Isoflurane and sevoflurane are used for inhalant anesthesia in dogs. They have similar cardiovascular effects at equipotent doses (measured as MAC) but differ in their potency and solubility in blood.1,2 Sevoflurane is less soluble in blood than is isoflurane; thus, changes in inhaled concentration will equilibrate more rapidly with alveolar concentration, compared with effects for isoflurane.3 This characteristic should theoretically result in more rapid induction and faster recovery with sevoflurane than with isoflurane. When both anesthetics have been used for slowly titrated inhalant induction, sevoflurane has resulted in conditions for intubation more rapidly than has isoflurane.2,4 However, some practitioners use inhalant induction in a rapid (also called a crash) manner, whereby the vaporizer is set to the highest concentration at the onset of induction. To our knowledge, the effect of this induction strategy on induction quality or amount of time required for intubation with isoflurane and sevoflurane has not been studied in dogs.
The traditional MAC value is established by determining the lowest alveolar concentration of inhalant at which a purposeful motor movement from a standard noxious stimulus is abolished in 50% of patients.5 Other pertinent MAC values are MACBAR6 and MACawake.7 The MACawake has been studied extensively in humans for > 30 years, and MACawake has been determined for most inhalant anesthetics and is commonly used to represent the hypnotic potency of an inhalant anesthetic.8,9
Knowledge of MACawake is a powerful tool. By applying the principles of MACawake, an anesthesiologist can titrate inhalant anesthesia to prevent consciousness in a patient while other components (such as muscle paralysis and opioid medications) are concurrently used to provide a balanced anesthetic technique, prevent gross movement, and provide analgesia. In humans, this allows a lower dose of inhalant anesthetic to be used because the MACawake for isoflurane and sevoflurane is approximately a third of the MAC.9 Inhalant agents may differ with regard to the ratio between MACawake and MAC. In humans, nitrous oxide has an MACawake value that is two thirds of the MAC and xenon has an MACawake ratio of 0.46, both of which are significantly different from the values for isoflurane and sevoflurane.9,10 Because cardiovascular depression is linearly related to isoflurane concentration, less isoflurane results in better cardiovascular stability.11
The purposes of the study reported here were to compare isoflurane and sevoflurane when used for rapid inhalant induction and to determine the MACawake for isoflurane and sevoflurane in healthy dogs. The hypothesis was that sevoflurane would cause a more rapid induction than would isoflurane but with similar cardiovascular effects and that MACawake for isoflurane or sevoflurane would be substantially lower than the MAC value for each agent.
Materials and Methods
Animals—Twenty purpose-bred 2-year-old sexually intact male Beagles were used in the study, which comprised 2 experiments. Animal husbandry was provided in accordance with established institutional guidelines. The protocol was approved by the University of Georgia Animal Care and Use Committee.
Body condition score was assessed (9-point scale) as described elsewhere.12 Dogs were deemed healthy on the basis of results of physical examination and measurement of PCV and total protein, blood glucose, and BUN concentrations estimated by reagent strip. A prospective power analysis based on publications in which investigators used methods similar to those for the study reported here was used to determine the number of dogs required to detect a 2-minute difference in induction time and a difference of 0.25 for the proportion of MACawake-noise/MAC with an A value of 0.05 and B value of 0.80. Results of the power analysis confirmed that a maximum of 10 dogs was required in each anesthetic group for experiment 1. Data from experiment 1 were used to perform a power analysis to determine the number of dogs required in experiment 2 to detect a difference of 0.25 for the proportion of MACawake/MAC with an A value of 0.05 and B value of 0.80. Results of that power analysis confirmed that a maximum of 6 dogs was required in each anesthetic group for experiment 2.
