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A systematic review of sevoflurane and isoflurane minimum alveolar concentration in domestic cats
Veterinary Anaesthesia and Analgesia, 2014, 41, 1–13
doi:10.1111/vaa.12083
REVIEW ARTICLE
A systematic review of sevoflurane and isoflurane minimum alveolar concentration in domestic cats Mike R Shaughnessy* & Erik H Hofmeister† *Veterinary Teaching Hospital, College of Veterinary Medicine, University of Georgia, Athens, GA, USA †Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
Correspondence: Erik Hofmeister, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens 30602, GA, USA. E-mail: [email protected]
Abstract Objective The purpose of this systematic review is to summarize the results of studies which have determined the minimum alveolar concentration (MAC) of isoflurane and sevoflurane in domestic cats. Study Design Systematic review. Animals Cats. Methods used A comprehensive search of research literature was performed without language restriction. The search utilized the Pubmed, Google Scholar, and CAB Abstracts electronic databases using a combination of free text terms ‘Minimum alveolar concentration’, ‘sevoflurane’, ‘isoflurane’, ‘anesthetic’, ‘cat’, ‘cats’ or ‘feline’. The search was conducted from November 2010 to June 2012. Results The MAC for isoflurane ranged from 1.20 0.13% to 2.22 0.35% and the MAC for sevoflurane ranged from 2.5 0.2% to 3.95 0.33%. The average MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Conclusions & Clinical Relevance The average MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Methodology differed among studies, and particular attention should be paid in the future to appropriate
reporting of methods to allow sound conclusions to be made from the results. Keywords cats, isoflurane, minimum concentration, sevoflurane, stimulation.
alveolar
Introduction The classical definition of minimum alveolar concentration (MAC) is a measurement of the concentration of inhaled anesthetic needed to prevent purposeful movement in 50% of subjects exposed to a supra maximal noxious stimulus (Quasha et al. 1980). It is the most common method used to estimate the potency of an inhaled anesthetic, but heterogeneity in research methodology can result in widely disparate values. Multiple studies have been published in an effort to define the MAC, but results among publications vary greatly. The wide variability in the findings may be due to several factors, including different methodology, poor methodology, or the many physiologic or pathologic factors that can affect the MAC value. Choice of end-point [purposeful movement or no movement (Seddighi et al. 2011)] is a major difference within methodology. Variables such as age, species, pregnancy, hypothermia, hyperthermia, genetic sensitivity, type and site of stimulus, and disease alter the results (Quasha et al. 1980; Thurmon et al. 1996). Methodology which does not include blinding or randomization may lead to erroneous results due to flaws with internal validity (i.e. bias; Macleod et al. 2004, 2008; Sargeant et al. 2010). 1
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
Clinically, knowledge of the appropriate MAC value should help the anesthetist to titrate anesthesia to a level suitable to accomplish the procedure being undertaken without overdosing the patient. In a research setting, MAC values are often used as a basis for future research, and precise estimates therefore are needed. The purpose of this systematic review is to summarize the results of studies, which have estimated the MAC of isoflurane and sevoflurane in domestic cats. Materials and methods Search strategy A comprehensive search of research literature was performed without language restriction. The search utilized the PubMed, Google Scholar, and CAB Abstracts electronic databases using a combination of free text terms ‘minimum alveolar concentration’, ‘sevoflurane’, ‘isoflurane’, ‘anesthetic’, ‘cat’,’cats’, or ‘feline’. The search was conducted from November 2010 to June 2012. Inclusion and exclusion criteria Any published research paper that utilized isoflurane or sevoflurane for MAC determination directly or indirectly in domestic cats was evaluated. Studies were excluded if they did not determine MAC, but instead use previously published values, or if they did not acquire a baseline MAC before applying an intervention or drug. Validity scoring A modification of a system used in a meta-analysis of experimental studies was used (Macleod et al. 2004). The studies were scored using eleven binary criteria: were subjects randomly allocated to treatment groups, were observers blinded to treatment group, was the MAC determination confirmed in triplicate, and was age, weight, temperature control, type of ventilation, type of breathing circuit, gas analyzer calibration, and equilibration time detailed in the study. Each study was given one point for each criterion that was met. The minimum score was 0, the maximum 11. Two authors scored the studies independently and any discrepancies in results were resolved with discussion.
2
Data extraction A baseline MAC for isoflurane and/or sevoflurane was extracted from the studies. The number of subjects, age, sex, body temperature, type of breathing circuit, equilibration time, calibration method, inhalant concentration measurement technology, MAC determination protocol, and method of ventilation was also collected, along with the type and location of noxious stimulus. The average MAC value was calculated as the weighted mean, using the sample size for weight. Only the MAC values from studies which used a peripheral somatic stimulus (i.e. tail clamp or electrical stimulation) were included in the overall MAC calculation. The mean MAC value and standard deviation were compared between those studies in which a single or triplicate MAC determination had been performed using an unpaired 2-way t-test. The mean MAC value was also compared between those studies in which spontaneous or controlled ventilation was used and between those studies in which a rebreathing or non-rebreathing circuit was used with an unpaired 2-way t-test. The relationship between year of publication of each study and study quality score was assessed using linear regression. Significance was set at a < 0.05. Results Systematic search Thirty-four potentially relevant studies met the inclusion criteria (Tables 1 & 2). Twelve studies were excluded because the cats were pre-medicated before a baseline MAC was found or the baseline MAC used in the paper was taken from a previously published study (Hikasa et al. 1996, 1997; Pascoe et al. 1997; Pypendop et al. 2003; Pypendop & Ilkiw 2004; Thomasy et al. 2005; Pypendop et al. 2006; Ko et al. 2008; Staffieri et al. 2010; Pypendop et al. 2011; Zwijnenberg et al. 2011; Escobar et al. 2012). All studies were written in English and published from 1977 to 2011. The average quality score was 6.8, with a range of 4–9. There was a significant positive relationship between year of publication and quality score (p < 0.001, R2 = 0.47). When only those studies published after 1990 were considered, there was no significant relationship (p = 0.46) and the average quality score was 7.3.
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Imai et al. (2002)
1.93 0.17
1.25 0.18
1.24 0.17
1.27 0.13
1.20 0.13
1.54 0.19
1.54 0.12
12
6
1.60 0.1
1.58 0.07
6
1.28 0.13
Ilkiw et al. (2002)
Tetanus
2–3
8M/4F
F/S
1.8 0.5 4.9 2.2
F/S
3.4 0.1
3.8–8.8
4.1 0.4
3 0.6
4.5 0.8
No
Yes
Yes
N/D
Circle
Circle
Tail Clamp
Tail Clamp
Tail Clamp
stimulus
Toe Pinch
Occlusion
Airway
Tail Clamp
Electrical
Tail Clamp
Tail Clamp
Tail Clamp
Tail Clamp
2.22 0.35
Non-Reb
Non-Reb
Circle
Circle
Non-Reb
N/D
Non-Reb
Bain
Method
Electrical
No
No
Yes
Yes
No
Yes
Yes
N/D
Circuit
Occlusion
3.5 0.1
4.2 0.66
4.7 0.8
3.9 0.5
4.3 1.2
2.9 0.7
4.2 0.2
3.5 0.3
IPPV
Airway
28M/6F
20M/4F
FS
2MN/4F
F
Mix
FS
F
(kg)
1.65 0.45
Adult
Adult
4
3–7
1.5
Adult
1.5
1.8–2.3
Sex
Weight
Airway
24
24
5
6
6
8
6
6
(Years)
Age
Pinch
1.5 0.38
1.7 0.2
1.7 0.3
1.6 0.2
1.65 0.14
1.66 0.08
2.07 0.10
1.61 0.04
1.94 0.08
1.9 0.18
Ilkiw et al. (1997)
Ide et al. (1998)
Ide et al. (2001)
et al. (1998)
Golder
et al. (2009)
Ferreira
et al. (2012)
Escobar
et al. (1983)
Drummond
et al. (2009)
Brosnan
(2004)
Barter et al.
Cats
Name
Iso MAC
No. of
Study
Table 1 Characteristics of publications of minimum alveolar concentrations (MAC) of isoflurane in cats
Tail
Tail
Tail
Left TL
Lungs
N/D
Lungs
Tail
TL
Tail
Tail
Tail
Tail
area
Stimulus
N/D
20 minute
N/D
20 minute
minute
1 hour/20
20 minute
15 minute
20 minute
15 minute
minute
1 hour/20
N/D
Time
Equilibrium
38.5
38
38
37–38
37–38
37.9–39
37.5–38.5
N/D
37.5
Normothermia
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Triple
Triple
Triple
Double
Double
Triple
Double
Triple
Double
difference
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
6
9
8
7
6
9
8
7
5
8
7
Score
Quality
(continued)
until <15%
Multiple
Triple
Method
38–39
Determination Calibration
°C
MAC Temperature
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
3
4
1.54 0.15
1.51 0.21 7
5
6 10
2.1 0.13
6
6
17
8
1.63 0.02
2.21 0.17
1.51 0.23
visceral
1.82 0.1
tail
1.87 0.14
1.8 0.2
1–1.5
2.9 0.3
Mix
1–2
1–2
Adult
N/D
3.2
(Years)
Age
4M/3F
F/S
Mix
N/D
N/D
F/S
F/S
4M/4F
Sex
2.8–4.6
4.3 0.7
3.5 0.4
4.8 0.6
5.1 0.4
5.1 0.9
N/D
4.1
(kg)
Weight
Yes
Yes
No
No
No
Yes
Yes
N/D
IPPV
Circle
Circle
Circle
Bain
Bain
Circle
Circle
Circle
Circuit
Electrical
Tail Clamp
N/D
Tail Clamp
Tail Clamp
Tail Clamp
Visceral
Electrical/
Tail Clamp
Method
Mucosa
Buccal
N/D
Tail
Tail
Tail
Tail
Bladder
Tail/
Tail
area
Stimulus
15 minute
N/D
N/D
15 minute
15 minute
N/D
15 minute
20 minute
Time
Equilibrium
37.5–38.5
38
38
38.5–39.5
38.5–39.5
38
36.6–38.3
No
Yes
No
Yes
Yes
Yes
No
Yes
Double
Triple
N/D
Triple
Triple
Triple
Double
Double
Method
N/D
Determination Calibration
°C
MAC Temperature
7
7
4
8
8
7
5
7
Score
Quality
IPPV: intermittent positive pressure ventilation used during MAC determination; Nonreb: non-rebreathing circuit used during MAC determination; TL: thoracic limb. Values are given as mean SD. Calibration was a method for calibrating the inhalant agent analyzer described. Quality score is out of a possible 11. N/D: Not determinable from the information in the paper.
et al. (2010)
Zwijnenberg
et al. (2004)
Yackey
Howland (1977)
Steffey &
Reid et al. (2010)
Ilkiw (2005)
Pypendop &
et al. (2007)
Pascoe
Muir (2003)
March &
et al. (2005)
Lamont
Cats
Name
Iso MAC
No. of
Study
Table 1 (continued)
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
8
8
24
2.58 0.3
3.18 0.06
3.07 0.76 Pinch 3.38 0.66 Airway 3.95 0.33 Tetanus 3.3 0.2
8
6
3.41 0.65
Sevo MAC
No of Cats
3.2
Adult
1–2
Adult
1.8–2.3
Age (Years)
4M/4F
28M/6F
4MN/4FS
6M/2F
F
Sex
4.1
3.5 0.1
5.82 0.42
3.4 0.8
3.5 0.3
Weight (kg)
Yes
No
Yes
Yes
N/D
IPPV
Circle
Non-reb
Non-reb
N/D
Bain
Circuit
Toe Pinch Electrical stimulus Airway Occlusion Tail Clamp
Tail Clamp
Tail Clamp
Tail Clamp
Method
Tail
N/A Left TL Lungs
Tail
Tail
Tail
Stimulus area
15 minute
2 minute
15 minute
15 minute
N/D
Equilibrium time
N/D
37–38
37–38.5
38
38–39
Temperature °C
No
No
Yes
No
Yes
Calibration
Double
Double
Triple
Double
Triple
MAC Determination method
6
7
9
4
7
Quality score
IPPV: intermittent positive pressure ventilation used during MAC determination; Nonreb: non-rebreathing circuit used during MAC determination; TL: thoracic limb. Values are given as mean SD. Calibration was a method for calibrating the inhalant agent analyzer described. Quality score is out of a possible 11.
