in the spleen and other organs (eg, liver, skin, and skeletal muscles), as has been reported for dogs22 and cats.23 Because lactate and creatinine concentrations did not increase toward the end of the experimental procedures, it is unlikely that systemic tissue or organ perfusion and, hence, aerobic function were severely compromised by the relatively brief period of pronounced arterial hypotension toward the end of the experimental procedures.

Acknowledgments

Supported by the Fondazione Banco di Sardegna; Regione Autonoma della Sardegna; Section of Large Animal Emergency, Critical Care and Anesthesia, Department of Clinical Studies–New Bolton Center, School of Veterinary Medicine, University of Pennsylvania; and Dräger Italia. Dr. Driessen was supported by a Visiting Professorship grant from the Central Administration of the University of Sassari.

The authors declare that there were no conflicts of interest.

The authors thank Prof. Eraldo Sanna Passino for assistance with obtaining funding resources in Italy and for logistic support.

ABBREVIATIONS

DAP

Diastolic arterial blood pressure

etDES

End-tidal concentration of desflurane

IQR

Interquartile (25th to 75th percentile) range

MAC

Minimum alveolar concentration

MACDES

Minimum alveolar concentration of desflurane

MAP

Mean arterial blood pressure

Petco2

End-tidal partial pressure of carbon dioxide

Sao2

Arterial oxygen saturation

SAP

Systolic arterial blood pressure

Footnotes

a.

Lukasik VM, Nogami WM, Morgan SE. Minimum alveolar concentration and cardiovascular effects of desflurane in sheep (abstr). Vet Surg 1998;27:167.

b.

Delta Ven 1, Delta Med, Viadana, Italy.

c.

Perseus A500, Dräger, Lübeck, Germany.

d.

Drägersorb 800 Plus, Dräger, Lübeck, Germany.

e.

D-Vapor 3000, Dräger, Lübeck, Germany.

f.

TurboVent2, Dräger, Lübeck, Germany.

g.

Baxter, Rome, Italy.

h.

Infinity Delta XL, Dräger, Lübeck, Germany.

i.

Perseus A500, Dräger, Lübeck, Germany.

j.

SCIO, Dräger, Lübeck, Germany.

k.

Air Liquide Healthcare America, Plumsteadville, Pa.

l.

Norotrode 20 bipolar SEMG electrodes, Myotronics-Noromed Inc, Kent, Wash.

m.

DS7A, Digitimer Ltd, Letchworth Garden City, England.

n.

DG2A train/delay generator, Digitimer Ltd, Letchworth Garden City, England.

o.

Personal 20, Mega Elettronica, Milan, Italy.

p.

ABL 80 CO-OX flex, Radiometer, Copenhagen, Denmark.

q.

Excel, version 2016, Microsoft Corp, Redmond, Wash.

References

  • 1. Rampil IJ, Lockhart SH, Zwass MS, et al. Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429433.

    • Search Google Scholar
    • Export Citation
  • 2. Eger EI. Desflurane: a compendium and reference. Rutherford, NJ: Healthpress Publishing Group, 1993.

  • 3. Steffey EP, Mama KR, Brosnan RJ. Inhalation anesthetics. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;297331.

    • Search Google Scholar
    • Export Citation
  • 4. Keijzer C, Perez RSGM, De Lange JJ. Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 2005;5:6.

    • Search Google Scholar
    • Export Citation
  • 5. Quasha AL, Eger EI II, Tinker JH. Determinations and application of MAC. Anesthesiology 1980;53:315334.

  • 6. Sayre RS, Lepiz MA, Horsley KT, et al. Effects of oxymorphone hydrochloride or hydromorphone hydrochloride on minimal alveolar concentration of desflurane in sheep. Am J Vet Res 2015;76:583590.

    • Search Google Scholar
    • Export Citation
  • 7. Valverde A, Morey TE, Hernández J, et al. Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 2003;64:957962.

    • Search Google Scholar
    • Export Citation
  • 8. Dixon WJ, Massey FJ. The “up-and-down” method. In: Dixon WJ, Massey FJ, eds. Introduction to statistical analysis. 4th ed. New York: McGraw-Hill, 1983;428439.

    • Search Google Scholar
    • Export Citation
  • 9. Figueiró MR, Soares JH, Ascoli FO, et al. Isoflurane MAC determination in dogs using three intensities of constant-current electrical stimulation. Vet Anaesth Analg 2016;43:464471.

    • Search Google Scholar
    • Export Citation
  • 10. Doorley BM, Waters SJ, Terrell RC, et al. MAC of I 653 in Beagle dogs and New Zealand White rabbits. Anesthesiology 1988;69:8991.

  • 11. Hammond RA, Alibhai HIK, Walsh KP, et al. Desflurane in the dog: minimum alveolar concentration (MAC) alone and in combination with nitrous oxide. J Vet Anaesth 1994;21:2123.

    • Search Google Scholar
    • Export Citation
  • 12. Wang B, Tang J, White PF, et al. The effect of GP683, an adenosine kinase inhibitor, on the desflurane anesthetic requirement in dogs. Anesth Analg 1997;85:675680.

    • Search Google Scholar
    • Export Citation
  • 13. McMurphy RM, Hodgson DS. The minimum alveolar concentration of desflurane in cats. Vet Surg 1995;24:453455.

  • 14. Eger EI II, Johnson BH, Weiskopf RB, et al. Minimum alveolar concentration of 1,653 and isoflurane in pigs: definition of a supramaximal stimulus. Anesth Analg 1988;67:11741176.

    • Search Google Scholar
    • Export Citation
  • 15. Tendillo FJ, Mascias A, Santos M, et al. Anesthetic potency of desflurane in the horse: determination of the minimum alveolar concentration. Vet Surg 1997;26:354357.

    • Search Google Scholar
    • Export Citation
  • 16. Steffey EP, Woliner MJ, Puschner B, et al. Effects of desflurane and mode of ventilation on cardiovascular and respiratory functions and clinicopathologic variables in horses. Am J Vet Res 2005;66:669677.

    • Search Google Scholar
    • Export Citation
  • 17. Hedenqvist P, Roughan JV, Antunes L, et al. Induction of anaesthesia with desflurane and isoflurane in the rabbit. Lab Anim 2001;35:172179.

    • Search Google Scholar
    • Export Citation
  • 18. Weiskopf RB, Holmes MA, Eger EI II, et al. Cardiovascular effects of I, 653 in swine. Anesthesiology 1988;69:303309.

  • 19. Weiskopf RB, Holmes MA, Rampil IJ, et al. Cardiovascular safety and actions of high concentrations of I 653 and isoflurane in swine. Anesthesiology 1989;70:793798.

    • Search Google Scholar
    • Export Citation
  • 20. Tranquilli WJ, Grimm KA. Introduction: use, definitions, history, concepts, classification, and considerations for anesthesia and analgesia. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;297331.

    • Search Google Scholar
    • Export Citation
  • 21. Weiskopf RB. Cardiovascular effects of desflurane in experimental animals and volunteers. Anaesthesia 1995;50(suppl):1417.

  • 22. Wilson DV, Evans AT, Carpenter RA, et al. The effect of four anesthetic protocols on splenic size in dogs. Vet Anaesth Analg 2004;31:102108.

    • Search Google Scholar
    • Export Citation
  • 23. Zlateva N, Marinov G. Effect of three anesthetic protocols on the haematological indices in cats during ovariohysterectomy. MedInform 2015;2:184193.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Address correspondence to Dr. Driessen (driessen@upenn.edu).