Study design—Dogs were randomly assigned by lottery to receive isoflurane or sevoflurane for induction and maintenance of anesthesia. Vaporizer settings (with 100% oxygen as the carrier gas) were 5% (vol/vol) for isoflurane and 8% (vol/vol) for sevoflurane. Oxygen flow was set to 3 L/min in a semiclosed circle (rebreathing) circuit with the agent delivered via a sealed face mask to each dog. Agentspecific, temperature-compensated, calibrated vaporizers were used for each agent.a Vaporizers delivered inhalant at ± 0.2% of the dial setting at a fresh gas flow of 3 L/min. One investigator who was not aware of the inhalant agent administered to each dog continuously assessed each dog until it was judged that a dog had achieved stage 3 anesthesia. Specifically, rotational position of the eyes and sufficient loss of jaw tone and laryngeal reflexes to allow orotracheal intubation were evaluated. Quality of induction was rated by the same investigator, who was not aware of the inhalant agent administration, on a scale of 0 to 3, with 0 considered excellent (walking without ataxia; smooth uncomplicated induction and recovery) and 3 considered rough (walking with substantial ataxia or crawling; difficult induction or recovery). The face mask was removed; each dog was then intubated, and IPPV was initiated to achieve a target end-tidal carbon dioxide concentration between 35 and 40 mm Hg.b The IPPV was continued until extubation. End-tidal agent concentrations were measured with a calibrated gas analyzerb by use of a side-stream sampling T-shaped connector. A 20-gauge, 1-inch polyurethane catheterc was inserted into a cephalic vein, and lactated Ringer's solutiond was administered at a rate of 10 mL/kg/h. Body temperature was measured continuously by a probe placed in the thoracic portion of the esophagus; body temperature was maintained between 36.9° and 37.8°C with a forced-air warming unit.e
Determination of MACawake-noise (experiment 1)—After anesthesia was induced, a Doppler probe was placed over a radial artery; SAP measurements were obtained by use of an audible pulse signal and mercury-calibrated sphygmomanometerf at each audible stimulus time point. Width of the blood pressure–occluding cuff was 40% of the circumference of the forelimb of each dog. When SAP decreased to < 95 mm Hg, a single bolus (5 mL of lactated Ringer's solution/kg) was administered.
After intubation was performed, the oxygen flow rate was decreased to 2 L/min and the vaporizer setting was slowly adjusted during a 20-minute period to achieve an end-tidal concentration of 1.2% for isoflurane and 2.2 vol % for sevoflurane. Each dog was positioned in left lateral recumbency. A standard prerecorded auditory stimulus (a person making a whistling sound followed by speaking the words “wakey wakey”) at a standardized volume of 88 to 92 A-weighted dB (sound pressure level) was then provided from a speaker located 5 cm from the upward-facing external ear canal. A positive response was interpreted as a dog that opened its eyes, had a purposeful motion (ie, lifted its head), rejected the endotracheal tube, or rotated its eyes to a central position and retracted the nictitating membrane. The appearance of these signs was assessed by 1 investigator who was unaware of the anesthetic administered to each dog during each anesthetic episode.
Once the target end-tidal concentration was achieved, the stimulus was repeated every 3 minutes for 15 minutes. The auditory stimulus was repeated every 3 minutes during the period of evaluation to prevent acclimatization. The end-tidal concentration was then decreased by 0.1 vol % for isoflurane and 0.2 vol % for sevoflurane and stabilized for 15 minutes. This protocol was repeated until each dog had a positive response as described previously. The MACawake-noise was then calculated as the mean of the lowest end-tidal concentration before a positive response was obtained and the end-tidal concentration when a positive response was obtained.
Determination of MAC and MACawake (experiment 2)—Six dogs from each anesthetic group in experiment 1 were assigned to experiment 2; each of these dogs received the same regimen it had received in experiment 1. Experiment 2 was conducted in a quiet environment where individuals in the same room would talk softly, which resulted in a quiet (but not silent) room.
After induction of anesthesia as described previously, an indwelling 22-gauge, 1-inch polyurethane catheterc was inserted in a peripheral artery for continuous monitoring of arterial blood pressure. A mercury-calibrated pressure transducer connected to a multivariable monitorg was used for direct blood pressure measurement and was calibrated to 0 at the level of the base of the heart. Heart rate was obtained from the arterial pressure waveform. Oxygen flow rate was decreased to 2 L/min, and the vaporizer setting was adjusted to achieve an end-tidal concentration of 1.8 vol % for isoflurane and 3.4 vol % for sevoflurane. This concentration was maintained for at least 20 minutes.
A Carmalt surgical clamp was then placed on the tail and closed up to the first ratchet for 60 seconds or until gross purposeful movement of the head or limbs was detected. The clamp was placed 4 cm proximal to the tip of the tail and moved progressively cranial with each subsequent stimulation. When no response was detected, the end-tidal concentration was decreased by 10%, the dog was allowed to stabilize for 15 minutes, and the clamp was then reapplied. When a response was detected, the end-tidal concentration was increased by 10%, the dog was allowed to stabilize for 15 minutes, and the clamp was then reapplied. Before each clamp application, blood pressure, heart rate, respiratory rate, and end-tidal carbon dioxide concentration were recorded. When the end-tidal concentration was 25% less than the published MAC for an inhalation agent and clamping of the tail failed to elicit a response, the clamp was then applied to the middle phalanx of digit V of a hind limb until purposeful movement or a maximum application of 60 seconds was reached.13 The MAC was defined as the mean of the concentration that allowed purposeful movement and the concentration that prevented such movement. The MAC for each dog was determined in duplicate by increasing the end-tidal concentration to a concentration that prevented a response and then decreasing it, as described previously, until a response was elicited.