Lamont et al. (2004)
Barter et al. (2004) Doi et al. (1988) Ferreira et al. (2011) Ide et al. (1998)
Study Name
Table 2 Characteristics of publications of minimum alveolar concentrations (MAC) of sevoflurane in cats
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
5
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
Baseline MAC MAC for isoflurane was found in seventeen studies (Steffey & Howland 1977; Drummond et al. 1983; Ilkiw et al. 1997; Golder et al. 1998; Ide et al. 2001; Ilkiw et al. 2002; Imai et al. 2002; March & Muir 2003; Yackey et al. 2004; Pypendop & Ilkiw 2005; Lamont et al. 2005; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012), the MAC for sevoflurane in three (Doi et al. 1988; Lamont et al. 2004; Ferreira et al. 2011), and findings for both anesthetic inhalants were recorded in two of the studies (Ide et al. 1998; Barter et al. 2004). The MAC for isoflurane ranged from 1.2% to 2.22% and the MAC for sevoflurane ranged from 2.5% to 3.95%. The average weighted MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Type and location of stimulus In 16 studies, a tail clamping technique was used as the noxious stimulus to determine the MAC (Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Imai et al. 2002; Barter et al. 2004; Lamont et al. 2004, 2005; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Brosnan et al. 2009; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). MAC for isoflurane with this method ranged from 1.2 0.13% to 2.21 0.17% and MAC for sevoflurane ranged from 2.5 0.20% to 3.41 0.65%. In four studies, an electrical stimulus was used: in two, a thoracic limb was used; in one, the tail was used; and, in the fourth, the electrodes were applied to the buccal mucosa. In the first study, when a thoracic limb electrical stimulus was used, the stimulus was applied for a full 10 seconds at 50 mA (Ide et al. 1998). In the second study using the thoracic limb electrical stimulus, the stimulus was applied by four stimuli at 5 second intervals; two single stimuli followed by two stimuli that were continuously applied for 3 seconds (Ferreira et al. 2009). The current applied was not reported in that study. In the third study, an electrical stimulus at a current of 25 mA was applied for 10 seconds on the cat’s tail (March & Muir 2003) and, in the fourth study, electrodes were attached to the buccal mucosa of each cat and delivered a stimulus for a 10 millisecond duration over one minute (Zwijnenberg 6
et al. 2010). The current applied was not reported in that study. In one study, MAC was determined by visceral stimulation by injecting the bladder with liquid (March & Muir 2003). Warmed (42 °C) saline (0.9% NaCl) solution was infused into the bladder at a rate of 10 mL m 2 body surface area per minute (approximately 2–2.5 mL minute 1) for stimulation. Five out of 17 cats were omitted from the study due to the inability of the researchers to place a urinary catheter in the cats. In two studies, airway occlusion was used as the noxious stimulus (Ide et al. 1998, 2001). This was achieved by occluding the airway by closing a 6 mm three way stopcock that was connected to the nonrebreathing circuit and the endotracheal tube. The subject was monitored for positive movement or apnea for up to 6 minutes after the occlusion. The results were 1.6 0.2%, 1.7 0.3%, and 1.7 0.2% for the three groups of cats used in one study (Ide et al. 2001) and 1.65% in the other study (Ide et al. 1998). In one study, visceral and somatic stimulation were compared for isoflurane (March & Muir 2003). The results were similar with a MAC of 1.87 0.14% for somatic stimulation induced with an electrical stimulus on the tail and 1.82 0.10% for visceral stimulation induced with fluid injected into the bladder. In another study, three different types of somatic stimulation were compared for the effect on the MAC of isoflurane and sevoflurane (Ide et al. 1998). A toe pinch, electrical current applied to the thoracic limb, and airway occlusion were used for stimulation. The results were 1.5 0.38%, 2.22 0.35%, and 1.65 0.45% for isoflurane and 3.07 0.76%, 3.95 0.33%, and 3.38 0.66% for sevoflurane, respectively. One study did not describe the type of stimulus used (Steffey & Howland 1977). Temperature The temperature for eighteen of the studies was kept between 37 and 39.5 °C (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998, 2001; Imai et al. 2002; March & Muir 2003; Barter et al. 2004; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010). The other four studies did not report a numeric body temperature
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister (Lamont et al. 2004, 2005; Brosnan et al. 2009; Escobar et al. 2012). Breathing systems In 13 of the studies, intermittent positive-pressure ventilation was used (Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Lamont et al. 2004; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Zwijnenberg et al. 2010), in seven, subjects were allowed to breathe spontaneously (Steffey & Howland 1977; Ide et al. 1998, 2001; Imai et al. 2002; Pypendop & Ilkiw 2005; Reid et al. 2010; Escobar et al. 2012), and the method of ventilation was not reported in two (Barter et al. 2004; Lamont et al. 2005). Isoflurane MAC ranged from 1.2 0.13% to 1.87 0.14% with controlled ventilation (Ilkiw et al. 1997, 2002; March & Muir 2003; Yackey et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009) and ranged from 1.5 0.38% to 2.22 0.35% with spontaneous ventilation (Steffey & Howland 1977; Ide et al. 1998, 2001; Imai et al. 2002; Reid et al. 2010; Escobar et al. 2012). The sevoflurane MAC with controlled ventilation had a range of 2.58 0.30% to 3.3 0.20% (Doi et al. 1988; Lamont et al. 2004), and this was lower than the range with spontaneous ventilation of 3.07 0.76% to 3.95 0.33% (Ide et al. 1998). Studies which reported using spontaneous ventilation reported a significantly higher isoflurane MAC value compared with studies which reported using controlled ventilation (1.86% versus 1.63%, p < 0.05). In 11 of the studies, a circle system was used (Steffey & Howland 1977; Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Lamont et al. 2004, 2005; Yackey et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009; Zwijnenberg et al. 2010), in eight a non-rebreathing, Mapleson F circuit, or Bain circuit was used (Ide et al. 1998, 2001; Barter et al. 2004; Pypendop & Ilkiw 2005; Brosnan et al. 2009; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012), and, in three studies, the type of breathing system used was not reported (Drummond et al. 1983; Doi et al. 1988; Imai et al. 2002). Studies which reported using a nonrebreathing system reported a significantly higher isoflurane MAC value compared with studies which reported using a rebreathing system (1.9% versus 1.61%, p < 0.02).
In 17 studies, a catheter was placed within the lumen of the orotracheal tube and infrared absorption (Steffey & Howland 1977; Drummond et al. 1983; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998; March & Muir 2003; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Zwijnenberg et al. 2010), Raman spectrometry (Barter et al. 2004; Pypendop & Ilkiw 2005; Reid et al. 2010), or gas chromatography (Doi et al. 1988) was used to measure inhalant concentrations. In two studies, a side stream system and infrared absorption (Lamont et al. 2005) or atomic absorption spectroscopy (Ide et al. 2001) was used to measure inhalant concentrations. Three studies did not report what type of equipment was used to measure inhalant concentrations (Imai et al. 2002; Lamont et al. 2004; Escobar et al. 2012). A fresh gas flow of 2 L minute 1 was used in four of the studies (Ilkiw et al. 2002; Yackey et al. 2004; Reid et al. 2010; Ferreira et al. 2011). A rate of 1 L minute 1 was used in two studies (Lamont et al. 2005; Brosnan et al. 2009), and a rate of 500 mL kg minute 1 was used in two (Barter et al. 2004; Pypendop & Ilkiw 2005). A rate of 200 mL kg minute 1 was used in one (Escobar et al. 2012). A rate of 4–5 L minute 1 was used in two (Ide et al. 1998, 2001), while the remaining eleven did not describe the fresh gas flow rate (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997; Golder et al. 1998; Imai et al. 2002; March & Muir 2003; Lamont et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009; Zwijnenberg et al. 2010). Age In 15 studies, adult cats ranging from one to 7 years old with a mean age of 2.6 years were used (Golder et al. 1998; Ilkiw et al. 1997, 2002; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Lamont et al. 2004; Pypendop & Ilkiw 2005; Lamont et al. 2005; Brosnan et al. 2009; Ferreira et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). Of the seven remaining studies, six studies did not document a numeric age, only describing the age of the cats using the words ‘Adult’ or ‘Mixed’ (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; Pascoe et al. 2007), and one did not report the age of the cats (March & Muir 2003). Differences between MAC values were
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
7
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
attributed to age in one study (Ilkiw et al. 2002). Two different age groups of cats were tested. The group ages averaged 1.75 and 4.92 years the MAC of isoflurane averaged 1.56 0.12% and 1.24 0.15%, respectively. This difference was not evaluated statistically. In five other studies, young cats between the ages of 1–2 years old were used (Pypendop & Ilkiw 2005; Brosnan et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012) and isoflurane MAC results trended towards the higher end of the range, 2.21 0.17%, 1.94 0.08%, 2.1 0.13%, 1.54 0.15% and 2.07 0.10% respectively. In only one sevoflurane study were cats between the ages of 1–2 years used (Ferreira et al. 2011). That study reported a high sevoflurane MAC of 3.18 0.06%. Sex In nine studies, strictly female cats were used (Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Barter et al. 2004; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Escobar et al. 2012). In three studies, an equal ratio of male and female cats were used (Lamont et al. 2004, 2005; Ferreira et al. 2011). In five studies, more males than females were used. In the first study, six males and two females were used (Doi et al. 1988), in the second study, 28 males and six females were used (Ide et al. 1998), in the third study, 20 males and four females were used (Ide et al. 2001), in the fourth study, eight males and four females were used (Imai et al. 2002), and in the fifth study, four males and three females were used (Zwijnenberg et al. 2010). In one study, more females than males were used, with four females and two males (Ferreira et al. 2009). Two studies reported using a “mix” of female and male cats (Steffey & Howland 1977; Drummond et al. 1983), and two studies did not report the sex of the cats used (Pypendop & Ilkiw 2005; Reid et al. 2010). The effect of sex on the MAC of isoflurane was explored in one study, which documented an isoflurane MAC of 2.06 0.08% for four females and 1.86 0.22% for eight males, which did not appear to be different (Imai et al. 2002). Weight The weight of the cats in 21 of the included studies ranged from 3 to 8.8 kg with a mean 8
weight of 4.2 kg (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998, 2001; Imai et al. 2002; Barter et al. 2004; Lamont et al. 2004, 2005; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012). In one study, a weight for the cats used was not reported (March & Muir 2003). Calibration In five studies, calibration of the analyzers was done with gases containing known concentrations of isoflurane at 0.5, 1.5, and 2.5% (Ilkiw et al. 1997, 2002; Golder et al. 1998; Yackey et al. 2004; Pascoe et al. 2007). This calibration was done prior, midway, and at the completion of each trial. In two studies, calibration was done every 80 minutes with gases containing known concentrations of isoflurane at 0.5, 1.5, and 2.5% (Pypendop & Ilkiw 2005; Reid et al. 2010). In one study, a calibration reference provide by the manufacturer of the analyzer was used (Ferreira et al. 2009). In two studies, calculated calibration curves were used to mathematically correct collected samples (Barter et al. 2004; Brosnan et al. 2009). In one study, calibration of the gas analyzer was done with gases containing known concentrations of sevoflurane at 1.5, 2.5, and 3.8% (Ferreira et al. 2011). In one study, the gas analyzer was calibrated, but no mention the calibration method was made (Lamont et al. 2005). No gas analyzer calibration was described in ten studies (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; Imai et al. 2002; March & Muir 2003; Lamont et al. 2004; Zwijnenberg et al. 2010; Escobar et al. 2012).
