The effect of experimentally induced hypothyroidism on the isoflurane minimum alveolar concentration in dogs

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1 Veterinary Anaesthesia and Analgesia, 2015, 42, doi: /vaa RESEARCH PAPER The effect of experimentally induced hypothyroidism on the isoflurane minimum alveolar concentration in dogs Stephanie H Berry & David L Panciera Department of Small Animal Clinical Sciences, Virginia Maryland Regional College of Veterinary Medicine, Blacksburg, VA, USA Correspondence: Stephanie Berry, Department of Companion Animals, Atlantic Veterinary College, 550 University Avenue, Charlottetown, PE C1A 4P3, Canada. sberry@upei.ca Abstract Objective To determine the effect of experimentally induced hypothyroidism on isoflurane (ISO) minimum alveolar concentration (MAC) in dogs. Study design Prospective experimental study. Conclusion and clinical relevance The MAC of ISO in dogs was not significantly affected by experimentally induced hypothyroidism. The dose of ISO in dogs with hypothyroidism does not need to be altered. Keywords dogs, hypothyroidism, isoflurane, minimum alveolar concentration. Animals Eighteen adult female mongrel dogs, age 2 4 years and weighing kg. Methods Hypothyroidism was induced in nine dogs by the intravenous administration of 1 mci kg 1 of 131 Iodine. The remaining nine dogs served as controls. Dogs were studied 9 12 months after the induction of hypothyroidism. Anesthesia was induced with ISO in oxygen via a mask. The trachea was intubated, and anesthesia was maintained using ISO in oxygen using a semi-closed rebreathing circle system. The dogs were mechanically ventilated to maintain an end-tidal carbon dioxide concentration between 35 and 45 mmhg. End-tidal ISO concentrations were measured with an infrared gas analyzer. The MAC was determined in duplicate using a tail clamp technique. The mean values for the groups were compared using a two sample t-test. Results The mean SD MAC of isoflurane in the hypothyroid and euthyroid dogs was % and %, respectively. The mean MAC of isoflurane in hypothyroid dogs was not significantly different from the mean MAC of isoflurane in the control dogs (p = ). Introduction Hypothyroidism is one of the most common endocrine disorders diagnosed in dogs. Because thyroid hormones are essential for normal function of all body systems, hypothyroidism is associated with a wide array of clinical abnormalities. The effects of this disorder on the neurologic and cardiovascular systems and on drug metabolism are of particular importance for appropriate anesthetic management of affected dogs. Not surprisingly, empirical observations in anesthetized hypothyroid dogs have led to opinions that they require less anesthetic agent for a given effect and are often difficult to manage during anesthesia. The standard measurement used to determine the potency of an inhaled anesthetic agent is the minimum alveolar concentration (MAC). The MAC of anesthetic agents is defined as the concentration at which 50% of patients will not move in response to a noxious stimulus (Quasha et al. 1980). The term was first used in 1963 by Merkel and Eger (Merkel & Eger 1963) and has been used as the 50

2 major index of anesthetic potency in anesthetic literature ever since. The concept of MAC not only provides a method to compare the potencies of different inhalation anesthetic agents, but it also serves as a sensitive tool to determine the interaction of altered physiologic states with the inhaled anesthetics (Stanski 2000). Several factors have been identified that may alter an animal s anesthetic requirements, or MAC. Of these variables, hypothyroidism has been commonly considered to decrease anesthetic requirements in both humans and dogs (Babad & Eger 1968; Stanski 2000). However, only one study evaluating the MAC value in hypothyroid dogs has been performed. In this study, the effect of hypothyroidism on halothane requirements was examined in six dogs (Babad & Eger 1968). The authors demonstrated that the MAC of halothane in hypothyroid dogs was reduced by approximately 4 6% (Babad & Eger 1968). No studies have been performed in dogs to evaluate the effect of hypothyroidism on the MAC value of a more modern inhaled anesthetic agent, such as isoflurane (ISO). The objective of this study was to evaluate the effects of experimentally induced hypothyroidism on the MAC of ISO in the dog. Materials and methods Eighteen healthy female adult mongrel dogs weighing between 8.2 and 13.1 kg were used. All dogs were determined to be healthy based on lack of significant abnormalities on physical examination, complete blood count, serum chemistries, urinalysis, Dirofilaria antigen test, and zinc sulfate fecal floatation. Serum concentrations of total thyroxine (T 4 ), free