After MAC determination, the end-tidal concentration of the inhalant was decreased by 10% and each dog was allowed to stabilize for 15 minutes. Blood pressure, heart rate, respiratory rate, and end-tidal carbon dioxide concentration were recorded, and then the inhalant concentration was decreased by another 10%. This was continued until the dog lifted its head or chewed on the endotracheal tube and was declared awake by an observer who was not aware of the anesthetic administered to each dog during each anesthetic episode. The MACawake was then calculated as mean of the end-tidal concentration before a positive response was obtained and the end-tidal concentration when a positive response was obtained.
Statistical analysis—Normality was tested by use of the Kolmogorov-Smirnov test. Time of day each dog was anesthetized, induction time, duration of anesthesia, MACawake-noise-to-MAC ratio, and MACawake-to-MAC ratio were compared between groups by use of an unpaired 2-tailed t test. Quality of induction and body condition score were compared by use of the Mann-Whitney U test. For the 12 dogs used in both experiments, induction time and quality of induction were treated as replicate values. The relationship between MAC and arterial blood pressure was determined by use of linear regression. Significance was set at values of P < 0.05.
Results
The groups did not differ significantly with regard to mean ± SD body weight (isoflurane, 11.3 ± 0.8 kg; sevoflurane, 10.9 ± 0.6 kg) or body condition score (isoflurane, 4.8 ± 0.4; sevoflurane, 4.6 ± 0.5). Induction time was significantly (P < 0.001) longer for isoflurane-anesthetized dogs (212 ± 29 seconds), compared with results for sevoflurane-anesthetized dogs (154 ± 22 seconds; Table 1). Induction quality was significantly (P = 0.03) better for sevoflurane-anesthetized dogs (0.8 ± 1.0), compared with results for isoflurane-anesthetized dogs (1.4 ± 0.5). All dogs were successfully intubated on the first attempt.
Mean ± SD MACawake-to-MAC ratio was significantly (P = 0.003) higher for isoflurane (0.8 ± 0.1) than for sevoflurane (0.6 ± 0.1). The MACawake-noise was significantly higher than the MACawake for sevoflurane (2.0 ± 0.2 vol % and 1.3 ± 0.3 vol %, respectively [P = 0.004]), but not for isoflurane (1.1 ± 0.1 vol % and 1.0 ± 0.1 vol %, respectively [P = 0.078]). Blood pressure decreased significantly (P < 0.001) in a linear manner with increasing concentrations of isoflurane (SAP, r2 = 0.36; diastolic arterial pressure, r2 = 0.42; and mean arterial pressure, r2 = 0.40) and sevoflurane (SAP, r2 = 0.85; diastolic arterial pressure, r2 = 0.64; and mean arterial pressure, r2 = 0.74). None of the dogs in experiment 1 had an SAP < 95 mm Hg. In experiment 2, 2 dogs anesthetized with sevoflurane required application of the clamp to digit V to elicit movement in response to a supramaximal stimulus.
Mean ± SD values of anesthetic variables for 20 dogs anesthetized with isoflurane or sevoflurane for determination of MACawake-noise and 12 dogs anesthetized with isoflurane or sevoflurane for determination of MAC and MACawake.
Discussion
Analysis of the data for the study reported here supported the idea that the MACawake-to-MAC ratio is not the same for dogs as it is for humans. The MACawake-to-MAC ratio in humans is reportedly8,14,15 between 0.2 and 0.35 for isoflurane and 0.35 and 0.64 for sevoflurane. The MACawake-to-MAC ratio for isoflurane reported in humans is dramatically lower than for the dogs of our study. The MACawake-to-MAC ratio for sevoflurane reported in 1 study15 is similar to the value obtained in the study reported here, but most experiments in humans have revealed lower MACawake-to-MAC ratios for sevoflurane.8 Furthermore, a noise stimulus resulted in a significantly higher MACawake-to-MAC ratio in the dogs receiving sevoflurane in our study, compared with values when no noise stimulus was used.
The relationship between MAC and other measures of anesthetic potency (eg, MACBAR) differs among species. For example, the MACBAR-to-MAC ratio for isoflurane in humans is 1.85,16 but this same ratio in cats is 1.07.17 Sevoflurane-anesthetized rats have an MACBAR-to-MAC ratio of 1.1,18 whereas sevoflurane-anesthetized humans have an MACBAR-to-MAC ratio of 1.95.19 This establishes a precedent for the possibility that measurements of anesthetic potency vary among species.