Defining individual MAC In nine studies, individual MAC was determined with a duplicate response to noxious stimulus (Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; March & Muir 2003; Ferreira et al. 2009; Zwijnenberg et al. 2010; Lamont et al. 2004, 2005). In 11 studies, individual MAC was determined in triplicate (Ilkiw et al. 1997, 2002; Golder et al. 1998; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister et al. 2007; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). In one study, individual MAC was determined until there was less than a 15% difference between two measurements that permitted and prevented movement (Brosnan et al. 2009). In one study, the MAC calculation was not specified (Steffey & Howland 1977). There was no significant difference in mean MAC or standard deviation between those studies using duplicate or triplicate determination. Equilibrium time In nine studies, there was a 15 minutes equilibration time (Drummond et al. 1983; Doi et al. 1988; March & Muir 2003; Lamont et al. 2004; Pypendop & Ilkiw 2005; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010). In these studies, the MAC for isoflurane ranged from 1.54 0.15% to 2.12 0.17 and the sevoflurane ranged from 2.58 0.3% to 3.3 0.2%. In five studies, the inhalant was equilibrated for 20 minutes (Golder et al. 1998; Ide et al. 1998; Ilkiw et al. 2002; Lamont et al. 2005; Escobar et al. 2012). The isoflurane MAC ranged from 1.20 0.13% to 2.07 0.10% in those studies. In two isoflurane studies, the inhalant was equilibrated for one hour before the initial stimulus test and then an interval of 20 minutes was used (Ide et al. 2001; Brosnan et al. 2009). The isoflurane MAC for those two studies was 1.6 0.2% and 1.94 0.08. The remaining six studies did not report an equilibration time (Steffey & Howland 1977; Ilkiw et al. 1997; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Pascoe et al. 2007). Barometric pressure Only two studies provided an altitude (Ide et al. 1998; Ferreira et al. 2009). The barometric pressure for the other studies was determined by researching the elevation of the institution where the study was conducted. One study was conducted at the University of S~ ao Paulo State, which has an elevation of 2600 ft. (800 m) above sea level (Ferreira et al. 2009). This was the highest elevation of the studies collected for isoflurane. The study reported a MAC of 1.7 0.1% for isoflurane. The highest elevation for the sevoflurane studies was conducted at Fort Collins Colorado, which has an elevation of 5003 ft. (1525 m) above sea level (Ferreira et al. 2011). The study reported a MAC of 3.18 0.06% for
sevoflurane. Both the isoflurane and the sevoflurane results are within the middle range of MAC values. The highest MAC concentration for both inhalant anesthetics was determined at Chiba University School of Medicine in Chiba, Japan (Ide et al. 1998), which is 72 ft. (22 m) above sea level. The lowest MAC concentration for isoflurane was reported in a study performed at the University of California, Davis (Ilkiw et al. 2002). The lowest MAC concentration for sevoflurane was found in a study authored at the Hamamatsu University School of Medicine in Shizuoka, Japan (Doi et al. 1988). Both Universities are located <150 ft. (46 m) above sea level. Discussion There is a relatively high degree of variability in the published MAC values for cats. In clinical trials in human medicine, when a high degree of variability or ambiguity exists, systematic reviews can help summarize results from past studies to arrive at a consensus. A single large study examining the MAC value of a multitude of cats under a variety of different conditions would be ideal to definitively determine the MAC of isoflurane and sevoflurane in the feline population. Until such a study can be undertaken, this systematic review can serve as a starting point for defining MAC in cats for future research and clinical applications. The highest baseline MAC for both anesthetics was found in one study where electrical stimulation was applied to the thoracic limb (Ide et al. 1998). The MAC was 2.22 0.35% for isoflurane and 3.95 0.33% for sevoflurane. However, in another study, electrical stimulation of the thoracic limb was used and the MAC for isoflurane was 1.66 0.08% (Ferreira et al. 2009). One reason for this difference may be that, in the study with the higher MAC value, electromyography (EMG) was used for monitoring movement. The highly sensitive EMG will pick up signs of motor response before the patient is able to progress to gross movement (Disselhorst-Klug et al. 2009). Therefore, it should take a higher concentration of anesthetic to abolish this minute response compared to the concentration of anesthetic required to stop movement detectable with a visual inspection. In all the other studies, including the other study in which electrical stimulation of the thoracic limb was used, movement in their subjects was determined by direct visual observation when determining the MAC.
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
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Cat MAC systematic review MR Shaughnessy and EH Hofmeister
In a third study, electrical stimulation was used and yielded an isoflurane MAC of 1.87 0.14% (March & Muir 2003). The tail was used instead of the thoracic limb in this study and the electrical device was set at 25 mA instead of 50 mA as in the study with the highest MAC value. Controlled ventilation was also used in this study. The fourth study in which electrical stimulation was used had an isoflurane MAC of 1.54 0.15% (Zwijnenberg et al. 2010). In this study, electrical probes were attached to the buccal mucosa and the subjects were mechanically ventilated. The lower current, different location, and type of ventilation could have contributed to the difference (Levionnois et al. 2009). A difference in MAC was also attributed to the type of ventilation used. The MAC for isoflurane was lower in the studies when controlled ventilation was used. Controlled ventilation may improve inhalant uptake relative to spontaneous ventilation (Vesely et al. 2003). It is also probable that controlled ventilation allowed for more accurate airway inhalant concentration sampling. The most common method of stimulation was the tail clamp technique. In two studies. Multiple types of stimulation and its effect on the MAC were evaluated (Ide et al. 1998; March & Muir 2003). In one study, visceral and somatic stimulation were compared and a similar MAC value was reported for both (March & Muir 2003). This suggests that visceral stimulation is comparable to somatic stimulation, and either may be acceptable for MAC determination in cats. Conversely, in dogs, an ovarian ligament visceral stimulus produces a higher MAC value than somatic stimulation (Boscan et al. 2011). Furthermore, in a second study, three different types of somatic stimulation and its effect on the MAC of isoflurane and sevoflurane were compared (Ide et al. 1998) and found that not all somatic stimulation is equivalent and that varying types of stimulation require different inhalant concentrations to achieve a similar anesthetic effect. Some of these stimuli may not be supramaximal stimuli, and so not fulfill the definitional criteria for MAC value. A study done in people which defined isoflurane’s anesthetic potency with different types of stimulus came to an equivalent conclusion (Zbinden et al. 1994). In that study, vocal commands, trapezius squeeze, electrical tetanic stimulation of the muscles of the thoracic limb, skin incision, laryngoscopy, and tracheal intubation were used for stimulation. The results of the study revealed 10
each type of stimuli, most of which were not supramaximal, required a different isoflurane concentration to abolish motor response. A study in which the MAC of isoflurane was determined using multiple types and sites of noxious stimuli in dogs and rabbits reported that different types of stimulus require different inhalant concentrations and that dogs and rabbits do not respond to stimulus the same (Valverde et al. 2003). Electrical, clamping, and surgical incision stimuli in multiple places on both species of animals were used in that study. It was found that not only does each type of stimulus produce a different MAC value, but that rabbits needed a higher concentration of isoflurane to prevent motion in response to a clamping stimulus as compared to an electrical stimulus. The reverse was found with dogs. Both species had the lowest MAC of isoflurane during surgical incision stimulation. One study determined that the sex of the subject does not have a statistically significant effect on the isoflurane MAC-sparing effect of N2O (Imai et al. 2002). The effect sex had on the MAC results of the remaining studies was impossible to compare because the sexes were mixed within the groups or because a breakdown of the relationship of MAC and sex in the study was not available. Eight studies used only female cats but there was not a study that used male cats exclusively for comparison. Therefore, the effect of gender on MAC values is still unknown. The equilibration time did not seem to have an effect on the MAC of isoflurane. The MAC of isoflurane was almost identical at the interval of 15 minutes and at an interval of 30 minutes. The MAC for sevoflurane at 30 minute intervals was slightly higher than the intervals at 15 minutes. The estimated equilibration time for isoflurane and sevoflurane are 11.8 and 14.4 minutes, respectively (Katoh et al. 1993), so no difference would be expected between a 15 minute equilibration and a 30 minute equilibration. There was no consensus on how calibration of the gas analyzer was conducted, but many studies failed to report their method of calibration, if any. This again illustrates the need for appropriate reporting of methods in MAC studies. In half of the studies, MAC was determined in triplicate. There is no evidence in the literature to support the use of one method over the other. The similarity in standard deviation found between double and triple measurements implies that a double measurement may be sufficient. However,