T 4 by equilibrium dialysis, and endogenous canine thyroid stimulating hormone (TSH) were within their respective reference ranges. Food was withheld for 12 hours before anesthesia. Water was available ad libitum. This study was approved by the University Animal Care and Use Committee. Induction and confirmation of hypothyroidism Hypothyroidism was induced in nine randomly selected dogs by the intravenous (IV) administration of 1 mci kg 1 of 131 Iodine (Panciera & Johnson 1996). Hypothyroidism was confirmed by measuring a serum T 4 concentration <5 nmol L 1 prior to and 4 hours post IV administration of 50 lg human recombinant TSH (Panciera & Johnson 1996). Confirmation testing was performed nine and weeks after 131 I administration. All control dogs had a serum T 4 concentration 37 nmol L 1 after TSH administration. The ISO MAC was determined 9 12 months after the induction of hypothyroidism. All studies were performed during anestrous. Determination of ISO MAC Anesthesia was induced with ISO in oxygen delivered via mask. The trachea was intubated and anesthesia was maintained with ISO in oxygen delivered via a circle system with an oxygen flow rate of ml kg 1 minute 1. The dogs were placed in lateral recumbency and a 20-gauge catheter was placed in a cephalic vein. Lactated Ringer s solution was administered at 5 ml kg 1 hour 1. Dogs were mechanically ventilated to maintain an end-tidal carbon dioxide tension (PE CO 2 ) of mmhg ( kpa). PE CO 2 and end-tidal ISO concentrations (FE Iso) were continually monitored using an infrared gas analyzer (AS/3; Datex-Ohmeda, Finland). The gas analyzer was calibrated at the start of each day using the calibration gases supplied by the manufacturer (DOT-39 NRC 300/375; Datex-Ohmeda). Esophageal temperature was monitored electronically. Warm water and forced air blankets were used to maintain the dogs temperatures between 37 and 39 C. The electrocardiogram, heart rate, and percent saturation of hemoglobin (SpO 2 ) were monitored throughout the experiment (AS/3; Datex- Ohmeda). FE Iso was held constant at 1.7% for at least 30 minutes prior to the determination of ISO MAC. At the end of this equilibration period, FE Iso was decreased to 1.2% and maintained for at least 20 minutes. A noxious stimulus, which consisted of clamping the tail, was then applied using a 24 cm sponge forceps with plastic tubing on each jaw (Valverde et al. 2003). The forceps was applied 10 cm from the base of the tail and closed to the first notch. The forceps remained in place for 60 seconds or until gross purposeful movement, defined as a twisting or lifting of the head or a paddling or running motion of the limbs, was observed. Movements that were not considered purposeful included swallowing, chewing, or coughing. If gross purposeful movement was observed, the FE Iso was increased by 0.1%. If no movement was recorded, the FE Iso Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 50 54

3 was decreased by 0.1%. After a 20 minute equilibration period, the stimulus was applied again, moving the clamp approximately 1 cm proximally each time. The FE Iso midway between the concentration of ISO that prevented movement and the ISO concentration that allowed movement was recorded as the ISO MAC. The ISO MAC was immediately determined again for each dog and the mean of these values was taken as the ISO MAC. After the determination of ISO MAC was completed, the ISO was discontinued and the dogs were allowed to recover from anesthesia. After verifying that the measurements followed an approximate Gaussian distribution, data were analyzed using a two sample t-test and reported as mean SD. The MAC values were adjusted to one atmosphere pressure. The level of significance was set at a p < Results Body weight of the control and hypothyroid groups before induction of hypothyroidism were and kg, respectively. At the time of study, hypothyroid dogs ( kg) weighed significantly more than control dogs ( kg; p = ). All hypothyroid dogs showed clinical signs including alopecia or thin hair coat, weight gain, seborrhea, and lethargy. The mean serum T 4 concentration before TSH administration was nmol L 1 and nmol L 1, and after TSH administration was nmol L 1 and nmol L 1, in the hypothyroid and control groups, respectively. The mean ISO MAC for the hypothyroid dogs was %. The mean ISO MAC for the control dogs was %. There was no significant difference between the groups (p = ). Mean body temperature at the start of anesthesia in the control dogs ( C) was significantly different (p < 0.001) from that of the hypothyroid group ( C). At the time of the first determination of ISO MAC, mean body temperature of the control group was C while the mean body temperature of the hypothyroid group was C, a difference that was significant (p = 0.003). SpO 2 was not <96% at any time in any of the dogs. PE CO 2 were maintained between 35 and 45 mmhg ( kpa) at all times in both groups. Discussion Based on the findings of this study, no alteration in the dose of isoflurane should be necessary in hypothyroid dogs. However, the anesthesiologist should remain vigilant and be prepared to address the decreased cardiac contractility, increased systemic vascular resistance, and altered response to catecholamines known to occur in hypothyroidism (Panciera 1994). While the present study did not address these issues, another small study failed to find important differences in measurements of cardiovascular status and function in hypothyroid dogs anesthetized with isoflurane (McMurphy et al. 1996). It has been suggested that anesthetic requirement, or MAC, is related to metabolic rate (Guedel 1924). More specifically, it has been shown that MAC correlates with cerebral oxygen consumption rates (Kety 1956; Gregory et al. 1969). While Munson et al. showed that hypothyroidism induced a marked reduction in basal metabolic rate in rats, cerebral oxygen consumption was unchanged (Munson et al. 1968). This may explain the insignificant reduction in ISO MAC demonstrated in this study. Hypothyroidism has also been shown to cause a decrease in cardiac output, stroke volume, heart rate, and contractility in dogs (Taylor et al. 1969). While a reduction in cardiac output will increase the rate of rise of alveolar concentrations of an inhaled anesthetic and, therefore, speed the induction of anesthesia, the MAC of the anesthetic agent should not be affected. Additionally, the effect of a reduction in cardiac output is minimized when using a poorly soluble anesthetic agent such as isoflurane. Severe hypotension (mean arterial pressure <40 50 mmhg) has been demonstrated to reduce MAC (Eger et al. 1965a). It should be noted that neither cardiac output nor mean arterial blood pressure were measured or controlled in this study, consequently it is possible that alterations in these variables may have occurred. Many other factors have been demonstrated to affect MAC in dogs, rats and humans, including hypercarbia (Eisele et al. 1967), hypoxemia (Cullen & Eger 1970a,b; Cullen et al. 1970), temperature (Eger et al. 1965b; Munson 1970; Vitez et al. 1974), and sedatives and tranquilizers (Tsunoda et al. 1973; Hellyer et al. 2001). Each of these variables was controlled in the present study. PE CO Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

4 was maintained within a specific range for the duration of the study, at tensions that should not affect the MAC of isoflurane (Eger et al. 1965a). Severe hypoxemia can reduce MAC. Although arterial oxygen saturation (SaO 2 ) was not monitored, SpO 2 was monitored continuously and values were always >96%. Factors that can result in inaccuracies in pulse oximetry were controlled, therefore, it can be assumed that pulse oximetry was reflective of SaO 2. This would suggest that hypoxemia was not present in these dogs and did not affect the MAC value determined here. Body temperature was maintained throughout the study with forced air and re-circulating warm water blankets. It is interesting to note, however, that the average body temperature of the hypothyroid dogs at the beginning of anesthesia was significantly lower than that of control dogs. The difference in temperature may be related to the decreased metabolic rate associated with hypothyroidism that sometimes is manifested as hypothermia, particularly in dogs with severe disease (Henik & Dixon 2000; Pullen & Hess 2006). At the time of ISO MAC determination, all dogs had been warmed to C. Although the difference in temperature between the two groups was still significant, substantial hypothermia was not present in any dog. It is possible that the ISO MAC of the hypothyroid dogs could have been affected by this lower body temperature had the dogs not been aggressively warmed prior to the determination of MAC (Eger 1974). Finally, in order to avoid the potential interaction of tranquilizers and sedatives with MAC, no other anesthetic agents were used during this study. Additionally, while only female dogs were used in the present study, it has been demonstrated that gender does not significantly affect MAC (Eger 1974). In this study ISO MAC was determined using a tail clamp technique. This technique has been validated for use in the dog with ISO (Valverde et al. 2003). In this study, a purposeful movement was defined as a twisting or lifting of the head or a paddling or running motion of the limbs. There can be variation in the interpretation of positive responses if multiple individuals are involved. In this study, only one investigator (SHB) performed all MAC determinations. The ISO MAC reported