The MACawake-to-MAC ratio is 0.65 in sevoflurane-anesthetized rats,18 which is similar to results for the dogs of our study. Horses anesthetized with isoflurane or halothane had head movement at MACawake-to-MAC ratios of 0.21 and 0.33, respectively.20 However, in that study, a fast alveolar washout technique was used, which can falsely lower the MACawake-to-MAC ratio in humans.15 It has been hypothesized that the concentration of isoflurane required to suppress conscious arousal in cats is not lower than the actual MAC in cats.17 On the basis of these findings and the data reported here, it is evident that the MACawake-to-MAC ratio differs among species.
The MAC values for isoflurane and sevoflurane obtained in the study reported here are similar to values for dogs in other reports.21,22 The decision to apply a clamp on a digit when application of a clamp to the tail failed to elicit a response was made on the basis of our preliminary experience wherein some sevoflurane-anesthetized dogs did not have a response to application of a clamp to the tail but did have a response to a clamp applied to a digit. In isoflurane- and halothane-anesthetized dogs, clamping of the tail did not alter the MAC values, compared with values for clamping of a paw,13 and the results obtained in the study reported here for isoflurane are nearly identical to those in other reports, which suggested that there was no systematic flaw in the experimental method for MAC determination. The reason that some sevoflurane-anesthetized dogs did not respond to tail clamping but did respond to toe clamping is not known.
In the sevoflurane-anesthetized dogs, a significantly lower MACawake was obtained, compared with the value for MACawake-noise, which suggested that the stimulus intensity was greater for the MACawake-noise groups, the definition of a positive response was too low for the MACawake-noise groups, or the definition of awareness was too conservative for the MACawake groups. The MACawake-noise was virtually identical to the MAC values obtained in these dogs. Experiments on MACawake in humans have involved the use of IPPV throughout recovery, with verbal stimuli given as often as every 20 seconds for 2 minutes.15 Sound intensity has not been reported in human MACawake studies, except to indicate that instructions were spoken in a normal tone of voice. Decibel measure is related to distance. A normal speaking voice at a distance of 1 m provides approximately 60 dB, and instructions spoken in a normal voice at a distance of 5 cm would be approximately 90 dB. The sound stimulus used in the investigation reported here was consistent with our typical clinical practice at the end of anesthesia, when some attempts (which include the use of auditory stimuli) to awaken dogs are made. It is possible that the noise generated was interpreted as a noxious stimulus by the dogs, thus resulting in a positive response similar to the tail-clamp MAC. An auditory stimulus at 75 dB induces rapid and marked increases in heart rate, blood pressure, blood flow to the adrenal glands, and stress hormone concentrations in dogs.23 However, it is unknown whether such noise can be compared with a supramaximal somatic stimulus, such as that used for MAC determination.
It is possible that the definition of a positive response to an auditory stimulus was too liberal. We attempted to duplicate studies in humans in which a positive response has been interpreted as the patient opening their eyes or squeezing a finger in response to a standard auditory command. In those experiments, a purposeful response is assumed to be related to consciousness.15 It was possible that the dogs of our study had a positive response (by our definition) to the auditory stimulus but were not yet conscious. Conversely, in the MACawake groups, it was possible that the dogs were conscious before they lifted their head and rejected the endotracheal tube, which would result in a falsely low MACawake value. The dogs may also have been stimulated to move by the stretch of the thoracic wall caused by IPPV. Regardless, the definition of a positive event in the study reported here included behaviors that would, in a clinical scenario, prompt an anesthetist to deepen the plane of anesthesia. In the case of consciousness during anesthesia and surgery, it is best to err on the side of loss of consciousness rather than to provide insufficient anesthesia, which would result in awareness during surgical procedures.