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister numerous other variables may contribute to variability, so this conclusion must be viewed with caution. In general, a greater number of repeat measurements will produce a smaller standard deviation, which would be advantageous when comparing MAC value changes in response to different interventions. This review showed that age may have an effect on MAC value in cats. Studies using younger cats tended to produce higher MAC values. This was not subject to statistical comparison within the studies, and insufficient detail was presented in the studies to analyze the effect of age on MAC in a systematic fashion in this review. Age does have an effect on the MAC in people (Mapleson 1996). A review of studies done on human patients of various ages showed a 6% decrease in MAC per decade for various inhalant anesthetics (Eger 2001). Future MAC studies in cats should investigate this possible relationship. The significant relationship between year of publication and quality score was due to the presence of three studies published before 1990, each with a score of 4. The quality score of the studies published after 1990 was relatively low, and there was not any improvement in quality score between 1990 and the present. It is possible that the studies used appropriate methodology, but these methods were not reported in the text of the study due to time or space limitations. Nonetheless, these results indicate the quality of reporting of methods is still suboptimal, and this deficit should be considered when reporting and publishing future MAC studies. None of the studies reported blinding procedures, whereas MAC studies in people at least occasionally incorporate blinding (Lin et al. 2007; Turan et al. 2010). Lack of blinding may introduce bias, which could affect results, even in an experimental setting (Macleod et al. 2004). MAC for isoflurane and sevoflurane for the feline patient is affected by many variables. This systematic review suggests how the type and location of stimulus, type of ventilation, type of breathing system, and age of the animal affect the MAC of isoflurane and sevoflurane in cats. Ideally, each of these variables should be submitted to an experimental study design to determine what, in any, contribution they have to the MAC value in cats. The MAC for isoflurane ranged from 1.20 0.13% to 2.22 0.35% and the MAC for sevoflurane ranged from 2.5 0.2% to 3.95 0.33%. This reflects a relatively wide range, and variables examined in this review
may be responsible for some of this variability. Methodology differed among studies, and particular attention should be paid in the future to appropriate reporting of methods to allow appropriate conclusions to be made from the results. Acknowledgements The authors would like to thank the referee for advice and suggestions, which have contributed considerably to the quality of this publication. References Barter LS, Ilkiw JE, Steffey EP et al. (2004) Animal dependence of inhaled anaesthetic requirements in cats. Br J Anaesth 92, 275–277. Boscan P, Monnet E, Mama K et al. (2011) A dog model to study ovary, ovarian ligament and visceral pain. Vet Anaesth Analg 28, 260–266. Brosnan RJ, Pypendop BH, Siao KT et al. (2009) Effects of remifentanil on measures of anesthetic immobility and analgesia in cats. Am J Vet Res 70, 1065–1071. Disselhorst-Klug C, Schmitz-Rode T, Rau G (2009) Surface electromyography and muscle force: limits in sEMG-force relationship and new approaches for applications. Clin Biochem 24, 225–235. Doi M, Yunoki H, Ikeda K. (1988) The minimum alveolar concentration of sevoflurane in cats. J Anesth 2, 113– 114. Drummond JC, Todd MM, Shapiro HM. (1983) Minimal alveolar concentrations for halothane, enflurane, and isoflurane in the cat. J Am Vet Med Assoc 182, 1099– 1101. Eger EL 2nd. (2001) Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 93, 947–953. Escobar A, Pypendop BH, Siao KT et al. (2012) Pharmacokinetics of dexmedetomidine administered intravenously in isoflurane-anesthetized cats. Am J Vet Res 73, 295–299. Ferreira TH, Aguiar AJ, Valverde A et al. (2009) Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 70, 581–588. Ferreira TH, Steffey EP, Mama KR et al. (2011) Determination of the sevoflurane sparing effect of methadone in cats. Vet Anaesth Analg 38, 310–319. Golder FJ, Pascoe PJ, Bailey CS et al. (1998) The effect of epidural morphine on the minimum alveolar concentration of isoflurane in cats. J Vet Anesth 25, 52–56. Hikasa Y, Kawanabe H, Takase K et al. (1996) Comparisons of sevoflurane, isoflurane, and halothane
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anesthesia in spontaneously breathing cats. Vet Surg 25, 234–243. Hikasa Y, Ohe N, Takase K et al. (1997) Cardiopulmonary effects of sevoflurane in cats: comparison with isoflurane, halothane, and enflurane. Res Vet Sci 63, 205–210. Ide T, Sakurai Y, Aono M et al. (1998) Minimum alveolar anesthetic concentrations for airway occlusion in cats: a new concept of minimum alveolar anesthetic concentration-airway occlusion response. Anesth Analg 86, 191–197. Ide T, Okitsu Y, Nehashi S et al. (2001) The effect of epidural anesthesia on respiratory distress induced by airway occlusion in isoflurane-anesthetized cats. Anesth Analg 92, 749–754. Ilkiw JE, Pascoe PJ, Fisher LD. (1997) Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 58, 1274–1279. Ilkiw JE, Pascoe PJ, Tripp LD. (2002) Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 63, 1198–1202. Imai A, Ilkiw JE, Pypendop BH et al. (2002) Nitrous oxide does not consistently reduce isoflurane requirements in cats. Vet Anaesth Analg 29, 97–112. Katoh T, Suguro Y, Kimura T et al. (1993) Cerebral awakening concentration of sevoflurane and isoflurane predicted during slow and fast alveolar washout. Anesth Analg 77, 1012–1017. Ko JC, Abbo LA, Weil AB et al. (2008) Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats. J Am Vet Med Assoc 232, 1834– 1840. Lamont LA, Greene SA, Grimm KA et al. (2004) Relationship of bispectral index to minimum alveolar concentration multiples of sevoflurane in cats. Am J Vet Res 65, 93–98. Lamont LA, Greene SA, Grimm KA et al. (2005) Relationship of feline bispectral index to multiples of isoflurane minimum alveolar concentration. Comp Med 55, 269–274. Levionnois OL, Spadavecchia C, Kronen PW et al. (2009) Determination of the minimum alveolar concentration of isoflurane in Shetland ponies using constant current or constant voltage electrical stimulation. Vet Anaesth Analg 36, 9–17. Lin CM, Wu CT, Lee ST et al. (2007) Sitting position does not alter minimum alveolar concentration for desflurane. Can J Anaesth 54, 523–530. Macleod MR, O’Collins T, Howells DW et al. (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35, 1203–1208. Macleod MR, van der Worp HB, Sena ES et al. (2008) Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 39, 2824–2829.
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Mapleson WW (1996) Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 76, 179–185. March PA, Muir WW 3rd (2003) Minimum alveolar concentration measures of central nervous system activation in cats anesthetized with isoflurane. Am J Vet Res 64, 1528–1533. Pascoe PJ, Ilkiw JE, Fisher LD. (1997) Cardiovascular effects of equipotent isoflurane and alfentanil/isoflurane minimum alveolar concentration multiple in cats. Am J Vet Res 58, 1267–1273. Pascoe PJ, Ilkiw JE, Craig C et al. (2007) The effects of ketamine on the minimum alveolar concentration of isoflurane in cats. Vet Anaesth Analg 34, 31–39. Pypendop BH, Ilkiw JE (2004) Hemodynamic effects of sevoflurane in cats. Am J Vet Res 65, 20–25. Pypendop BH, Ilkiw JE (2005) The effects of intravenous lidocaine administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 100, 97–101. Pypendop BH, Ilkiw JE et al. (2003) Hemodynamic effects of nitrous oxide in isoflurane- anesthetized cats. Am J Vet Res 64, 273–278. Pypendop BH, Pascoe PJ, Ilkiw JE. (2006) Effects of epidural administration of morphine and buprenorphine on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 67, 1471–1475. Pypendop BH, Barter LS, Stanley SD et al. (2011) Hemodynamic effects of dexmedetomidine in isofluraneanesthetized cats. Anes Analg 38, 555–567. Quasha AL, Eger EL 2nd, Tinker JH (1980) Determination and applications of MAC. Anesthesiology 53, 315–334. Reid P, Pypendop BH, Ilkiw JE. (2010) The effects of intravenous gabapentin administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 111, 633–637. Sargeant JM, Thompson A, Valcour J et al. (2010) Quality of reporting of clinical trials of dogs and cats and associations with treatment effects. J Vet Intern Med 24, 44–50. Seddighi R, Egger CM, Rohrbach BW et al. (2011) The effect of midazolam on the end-tidal concentration of isoflurane necessary to prevent movement in dogs. Vet Anaesth Analg. 38, 195–202. Staffieri F, De Monte V, De Marzo C et al. (2010) Effects of two fractions of inspired oxygen on lung aeration and gas exchange in cats under inhalant anaesthesia. Vet Anaesth Analg 37, 483–490. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Thomasy SM, Pypendop BH, IIkiw JE et al. (2005) Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isofluraneanesthetized cats. Am J Vet Res 66, 1162–1166.
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Cat MAC systematic review MR Shaughnessy and EH Hofmeister Thurmon JC, Tranquilli WJ, Benson JG et al. (1996) Lumb and Jones Veterinary Anesthesia (3rd ed.), Williams and Wilkins, Baltimore, MD, USA, 312–315. Turan A, Kasuya Y, Govinda R et al. (2010) The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg 110, 449–454. 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, 957– 962. Vesely A, Fisher JA, Sasano N et al. (2003) Isocapnic hyperpnoea accelerates recovery from isoflurane anesthesia. Br J Anaesth 91, 787–792. Yackey M, Ilkiw JE, Pascoe PJ et al. (2004) Effect of transdermally administered fentanyl on the minimum
alveolar concentration of isoflurane in cats. Vet Anaesth Analg 31, 183–189. Zbinden AM, Peterson-Felix S, Thomson DA. (1994) Anesthetic depth using multiple noxious stimuli during isoflurane/oxygen anesthesia. Anesthesiology 80, 261– 267. Zwijnenberg RJ, del Rio CL, Pollet RA et al. (2010) Effects of perzinfotel, butorphanol tartrate, and a butorphanolperzinfotel combination on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 71, 1270–1276. Zwijnenberg RJ, del Rio CL, Cobb RM et al. (2011) Evaluation of oscillometric and vascular access port arterial blood pressure measurement techniques versus implanted telemetry in anesthetized cats. Am J Vet Res 72, 1015–1021. Received 3 December 2012; accepted 13 March 2013.