here is slightly lower than the values reported in other studies (Steffey & Howland 1977; Kazama & Ikeda 1988; Valverde et al. 2003, 2004). As blood pressure was not recorded, hypotension may have been present in these dogs, thereby resulting in a reduction in the MAC of isoflurane in both groups. Additionally, even though all MAC determinations were performed by one investigator, the interpretation of movements is subjective. This may also have resulted in the lower MAC values reported in both groups. In conclusion, the MAC of isoflurane was not significantly different in dogs with experimentally induced hypothyroidism as compared to controls. The results indicate that the dose of ISO does not need to be altered in dogs with experimentally induced hypothyroidism. References Babad AA, Eger EI 2nd (1968) The effects of hyperthyroidism and hypothyroidism on halothane and oxygen requirements in dogs. Anesthesiology 29, Cullen DJ, Eger EI 2nd (1970a) The effects of hypoxia and isovolemic anemia on the halothane requirement (MAC) of dogs. 3. The effects of acute isovolemic anemia. Anesthesiology 32, Cullen DJ, Eger EI 2nd (1970b) The effects of hypoxia and isovolemic anemia on the halothane requirement (MAC) ofdogs. I. Theeffectof hypoxia. Anesthesiology32, Cullen DJ, Cotev S, Severinghaus JW et al. (1970) The effects of hypoxia and isovolemic anemia on the halothane requirement (MAC) of dogs. II. The effects of acute hypoxia on halothane requirement and cerebralsurface Po2, Pco2, ph and HCO3. Anesthesiology 32, Eger EI 2nd (1974) Anesthetic Uptake and Action. Williams & Wilkins, Baltimore, USA. Eger EI 2nd, Saidman LJ, Brandstater B (1965a) Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 26, Eger EI 2nd, Saidman LJ, Brandstater B (1965b) Temperature dependence of halothane and cyclopropane anesthesia in dogs: correlation with some theories of anesthetic action. Anesthesiology 26, Eisele JH, Eger EI 2nd, Muallem M (1967) Narcotic properties of carbon dioxide in the dog. Anesthesiology 28, Gregory GA, Eger EI 2nd, Munson ES (1969) The relationship between age and halothane requirement in man. Anesthesiology 30, Guedel AE (1924) Metabolism and reflex irritability in anesthesia. J Am Med Assoc 83, Hellyer PW, Mama KR, Shafford HL et al. (2001) Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 50 54

5 a combination of isoflurane and fentanyl. Am J Vet Res 62, Henik RA, Dixon RM (2000) Intravenous administration of levothyroxine for treatment of suspected myxedema coma complicated by severe hypothermia in a dog. J Am Vet Med Assoc 216, , 685. Kazama T, Ikeda K (1988) Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology 68, Kety SS (1956) Human cerebral blood flow and oxygen consumptionasrelatedtoaging.jchronicdis3, McMurphy RM, Hodgson DS, Bruyette DS et al. (1996) Cardiovascular effects of 1.0, 1.5, and 2.0 minimum alveolar concentrations of isoflurane in experimentally induced hypothyroidism in dogs. Vet Surg 25, Merkel G, Eger EI 2nd (1963) A comparative study of halothane and halopropane anesthesia including method for determining equipotency. Anesthesiology 24, Munson ES (1970) Effect of hypothermia on anesthetic requirement in rats. Lab Anim Care 20, Munson ES, Hoffman JC, DiFazio CA (1968) The effects of acute hypothyroidism and hyperthyroidism on cyclopropane requirement (MAC) in rats. Anesthesiology 29, Panciera DL (1994) An echocardiographic and electrocardiographic study of cardiovascular function in hypothyroid dogs. J Am Vet Med Assoc 205, Panciera DL, Johnson GS (1996) Plasma von Willebrand factor antigen concentration and buccal mucosal bleeding time in dogs with experimental hypothyroidism. J Vet Intern Med 10, Pullen WH, Hess RS (2006) Hypothyroid dogs treated with intravenous levothyroxine. J Vet Intern Med 20, Quasha AL, Eger EI 2nd, Tinker JH (1980) Determination and applications of MAC. Anesthesiology 53, Stanski DR (2000) Monitoring depth of anesthesia. In: Anesthesia (5th edn). Miller RD (ed). Churchill Livingstone, Phildelphia, USA. pp Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, Taylor RR, Covell JW, Ross J Jr (1969) Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. J Clin Invest 48, Tsunoda Y, Hattori Y, Takatsuka E et al. (1973) Effects of hydroxyzine, diazepam, and pentazocine on halothane minimum alveolar anesthetic concentration. Anesth Analg 52, Valverde A, Morey TE, Hernandez J et al. (2003) 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 64, Valverde A, Doherty TJ, Hernandez J et al. (2004) Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 31, Vitez TS, White PF, Eger EI 2nd (1974) Effects of hypothermia on halothane MAC and isoflurane MAC in the rat. Anesthesiology 41, Received 12 June 2013; accepted 14 January Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,