Induction times obtained in this study were less than half those obtained in another study2 in which dogs were induced with 0.5-MAC increments every 15 seconds to a maximum of 2.6 vol % isoflurane and 4.8 vol % sevoflurane. In that study, mean score for induction quality was 1.9 for isoflurane and 0.4 for sevoflurane, which does not differ substantially from the scores for induction quality reported in our study. This suggests that rapid induction via a face mask results in a shorter interval to intubation without a necessarily poorer quality of induction, although a side-by-side comparison would need to be performed to definitively determine this. Induction times for the dogs of our study were similar to those in a study4 in which a stepwise induction was used after IV administration of preanesthetic medication with midazolam (0.1 mg/kg) and butorphanol (0.2 mg/kg). Given that preanesthetic medications reduced the interval until intubation with a stepwise induction, preanesthetic medication may cause a similar effect with a rapid induction, although additional studies must be performed to confirm this hypothesis. Induction time for sevoflurane was significantly less than that for isoflurane, which is consistent with the lower blood-gas solubility for sevoflurane. Quality of induction was also better for sevoflurane, compared with quality of induction for isoflurane, which may have been attributable to more rapid loss of consciousness or more aversion to isoflurane because of its irritation to airways.24 Blood pressure decreased with increasing doses of both anesthetic agents, which was expected.1
The definition of a positive response to auditory stimulus in experiment 1 encompassed a broad range of responses that may have reflected various levels of conscious response. In human studies,7–10,14,15 a positive response is opening of an eye or squeezing of a hand in response to a command. It is unclear what value is recorded when a patient awakens rapidly or violently, exceeding the response of simply opening an eye. The intent of the study reported here was to capture the point at which there was a return to consciousness. In some patients, the first response that indicated consciousness involved a dog lifting its head, chewing on the endotracheal tube, and almost jumping off the table, without any antecedent behaviors. Because some of those dogs had been stimulated within the preceding 3 minutes without a mild positive response (ie, opening of the eyes), it was assumed that those dogs were most likely unconscious at the time of the preceding stimulus and had crossed the threshold into consciousness during the subsequent 3-mintue period to display these pronounced behaviors. It is unknown whether a milder response would have been evoked with more regular application of stimulation (eg, every 30 seconds). Given the narrow SDs for MACawake values detected in this study, the chosen definition of a positive response was appropriate to evaluate the return to consciousness. The difference between dogs that manifested this return as opening of the eyes and slowly regaining consciousness and those that manifested the return as excitatory behavior did not introduce substantial variability into our data.
Instead of the use of published MAC-multiples of the inhalant for rapid induction, we used the highest setting available on the vaporizer. Clinically, this is the technique we use to perform rapid induction via a face mask, and we believed it mimics the use of rapid induction performed by most general practitioners. On the basis of the MAC values obtained in this study, induction concentrations as a proportion of the agent MAC were equivalent (ie, 8 vol %/2.1 vol % = 3.8 for sevoflurane and 5 vol %/1.3 vol % = 3.8 for isoflurane). The initial target end-tidal concentrations for experiment 1 were chosen on the assumption that the MACawake-noise value would be substantially less than the published MAC value and that decreasing the concentration from these values would provide initial general anesthesia and a clear distinction between conscious and unconscious. The initial target end-tidal concentrations for experiment 2 represented 1.4 times the published MAC value, which was established to ensure adequacy of anesthesia for the initial tail-clamping procedure.
Clinicians should exercise caution when anesthetic techniques involving neuromuscular blockade are used. The additional muscle relaxation obtained as a result of neuromuscular blockade will not allow substantial decreases in inhalant anesthetic concentrations in dogs while still ensuring loss of consciousness. It is imperative that agents that may help to prevent consciousness, such as benzodiazepines, as well as analgesic agents are provided in protocols that include the use of neuromuscular blocking agents.
In the study reported here, the MACawake-to-MAC ratio for dogs anesthetized by administration of isoflurane or sevoflurane was significantly higher than the published ratio for humans anesthetized by use of the same conditions. Rapid induction via a face mask resulted in a smooth induction and short interval to intubation, with sevoflurane resulting in a shorter interval to intubation than was determined for isoflurane. Future investigations need to focus on validating that the techniques reported here are reliable and appropriate methods for use in determining consciousness in dogs. Additional studies should compare rapid induction versus stepwise induction; EEG changes to MACawake values; and effects of preanesthetic medications on the quality of induction, interval to induction, or the MACawake value.
ABBREVIATIONS
MAC | Minimum alveolar concentration |
MACBAR | Minimum alveolar concentration at which sympathetic responses to painful stimuli are abolished |
MACawake | Minimum alveolar concentration at which consciousness is regained |
MACawake-noise | Minimum alveolar concentration at which conscious response to a standard auditory stimulus is abolished |
IPPV | Intermittent positive-pressure ventilation |
SAP | Systolic arterial pressure |
vol % | Volume percent |
Penlon, Abingdon, England.
POET IQ, Criticare Systems Inc, Waukesha, Wis.
Terumo, Somerset, NJ.
Hospira Inc, North Chicago, Ill.
Bair Hugger, Arizant Healthcare Inc, Eden Prairie, Minn.
Model 811-B, Parks Medical Electronics Inc, Aloha, Ore.
Surgivet Advisor, Surgivet, Waukesha, Wis.
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