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doi:10.1111/vaa.12083
REVIEW ARTICLE
A systematic review of sevoflurane and isoflurane minimum alveolar concentration in domestic cats Mike R Shaughnessy* & Erik H Hofmeister† *Veterinary Teaching Hospital, College of Veterinary Medicine, University of Georgia, Athens, GA, USA †Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
Correspondence: Erik Hofmeister, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens 30602, GA, USA. E-mail: [email protected]
Abstract Objective The purpose of this systematic review is to summarize the results of studies which have determined the minimum alveolar concentration (MAC) of isoflurane and sevoflurane in domestic cats. Study Design Systematic review. Animals Cats. Methods used A comprehensive search of research literature was performed without language restriction. The search utilized the Pubmed, Google Scholar, and CAB Abstracts electronic databases using a combination of free text terms ‘Minimum alveolar concentration’, ‘sevoflurane’, ‘isoflurane’, ‘anesthetic’, ‘cat’, ‘cats’ or ‘feline’. The search was conducted from November 2010 to June 2012. Results The MAC for isoflurane ranged from 1.20 0.13% to 2.22 0.35% and the MAC for sevoflurane ranged from 2.5 0.2% to 3.95 0.33%. The average MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Conclusions & Clinical Relevance The average MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Methodology differed among studies, and particular attention should be paid in the future to appropriate
reporting of methods to allow sound conclusions to be made from the results. Keywords cats, isoflurane, minimum concentration, sevoflurane, stimulation.
alveolar
Introduction The classical definition of minimum alveolar concentration (MAC) is a measurement of the concentration of inhaled anesthetic needed to prevent purposeful movement in 50% of subjects exposed to a supra maximal noxious stimulus (Quasha et al. 1980). It is the most common method used to estimate the potency of an inhaled anesthetic, but heterogeneity in research methodology can result in widely disparate values. Multiple studies have been published in an effort to define the MAC, but results among publications vary greatly. The wide variability in the findings may be due to several factors, including different methodology, poor methodology, or the many physiologic or pathologic factors that can affect the MAC value. Choice of end-point [purposeful movement or no movement (Seddighi et al. 2011)] is a major difference within methodology. Variables such as age, species, pregnancy, hypothermia, hyperthermia, genetic sensitivity, type and site of stimulus, and disease alter the results (Quasha et al. 1980; Thurmon et al. 1996). Methodology which does not include blinding or randomization may lead to erroneous results due to flaws with internal validity (i.e. bias; Macleod et al. 2004, 2008; Sargeant et al. 2010). 1
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
Clinically, knowledge of the appropriate MAC value should help the anesthetist to titrate anesthesia to a level suitable to accomplish the procedure being undertaken without overdosing the patient. In a research setting, MAC values are often used as a basis for future research, and precise estimates therefore are needed. The purpose of this systematic review is to summarize the results of studies, which have estimated the MAC of isoflurane and sevoflurane in domestic cats. Materials and methods Search strategy A comprehensive search of research literature was performed without language restriction. The search utilized the PubMed, Google Scholar, and CAB Abstracts electronic databases using a combination of free text terms ‘minimum alveolar concentration’, ‘sevoflurane’, ‘isoflurane’, ‘anesthetic’, ‘cat’,’cats’, or ‘feline’. The search was conducted from November 2010 to June 2012. Inclusion and exclusion criteria Any published research paper that utilized isoflurane or sevoflurane for MAC determination directly or indirectly in domestic cats was evaluated. Studies were excluded if they did not determine MAC, but instead use previously published values, or if they did not acquire a baseline MAC before applying an intervention or drug. Validity scoring A modification of a system used in a meta-analysis of experimental studies was used (Macleod et al. 2004). The studies were scored using eleven binary criteria: were subjects randomly allocated to treatment groups, were observers blinded to treatment group, was the MAC determination confirmed in triplicate, and was age, weight, temperature control, type of ventilation, type of breathing circuit, gas analyzer calibration, and equilibration time detailed in the study. Each study was given one point for each criterion that was met. The minimum score was 0, the maximum 11. Two authors scored the studies independently and any discrepancies in results were resolved with discussion.
2
Data extraction A baseline MAC for isoflurane and/or sevoflurane was extracted from the studies. The number of subjects, age, sex, body temperature, type of breathing circuit, equilibration time, calibration method, inhalant concentration measurement technology, MAC determination protocol, and method of ventilation was also collected, along with the type and location of noxious stimulus. The average MAC value was calculated as the weighted mean, using the sample size for weight. Only the MAC values from studies which used a peripheral somatic stimulus (i.e. tail clamp or electrical stimulation) were included in the overall MAC calculation. The mean MAC value and standard deviation were compared between those studies in which a single or triplicate MAC determination had been performed using an unpaired 2-way t-test. The mean MAC value was also compared between those studies in which spontaneous or controlled ventilation was used and between those studies in which a rebreathing or non-rebreathing circuit was used with an unpaired 2-way t-test. The relationship between year of publication of each study and study quality score was assessed using linear regression. Significance was set at a < 0.05. Results Systematic search Thirty-four potentially relevant studies met the inclusion criteria (Tables 1 & 2). Twelve studies were excluded because the cats were pre-medicated before a baseline MAC was found or the baseline MAC used in the paper was taken from a previously published study (Hikasa et al. 1996, 1997; Pascoe et al. 1997; Pypendop et al. 2003; Pypendop & Ilkiw 2004; Thomasy et al. 2005; Pypendop et al. 2006; Ko et al. 2008; Staffieri et al. 2010; Pypendop et al. 2011; Zwijnenberg et al. 2011; Escobar et al. 2012). All studies were written in English and published from 1977 to 2011. The average quality score was 6.8, with a range of 4–9. There was a significant positive relationship between year of publication and quality score (p < 0.001, R2 = 0.47). When only those studies published after 1990 were considered, there was no significant relationship (p = 0.46) and the average quality score was 7.3.
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Imai et al. (2002)
1.93 0.17
1.25 0.18
1.24 0.17
1.27 0.13
1.20 0.13
1.54 0.19
1.54 0.12
12
6
1.60 0.1
1.58 0.07
6
1.28 0.13
Ilkiw et al. (2002)
Tetanus
2–3
8M/4F
F/S
1.8 0.5 4.9 2.2
F/S
3.4 0.1
3.8–8.8
4.1 0.4
3 0.6
4.5 0.8
No
Yes
Yes
N/D
Circle
Circle
Tail Clamp
Tail Clamp
Tail Clamp
stimulus
Toe Pinch
Occlusion
Airway
Tail Clamp
Electrical
Tail Clamp
Tail Clamp
Tail Clamp
Tail Clamp
2.22 0.35
Non-Reb
Non-Reb
Circle
Circle
Non-Reb
N/D
Non-Reb
Bain
Method
Electrical
No
No
Yes
Yes
No
Yes
Yes
N/D
Circuit
Occlusion
3.5 0.1
4.2 0.66
4.7 0.8
3.9 0.5
4.3 1.2
2.9 0.7
4.2 0.2
3.5 0.3
IPPV
Airway
28M/6F
20M/4F
FS
2MN/4F
F
Mix
FS
F
(kg)
1.65 0.45
Adult
Adult
4
3–7
1.5
Adult
1.5
1.8–2.3
Sex
Weight
Airway
24
24
5
6
6
8
6
6
(Years)
Age
Pinch
1.5 0.38
1.7 0.2
1.7 0.3
1.6 0.2
1.65 0.14
1.66 0.08
2.07 0.10
1.61 0.04
1.94 0.08
1.9 0.18
Ilkiw et al. (1997)
Ide et al. (1998)
Ide et al. (2001)
et al. (1998)
Golder
et al. (2009)
Ferreira
et al. (2012)
Escobar
et al. (1983)
Drummond
et al. (2009)
Brosnan
(2004)
Barter et al.
Cats
Name
Iso MAC
No. of
Study
Table 1 Characteristics of publications of minimum alveolar concentrations (MAC) of isoflurane in cats
Tail
Tail
Tail
Left TL
Lungs
N/D
Lungs
Tail
TL
Tail
Tail
Tail
Tail
area
Stimulus
N/D
20 minute
N/D
20 minute
minute
1 hour/20
20 minute
15 minute
20 minute
15 minute
minute
1 hour/20
N/D
Time
Equilibrium
38.5
38
38
37–38
37–38
37.9–39
37.5–38.5
N/D
37.5
Normothermia
No
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Triple
Triple
Triple
Double
Double
Triple
Double
Triple
Double
difference
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
6
9
8
7
6
9
8
7
5
8
7
Score
Quality
(continued)
until <15%
Multiple
Triple
Method
38–39
Determination Calibration
°C
MAC Temperature
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
3
4
1.54 0.15
1.51 0.21 7
5
6 10
2.1 0.13
6
6
17
8
1.63 0.02
2.21 0.17
1.51 0.23
visceral
1.82 0.1
tail
1.87 0.14
1.8 0.2
1–1.5
2.9 0.3
Mix
1–2
1–2
Adult
N/D
3.2
(Years)
Age
4M/3F
F/S
Mix
N/D
N/D
F/S
F/S
4M/4F
Sex
2.8–4.6
4.3 0.7
3.5 0.4
4.8 0.6
5.1 0.4
5.1 0.9
N/D
4.1
(kg)
Weight
Yes
Yes
No
No
No
Yes
Yes
N/D
IPPV
Circle
Circle
Circle
Bain
Bain
Circle
Circle
Circle
Circuit
Electrical
Tail Clamp
N/D
Tail Clamp
Tail Clamp
Tail Clamp
Visceral
Electrical/
Tail Clamp
Method
Mucosa
Buccal
N/D
Tail
Tail
Tail
Tail
Bladder
Tail/
Tail
area
Stimulus
15 minute
N/D
N/D
15 minute
15 minute
N/D
15 minute
20 minute
Time
Equilibrium
37.5–38.5
38
38
38.5–39.5
38.5–39.5
38
36.6–38.3
No
Yes
No
Yes
Yes
Yes
No
Yes
Double
Triple
N/D
Triple
Triple
Triple
Double
Double
Method
N/D
Determination Calibration
°C
MAC Temperature
7
7
4
8
8
7
5
7
Score
Quality
IPPV: intermittent positive pressure ventilation used during MAC determination; Nonreb: non-rebreathing circuit used during MAC determination; TL: thoracic limb. Values are given as mean SD. Calibration was a method for calibrating the inhalant agent analyzer described. Quality score is out of a possible 11. N/D: Not determinable from the information in the paper.
et al. (2010)
Zwijnenberg
et al. (2004)
Yackey
Howland (1977)
Steffey &
Reid et al. (2010)
Ilkiw (2005)
Pypendop &
et al. (2007)
Pascoe
Muir (2003)
March &
et al. (2005)
Lamont
Cats
Name
Iso MAC
No. of
Study
Table 1 (continued)
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
8
8
24
2.58 0.3
3.18 0.06
3.07 0.76 Pinch 3.38 0.66 Airway 3.95 0.33 Tetanus 3.3 0.2
8
6
3.41 0.65
Sevo MAC
No of Cats
3.2
Adult
1–2
Adult
1.8–2.3
Age (Years)
4M/4F
28M/6F
4MN/4FS
6M/2F
F
Sex
4.1
3.5 0.1
5.82 0.42
3.4 0.8
3.5 0.3
Weight (kg)
Yes
No
Yes
Yes
N/D
IPPV
Circle
Non-reb
Non-reb
N/D
Bain
Circuit
Toe Pinch Electrical stimulus Airway Occlusion Tail Clamp
Tail Clamp
Tail Clamp
Tail Clamp
Method
Tail
N/A Left TL Lungs
Tail
Tail
Tail
Stimulus area
15 minute
2 minute
15 minute
15 minute
N/D
Equilibrium time
N/D
37–38
37–38.5
38
38–39
Temperature °C
No
No
Yes
No
Yes
Calibration
Double
Double
Triple
Double
Triple
MAC Determination method
6
7
9
4
7
Quality score
IPPV: intermittent positive pressure ventilation used during MAC determination; Nonreb: non-rebreathing circuit used during MAC determination; TL: thoracic limb. Values are given as mean SD. Calibration was a method for calibrating the inhalant agent analyzer described. Quality score is out of a possible 11.
Lamont et al. (2004)
Barter et al. (2004) Doi et al. (1988) Ferreira et al. (2011) Ide et al. (1998)
Study Name
Table 2 Characteristics of publications of minimum alveolar concentrations (MAC) of sevoflurane in cats
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
5
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
Baseline MAC MAC for isoflurane was found in seventeen studies (Steffey & Howland 1977; Drummond et al. 1983; Ilkiw et al. 1997; Golder et al. 1998; Ide et al. 2001; Ilkiw et al. 2002; Imai et al. 2002; March & Muir 2003; Yackey et al. 2004; Pypendop & Ilkiw 2005; Lamont et al. 2005; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012), the MAC for sevoflurane in three (Doi et al. 1988; Lamont et al. 2004; Ferreira et al. 2011), and findings for both anesthetic inhalants were recorded in two of the studies (Ide et al. 1998; Barter et al. 2004). The MAC for isoflurane ranged from 1.2% to 2.22% and the MAC for sevoflurane ranged from 2.5% to 3.95%. The average weighted MAC for isoflurane was 1.71 0.07% and for sevoflurane was 3.08 0.4%. Type and location of stimulus In 16 studies, a tail clamping technique was used as the noxious stimulus to determine the MAC (Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Imai et al. 2002; Barter et al. 2004; Lamont et al. 2004, 2005; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Brosnan et al. 2009; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). MAC for isoflurane with this method ranged from 1.2 0.13% to 2.21 0.17% and MAC for sevoflurane ranged from 2.5 0.20% to 3.41 0.65%. In four studies, an electrical stimulus was used: in two, a thoracic limb was used; in one, the tail was used; and, in the fourth, the electrodes were applied to the buccal mucosa. In the first study, when a thoracic limb electrical stimulus was used, the stimulus was applied for a full 10 seconds at 50 mA (Ide et al. 1998). In the second study using the thoracic limb electrical stimulus, the stimulus was applied by four stimuli at 5 second intervals; two single stimuli followed by two stimuli that were continuously applied for 3 seconds (Ferreira et al. 2009). The current applied was not reported in that study. In the third study, an electrical stimulus at a current of 25 mA was applied for 10 seconds on the cat’s tail (March & Muir 2003) and, in the fourth study, electrodes were attached to the buccal mucosa of each cat and delivered a stimulus for a 10 millisecond duration over one minute (Zwijnenberg 6
et al. 2010). The current applied was not reported in that study. In one study, MAC was determined by visceral stimulation by injecting the bladder with liquid (March & Muir 2003). Warmed (42 °C) saline (0.9% NaCl) solution was infused into the bladder at a rate of 10 mL m 2 body surface area per minute (approximately 2–2.5 mL minute 1) for stimulation. Five out of 17 cats were omitted from the study due to the inability of the researchers to place a urinary catheter in the cats. In two studies, airway occlusion was used as the noxious stimulus (Ide et al. 1998, 2001). This was achieved by occluding the airway by closing a 6 mm three way stopcock that was connected to the nonrebreathing circuit and the endotracheal tube. The subject was monitored for positive movement or apnea for up to 6 minutes after the occlusion. The results were 1.6 0.2%, 1.7 0.3%, and 1.7 0.2% for the three groups of cats used in one study (Ide et al. 2001) and 1.65% in the other study (Ide et al. 1998). In one study, visceral and somatic stimulation were compared for isoflurane (March & Muir 2003). The results were similar with a MAC of 1.87 0.14% for somatic stimulation induced with an electrical stimulus on the tail and 1.82 0.10% for visceral stimulation induced with fluid injected into the bladder. In another study, three different types of somatic stimulation were compared for the effect on the MAC of isoflurane and sevoflurane (Ide et al. 1998). A toe pinch, electrical current applied to the thoracic limb, and airway occlusion were used for stimulation. The results were 1.5 0.38%, 2.22 0.35%, and 1.65 0.45% for isoflurane and 3.07 0.76%, 3.95 0.33%, and 3.38 0.66% for sevoflurane, respectively. One study did not describe the type of stimulus used (Steffey & Howland 1977). Temperature The temperature for eighteen of the studies was kept between 37 and 39.5 °C (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998, 2001; Imai et al. 2002; March & Muir 2003; Barter et al. 2004; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010). The other four studies did not report a numeric body temperature
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister (Lamont et al. 2004, 2005; Brosnan et al. 2009; Escobar et al. 2012). Breathing systems In 13 of the studies, intermittent positive-pressure ventilation was used (Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Lamont et al. 2004; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Zwijnenberg et al. 2010), in seven, subjects were allowed to breathe spontaneously (Steffey & Howland 1977; Ide et al. 1998, 2001; Imai et al. 2002; Pypendop & Ilkiw 2005; Reid et al. 2010; Escobar et al. 2012), and the method of ventilation was not reported in two (Barter et al. 2004; Lamont et al. 2005). Isoflurane MAC ranged from 1.2 0.13% to 1.87 0.14% with controlled ventilation (Ilkiw et al. 1997, 2002; March & Muir 2003; Yackey et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009) and ranged from 1.5 0.38% to 2.22 0.35% with spontaneous ventilation (Steffey & Howland 1977; Ide et al. 1998, 2001; Imai et al. 2002; Reid et al. 2010; Escobar et al. 2012). The sevoflurane MAC with controlled ventilation had a range of 2.58 0.30% to 3.3 0.20% (Doi et al. 1988; Lamont et al. 2004), and this was lower than the range with spontaneous ventilation of 3.07 0.76% to 3.95 0.33% (Ide et al. 1998). Studies which reported using spontaneous ventilation reported a significantly higher isoflurane MAC value compared with studies which reported using controlled ventilation (1.86% versus 1.63%, p < 0.05). In 11 of the studies, a circle system was used (Steffey & Howland 1977; Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Lamont et al. 2004, 2005; Yackey et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009; Zwijnenberg et al. 2010), in eight a non-rebreathing, Mapleson F circuit, or Bain circuit was used (Ide et al. 1998, 2001; Barter et al. 2004; Pypendop & Ilkiw 2005; Brosnan et al. 2009; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012), and, in three studies, the type of breathing system used was not reported (Drummond et al. 1983; Doi et al. 1988; Imai et al. 2002). Studies which reported using a nonrebreathing system reported a significantly higher isoflurane MAC value compared with studies which reported using a rebreathing system (1.9% versus 1.61%, p < 0.02).
In 17 studies, a catheter was placed within the lumen of the orotracheal tube and infrared absorption (Steffey & Howland 1977; Drummond et al. 1983; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998; March & Muir 2003; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Zwijnenberg et al. 2010), Raman spectrometry (Barter et al. 2004; Pypendop & Ilkiw 2005; Reid et al. 2010), or gas chromatography (Doi et al. 1988) was used to measure inhalant concentrations. In two studies, a side stream system and infrared absorption (Lamont et al. 2005) or atomic absorption spectroscopy (Ide et al. 2001) was used to measure inhalant concentrations. Three studies did not report what type of equipment was used to measure inhalant concentrations (Imai et al. 2002; Lamont et al. 2004; Escobar et al. 2012). A fresh gas flow of 2 L minute 1 was used in four of the studies (Ilkiw et al. 2002; Yackey et al. 2004; Reid et al. 2010; Ferreira et al. 2011). A rate of 1 L minute 1 was used in two studies (Lamont et al. 2005; Brosnan et al. 2009), and a rate of 500 mL kg minute 1 was used in two (Barter et al. 2004; Pypendop & Ilkiw 2005). A rate of 200 mL kg minute 1 was used in one (Escobar et al. 2012). A rate of 4–5 L minute 1 was used in two (Ide et al. 1998, 2001), while the remaining eleven did not describe the fresh gas flow rate (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997; Golder et al. 1998; Imai et al. 2002; March & Muir 2003; Lamont et al. 2004; Pascoe et al. 2007; Ferreira et al. 2009; Zwijnenberg et al. 2010). Age In 15 studies, adult cats ranging from one to 7 years old with a mean age of 2.6 years were used (Golder et al. 1998; Ilkiw et al. 1997, 2002; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Lamont et al. 2004; Pypendop & Ilkiw 2005; Lamont et al. 2005; Brosnan et al. 2009; Ferreira et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). Of the seven remaining studies, six studies did not document a numeric age, only describing the age of the cats using the words ‘Adult’ or ‘Mixed’ (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; Pascoe et al. 2007), and one did not report the age of the cats (March & Muir 2003). Differences between MAC values were
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
7
Cat MAC systematic review MR Shaughnessy and EH Hofmeister
attributed to age in one study (Ilkiw et al. 2002). Two different age groups of cats were tested. The group ages averaged 1.75 and 4.92 years the MAC of isoflurane averaged 1.56 0.12% and 1.24 0.15%, respectively. This difference was not evaluated statistically. In five other studies, young cats between the ages of 1–2 years old were used (Pypendop & Ilkiw 2005; Brosnan et al. 2009; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012) and isoflurane MAC results trended towards the higher end of the range, 2.21 0.17%, 1.94 0.08%, 2.1 0.13%, 1.54 0.15% and 2.07 0.10% respectively. In only one sevoflurane study were cats between the ages of 1–2 years used (Ferreira et al. 2011). That study reported a high sevoflurane MAC of 3.18 0.06%. Sex In nine studies, strictly female cats were used (Ilkiw et al. 1997, 2002; Golder et al. 1998; March & Muir 2003; Barter et al. 2004; Yackey et al. 2004; Pascoe et al. 2007; Brosnan et al. 2009; Escobar et al. 2012). In three studies, an equal ratio of male and female cats were used (Lamont et al. 2004, 2005; Ferreira et al. 2011). In five studies, more males than females were used. In the first study, six males and two females were used (Doi et al. 1988), in the second study, 28 males and six females were used (Ide et al. 1998), in the third study, 20 males and four females were used (Ide et al. 2001), in the fourth study, eight males and four females were used (Imai et al. 2002), and in the fifth study, four males and three females were used (Zwijnenberg et al. 2010). In one study, more females than males were used, with four females and two males (Ferreira et al. 2009). Two studies reported using a “mix” of female and male cats (Steffey & Howland 1977; Drummond et al. 1983), and two studies did not report the sex of the cats used (Pypendop & Ilkiw 2005; Reid et al. 2010). The effect of sex on the MAC of isoflurane was explored in one study, which documented an isoflurane MAC of 2.06 0.08% for four females and 1.86 0.22% for eight males, which did not appear to be different (Imai et al. 2002). Weight The weight of the cats in 21 of the included studies ranged from 3 to 8.8 kg with a mean 8
weight of 4.2 kg (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ilkiw et al. 1997, 2002; Golder et al. 1998; Ide et al. 1998, 2001; Imai et al. 2002; Barter et al. 2004; Lamont et al. 2004, 2005; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe et al. 2007; Brosnan et al. 2009; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010; Escobar et al. 2012). In one study, a weight for the cats used was not reported (March & Muir 2003). Calibration In five studies, calibration of the analyzers was done with gases containing known concentrations of isoflurane at 0.5, 1.5, and 2.5% (Ilkiw et al. 1997, 2002; Golder et al. 1998; Yackey et al. 2004; Pascoe et al. 2007). This calibration was done prior, midway, and at the completion of each trial. In two studies, calibration was done every 80 minutes with gases containing known concentrations of isoflurane at 0.5, 1.5, and 2.5% (Pypendop & Ilkiw 2005; Reid et al. 2010). In one study, a calibration reference provide by the manufacturer of the analyzer was used (Ferreira et al. 2009). In two studies, calculated calibration curves were used to mathematically correct collected samples (Barter et al. 2004; Brosnan et al. 2009). In one study, calibration of the gas analyzer was done with gases containing known concentrations of sevoflurane at 1.5, 2.5, and 3.8% (Ferreira et al. 2011). In one study, the gas analyzer was calibrated, but no mention the calibration method was made (Lamont et al. 2005). No gas analyzer calibration was described in ten studies (Steffey & Howland 1977; Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; Imai et al. 2002; March & Muir 2003; Lamont et al. 2004; Zwijnenberg et al. 2010; Escobar et al. 2012).
Defining individual MAC In nine studies, individual MAC was determined with a duplicate response to noxious stimulus (Drummond et al. 1983; Doi et al. 1988; Ide et al. 1998, 2001; March & Muir 2003; Ferreira et al. 2009; Zwijnenberg et al. 2010; Lamont et al. 2004, 2005). In 11 studies, individual MAC was determined in triplicate (Ilkiw et al. 1997, 2002; Golder et al. 1998; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Pypendop & Ilkiw 2005; Pascoe
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister et al. 2007; Reid et al. 2010; Ferreira et al. 2011; Escobar et al. 2012). In one study, individual MAC was determined until there was less than a 15% difference between two measurements that permitted and prevented movement (Brosnan et al. 2009). In one study, the MAC calculation was not specified (Steffey & Howland 1977). There was no significant difference in mean MAC or standard deviation between those studies using duplicate or triplicate determination. Equilibrium time In nine studies, there was a 15 minutes equilibration time (Drummond et al. 1983; Doi et al. 1988; March & Muir 2003; Lamont et al. 2004; Pypendop & Ilkiw 2005; Ferreira et al. 2009, 2011; Reid et al. 2010; Zwijnenberg et al. 2010). In these studies, the MAC for isoflurane ranged from 1.54 0.15% to 2.12 0.17 and the sevoflurane ranged from 2.58 0.3% to 3.3 0.2%. In five studies, the inhalant was equilibrated for 20 minutes (Golder et al. 1998; Ide et al. 1998; Ilkiw et al. 2002; Lamont et al. 2005; Escobar et al. 2012). The isoflurane MAC ranged from 1.20 0.13% to 2.07 0.10% in those studies. In two isoflurane studies, the inhalant was equilibrated for one hour before the initial stimulus test and then an interval of 20 minutes was used (Ide et al. 2001; Brosnan et al. 2009). The isoflurane MAC for those two studies was 1.6 0.2% and 1.94 0.08. The remaining six studies did not report an equilibration time (Steffey & Howland 1977; Ilkiw et al. 1997; Imai et al. 2002; Barter et al. 2004; Yackey et al. 2004; Pascoe et al. 2007). Barometric pressure Only two studies provided an altitude (Ide et al. 1998; Ferreira et al. 2009). The barometric pressure for the other studies was determined by researching the elevation of the institution where the study was conducted. One study was conducted at the University of S~ ao Paulo State, which has an elevation of 2600 ft. (800 m) above sea level (Ferreira et al. 2009). This was the highest elevation of the studies collected for isoflurane. The study reported a MAC of 1.7 0.1% for isoflurane. The highest elevation for the sevoflurane studies was conducted at Fort Collins Colorado, which has an elevation of 5003 ft. (1525 m) above sea level (Ferreira et al. 2011). The study reported a MAC of 3.18 0.06% for
sevoflurane. Both the isoflurane and the sevoflurane results are within the middle range of MAC values. The highest MAC concentration for both inhalant anesthetics was determined at Chiba University School of Medicine in Chiba, Japan (Ide et al. 1998), which is 72 ft. (22 m) above sea level. The lowest MAC concentration for isoflurane was reported in a study performed at the University of California, Davis (Ilkiw et al. 2002). The lowest MAC concentration for sevoflurane was found in a study authored at the Hamamatsu University School of Medicine in Shizuoka, Japan (Doi et al. 1988). Both Universities are located <150 ft. (46 m) above sea level. Discussion There is a relatively high degree of variability in the published MAC values for cats. In clinical trials in human medicine, when a high degree of variability or ambiguity exists, systematic reviews can help summarize results from past studies to arrive at a consensus. A single large study examining the MAC value of a multitude of cats under a variety of different conditions would be ideal to definitively determine the MAC of isoflurane and sevoflurane in the feline population. Until such a study can be undertaken, this systematic review can serve as a starting point for defining MAC in cats for future research and clinical applications. The highest baseline MAC for both anesthetics was found in one study where electrical stimulation was applied to the thoracic limb (Ide et al. 1998). The MAC was 2.22 0.35% for isoflurane and 3.95 0.33% for sevoflurane. However, in another study, electrical stimulation of the thoracic limb was used and the MAC for isoflurane was 1.66 0.08% (Ferreira et al. 2009). One reason for this difference may be that, in the study with the higher MAC value, electromyography (EMG) was used for monitoring movement. The highly sensitive EMG will pick up signs of motor response before the patient is able to progress to gross movement (Disselhorst-Klug et al. 2009). Therefore, it should take a higher concentration of anesthetic to abolish this minute response compared to the concentration of anesthetic required to stop movement detectable with a visual inspection. In all the other studies, including the other study in which electrical stimulation of the thoracic limb was used, movement in their subjects was determined by direct visual observation when determining the MAC.
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
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Cat MAC systematic review MR Shaughnessy and EH Hofmeister
In a third study, electrical stimulation was used and yielded an isoflurane MAC of 1.87 0.14% (March & Muir 2003). The tail was used instead of the thoracic limb in this study and the electrical device was set at 25 mA instead of 50 mA as in the study with the highest MAC value. Controlled ventilation was also used in this study. The fourth study in which electrical stimulation was used had an isoflurane MAC of 1.54 0.15% (Zwijnenberg et al. 2010). In this study, electrical probes were attached to the buccal mucosa and the subjects were mechanically ventilated. The lower current, different location, and type of ventilation could have contributed to the difference (Levionnois et al. 2009). A difference in MAC was also attributed to the type of ventilation used. The MAC for isoflurane was lower in the studies when controlled ventilation was used. Controlled ventilation may improve inhalant uptake relative to spontaneous ventilation (Vesely et al. 2003). It is also probable that controlled ventilation allowed for more accurate airway inhalant concentration sampling. The most common method of stimulation was the tail clamp technique. In two studies. Multiple types of stimulation and its effect on the MAC were evaluated (Ide et al. 1998; March & Muir 2003). In one study, visceral and somatic stimulation were compared and a similar MAC value was reported for both (March & Muir 2003). This suggests that visceral stimulation is comparable to somatic stimulation, and either may be acceptable for MAC determination in cats. Conversely, in dogs, an ovarian ligament visceral stimulus produces a higher MAC value than somatic stimulation (Boscan et al. 2011). Furthermore, in a second study, three different types of somatic stimulation and its effect on the MAC of isoflurane and sevoflurane were compared (Ide et al. 1998) and found that not all somatic stimulation is equivalent and that varying types of stimulation require different inhalant concentrations to achieve a similar anesthetic effect. Some of these stimuli may not be supramaximal stimuli, and so not fulfill the definitional criteria for MAC value. A study done in people which defined isoflurane’s anesthetic potency with different types of stimulus came to an equivalent conclusion (Zbinden et al. 1994). In that study, vocal commands, trapezius squeeze, electrical tetanic stimulation of the muscles of the thoracic limb, skin incision, laryngoscopy, and tracheal intubation were used for stimulation. The results of the study revealed 10
each type of stimuli, most of which were not supramaximal, required a different isoflurane concentration to abolish motor response. A study in which the MAC of isoflurane was determined using multiple types and sites of noxious stimuli in dogs and rabbits reported that different types of stimulus require different inhalant concentrations and that dogs and rabbits do not respond to stimulus the same (Valverde et al. 2003). Electrical, clamping, and surgical incision stimuli in multiple places on both species of animals were used in that study. It was found that not only does each type of stimulus produce a different MAC value, but that rabbits needed a higher concentration of isoflurane to prevent motion in response to a clamping stimulus as compared to an electrical stimulus. The reverse was found with dogs. Both species had the lowest MAC of isoflurane during surgical incision stimulation. One study determined that the sex of the subject does not have a statistically significant effect on the isoflurane MAC-sparing effect of N2O (Imai et al. 2002). The effect sex had on the MAC results of the remaining studies was impossible to compare because the sexes were mixed within the groups or because a breakdown of the relationship of MAC and sex in the study was not available. Eight studies used only female cats but there was not a study that used male cats exclusively for comparison. Therefore, the effect of gender on MAC values is still unknown. The equilibration time did not seem to have an effect on the MAC of isoflurane. The MAC of isoflurane was almost identical at the interval of 15 minutes and at an interval of 30 minutes. The MAC for sevoflurane at 30 minute intervals was slightly higher than the intervals at 15 minutes. The estimated equilibration time for isoflurane and sevoflurane are 11.8 and 14.4 minutes, respectively (Katoh et al. 1993), so no difference would be expected between a 15 minute equilibration and a 30 minute equilibration. There was no consensus on how calibration of the gas analyzer was conducted, but many studies failed to report their method of calibration, if any. This again illustrates the need for appropriate reporting of methods in MAC studies. In half of the studies, MAC was determined in triplicate. There is no evidence in the literature to support the use of one method over the other. The similarity in standard deviation found between double and triple measurements implies that a double measurement may be sufficient. However,
© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 1–13
Cat MAC systematic review MR Shaughnessy and EH Hofmeister numerous other variables may contribute to variability, so this conclusion must be viewed with caution. In general, a greater number of repeat measurements will produce a smaller standard deviation, which would be advantageous when comparing MAC value changes in response to different interventions. This review showed that age may have an effect on MAC value in cats. Studies using younger cats tended to produce higher MAC values. This was not subject to statistical comparison within the studies, and insufficient detail was presented in the studies to analyze the effect of age on MAC in a systematic fashion in this review. Age does have an effect on the MAC in people (Mapleson 1996). A review of studies done on human patients of various ages showed a 6% decrease in MAC per decade for various inhalant anesthetics (Eger 2001). Future MAC studies in cats should investigate this possible relationship. The significant relationship between year of publication and quality score was due to the presence of three studies published before 1990, each with a score of 4. The quality score of the studies published after 1990 was relatively low, and there was not any improvement in quality score between 1990 and the present. It is possible that the studies used appropriate methodology, but these methods were not reported in the text of the study due to time or space limitations. Nonetheless, these results indicate the quality of reporting of methods is still suboptimal, and this deficit should be considered when reporting and publishing future MAC studies. None of the studies reported blinding procedures, whereas MAC studies in people at least occasionally incorporate blinding (Lin et al. 2007; Turan et al. 2010). Lack of blinding may introduce bias, which could affect results, even in an experimental setting (Macleod et al. 2004). MAC for isoflurane and sevoflurane for the feline patient is affected by many variables. This systematic review suggests how the type and location of stimulus, type of ventilation, type of breathing system, and age of the animal affect the MAC of isoflurane and sevoflurane in cats. Ideally, each of these variables should be submitted to an experimental study design to determine what, in any, contribution they have to the MAC value in cats. The MAC for isoflurane ranged from 1.20 0.13% to 2.22 0.35% and the MAC for sevoflurane ranged from 2.5 0.2% to 3.95 0.33%. This reflects a relatively wide range, and variables examined in this review
may be responsible for some of this variability. Methodology differed among studies, and particular attention should be paid in the future to appropriate reporting of methods to allow appropriate conclusions to be made from the results. Acknowledgements The authors would like to thank the referee for advice and suggestions, which have contributed considerably to the quality of this publication. References Barter LS, Ilkiw JE, Steffey EP et al. (2004) Animal dependence of inhaled anaesthetic requirements in cats. Br J Anaesth 92, 275–277. Boscan P, Monnet E, Mama K et al. (2011) A dog model to study ovary, ovarian ligament and visceral pain. Vet Anaesth Analg 28, 260–266. Brosnan RJ, Pypendop BH, Siao KT et al. (2009) Effects of remifentanil on measures of anesthetic immobility and analgesia in cats. Am J Vet Res 70, 1065–1071. Disselhorst-Klug C, Schmitz-Rode T, Rau G (2009) Surface electromyography and muscle force: limits in sEMG-force relationship and new approaches for applications. Clin Biochem 24, 225–235. Doi M, Yunoki H, Ikeda K. (1988) The minimum alveolar concentration of sevoflurane in cats. J Anesth 2, 113– 114. Drummond JC, Todd MM, Shapiro HM. (1983) Minimal alveolar concentrations for halothane, enflurane, and isoflurane in the cat. J Am Vet Med Assoc 182, 1099– 1101. Eger EL 2nd. (2001) Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 93, 947–953. Escobar A, Pypendop BH, Siao KT et al. (2012) Pharmacokinetics of dexmedetomidine administered intravenously in isoflurane-anesthetized cats. Am J Vet Res 73, 295–299. Ferreira TH, Aguiar AJ, Valverde A et al. (2009) Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 70, 581–588. Ferreira TH, Steffey EP, Mama KR et al. (2011) Determination of the sevoflurane sparing effect of methadone in cats. Vet Anaesth Analg 38, 310–319. Golder FJ, Pascoe PJ, Bailey CS et al. (1998) The effect of epidural morphine on the minimum alveolar concentration of isoflurane in cats. J Vet Anesth 25, 52–56. Hikasa Y, Kawanabe H, Takase K et al. (1996) Comparisons of sevoflurane, isoflurane, and halothane
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anesthesia in spontaneously breathing cats. Vet Surg 25, 234–243. Hikasa Y, Ohe N, Takase K et al. (1997) Cardiopulmonary effects of sevoflurane in cats: comparison with isoflurane, halothane, and enflurane. Res Vet Sci 63, 205–210. Ide T, Sakurai Y, Aono M et al. (1998) Minimum alveolar anesthetic concentrations for airway occlusion in cats: a new concept of minimum alveolar anesthetic concentration-airway occlusion response. Anesth Analg 86, 191–197. Ide T, Okitsu Y, Nehashi S et al. (2001) The effect of epidural anesthesia on respiratory distress induced by airway occlusion in isoflurane-anesthetized cats. Anesth Analg 92, 749–754. Ilkiw JE, Pascoe PJ, Fisher LD. (1997) Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 58, 1274–1279. Ilkiw JE, Pascoe PJ, Tripp LD. (2002) Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 63, 1198–1202. Imai A, Ilkiw JE, Pypendop BH et al. (2002) Nitrous oxide does not consistently reduce isoflurane requirements in cats. Vet Anaesth Analg 29, 97–112. Katoh T, Suguro Y, Kimura T et al. (1993) Cerebral awakening concentration of sevoflurane and isoflurane predicted during slow and fast alveolar washout. Anesth Analg 77, 1012–1017. Ko JC, Abbo LA, Weil AB et al. (2008) Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats. J Am Vet Med Assoc 232, 1834– 1840. Lamont LA, Greene SA, Grimm KA et al. (2004) Relationship of bispectral index to minimum alveolar concentration multiples of sevoflurane in cats. Am J Vet Res 65, 93–98. Lamont LA, Greene SA, Grimm KA et al. (2005) Relationship of feline bispectral index to multiples of isoflurane minimum alveolar concentration. Comp Med 55, 269–274. Levionnois OL, Spadavecchia C, Kronen PW et al. (2009) Determination of the minimum alveolar concentration of isoflurane in Shetland ponies using constant current or constant voltage electrical stimulation. Vet Anaesth Analg 36, 9–17. Lin CM, Wu CT, Lee ST et al. (2007) Sitting position does not alter minimum alveolar concentration for desflurane. Can J Anaesth 54, 523–530. Macleod MR, O’Collins T, Howells DW et al. (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35, 1203–1208. Macleod MR, van der Worp HB, Sena ES et al. (2008) Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 39, 2824–2829.
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Mapleson WW (1996) Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 76, 179–185. March PA, Muir WW 3rd (2003) Minimum alveolar concentration measures of central nervous system activation in cats anesthetized with isoflurane. Am J Vet Res 64, 1528–1533. Pascoe PJ, Ilkiw JE, Fisher LD. (1997) Cardiovascular effects of equipotent isoflurane and alfentanil/isoflurane minimum alveolar concentration multiple in cats. Am J Vet Res 58, 1267–1273. Pascoe PJ, Ilkiw JE, Craig C et al. (2007) The effects of ketamine on the minimum alveolar concentration of isoflurane in cats. Vet Anaesth Analg 34, 31–39. Pypendop BH, Ilkiw JE (2004) Hemodynamic effects of sevoflurane in cats. Am J Vet Res 65, 20–25. Pypendop BH, Ilkiw JE (2005) The effects of intravenous lidocaine administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 100, 97–101. Pypendop BH, Ilkiw JE et al. (2003) Hemodynamic effects of nitrous oxide in isoflurane- anesthetized cats. Am J Vet Res 64, 273–278. Pypendop BH, Pascoe PJ, Ilkiw JE. (2006) Effects of epidural administration of morphine and buprenorphine on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 67, 1471–1475. Pypendop BH, Barter LS, Stanley SD et al. (2011) Hemodynamic effects of dexmedetomidine in isofluraneanesthetized cats. Anes Analg 38, 555–567. Quasha AL, Eger EL 2nd, Tinker JH (1980) Determination and applications of MAC. Anesthesiology 53, 315–334. Reid P, Pypendop BH, Ilkiw JE. (2010) The effects of intravenous gabapentin administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 111, 633–637. Sargeant JM, Thompson A, Valcour J et al. (2010) Quality of reporting of clinical trials of dogs and cats and associations with treatment effects. J Vet Intern Med 24, 44–50. Seddighi R, Egger CM, Rohrbach BW et al. (2011) The effect of midazolam on the end-tidal concentration of isoflurane necessary to prevent movement in dogs. Vet Anaesth Analg. 38, 195–202. Staffieri F, De Monte V, De Marzo C et al. (2010) Effects of two fractions of inspired oxygen on lung aeration and gas exchange in cats under inhalant anaesthesia. Vet Anaesth Analg 37, 483–490. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833–1836. Thomasy SM, Pypendop BH, IIkiw JE et al. (2005) Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isofluraneanesthetized cats. Am J Vet Res 66, 1162–1166.
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Cat MAC systematic review MR Shaughnessy and EH Hofmeister Thurmon JC, Tranquilli WJ, Benson JG et al. (1996) Lumb and Jones Veterinary Anesthesia (3rd ed.), Williams and Wilkins, Baltimore, MD, USA, 312–315. Turan A, Kasuya Y, Govinda R et al. (2010) The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg 110, 449–454. 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, 957– 962. Vesely A, Fisher JA, Sasano N et al. (2003) Isocapnic hyperpnoea accelerates recovery from isoflurane anesthesia. Br J Anaesth 91, 787–792. Yackey M, Ilkiw JE, Pascoe PJ et al. (2004) Effect of transdermally administered fentanyl on the minimum
alveolar concentration of isoflurane in cats. Vet Anaesth Analg 31, 183–189. Zbinden AM, Peterson-Felix S, Thomson DA. (1994) Anesthetic depth using multiple noxious stimuli during isoflurane/oxygen anesthesia. Anesthesiology 80, 261– 267. Zwijnenberg RJ, del Rio CL, Pollet RA et al. (2010) Effects of perzinfotel, butorphanol tartrate, and a butorphanolperzinfotel combination on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 71, 1270–1276. Zwijnenberg RJ, del Rio CL, Cobb RM et al. (2011) Evaluation of oscillometric and vascular access port arterial blood pressure measurement techniques versus implanted telemetry in anesthetized cats. Am J Vet Res 72, 1015–1021. Received 3 December 2012; accepted 13 March 2013.
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