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Anesth Analg 2001;93:947-953
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Age, Minimum Alveolar Anesthetic Concentration, and Minimum Alveolar Anesthetic Concentration-Awake

Edmond I Eger, II, MD

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Address correspondence and reprint requests to Dr. Eger, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Appendix 1
 References
 
Two defining effects of inhaled anesthetics (immobility in the face of noxious stimulation, and absence of memory) correlate with the end-tidal concentrations of the anesthetics. Such defining effects are characterized as MAC (the concentration producing immobility in 50% of patients subjected to a noxious stimulus) and MAC-Awake (the concentration suppressing appropriate response to command in 50% of patients; memory is usually lost at MAC-Awake). If the concentrations are monitored and corrected for the effects of age and temperature, the concentrations may be displayed as multiples of MAC for a standard age, usually 40 yr. This article provides an algorithm that might be used to produce such a display, including provision of an estimate of the effect of nitrous oxide.

IMPLICATIONS: Two defining effects of inhaled anesthetics (immobility in the face of noxious stimulation, and absence of memory) correlate with the end-tidal concentrations of the anesthetics. Thus, these defining effects may be monitored and the results displayed if the concentrations are known and corrected for the effects of age and temperature.


   Introduction
Top
 Abstract
 Introduction
Appendix 1
 References
 
A definition of anesthetic requirement requires an appreciation of the diverse effects of anesthetics. These effects include the capacity of anesthetics to produce immobility (the basis of MAC, the minimum alveolar concentration of inhaled anesthetics at 1 atm that produces immobility in response to a noxious stimulus in 50% of subjects) and to suppress appropriate response to command (i.e., MAC-Awake, the end-tidal anesthetic concentration at 1 atm that suppresses the appropriate response to command in 50% of subjects). Age influences both MAC and MAC-Awake in humans, and temperature influences MAC in animals and, presumably, in humans. Finally, combining inhaled anesthetics, particularly combining nitrous oxide (N2O) with a potent inhaled anesthetic, may produce a roughly additive effect. This article reviews these relationships for humans and suggests how this information might be used to improve the display available to the anesthetist on anesthetic monitors.

Age and MAC
Mapleson (1) applied a metaanalysis to estimate the effect of age on MAC, finding a decrease in MAC of approximately 6% per decade for various inhaled anesthetics. This study applies the data considered by Mapleson and adds data published subsequently for sevoflurane (Table 1) (2–37), focusing on the anesthetics in widest use, namely desflurane (2–4), halothane (7–14,18), isoflurane (15–21), N2O (22), and sevoflurane (23–34,36,37). After excluding data for subjects <1 yr old (because such data can deviate from the age-related decrease in MAC with increasing age), least-squares regression of log MAC on age was applied separately (Table 2) for the individual potent inhaled anesthetics listed in Table 1 (note that, although data for enflurane are included in Table 1, they are not used in the analysis because they are insufficient to define the effect of age for the individual anesthetic). The regression deliberately did not apply weighting to account for the number of subjects tested in each study because M. Paul and D. Fisher (personal communication, 2001) have shown through simulations that the accuracy of a MAC determination is not appreciably increased by making more than two to four cross-over determinations. Because each of the published values for MAC in humans resulted from at least four determinations, we elected to give equal weight to each.


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  		Table 1.  MAC for Inhaled Anesthetics Given in a Background of Oxygen
 

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  		Table 2.  Factors in the Determination of the Effect of Age on MAC
 
By using the MAC value at age 40 yr determined by the regression analysis for the data for each individual anesthetic (Table 2; the value for MAC at 40 yr is nearly identical to the MAC obtained by Mapleson), each MAC value at different ages was normalized to the MAC value at 40 yr (i.e., the MAC for a given age was divided by the MAC at 40 yr; fourth column, Table 1). We chose the MAC at 40 yr because the largest body of data is for patients near this age (Table 1, Fig. 1). A least-squares analysis of these normalized values for the different potent inhaled anesthetics (MACPnor40) for the data from age 1 yr and older gave the following regression:



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  		Figure 1. Minimum alveolar anesthetic (MAC) values were obtained from various studies, as listed in Table 1. For a given potent inhaled anesthetic, a least-squares regression was used to calculate the MAC at age 40 yr (Table 2). Each value for MAC at the patient age studied was divided by the MAC at age 40 yr. The resulting normalized ratios are plotted here (note that the ordinate has a logarithmic scale). A least-squares regression through these values provided an estimate of the ratio as a function of age: MACPnor40 (MAC as a fraction of MAC at age 40 yr) = 1.32 x 10-0.00303age. Thus, MAC decreased by 6.7% with each increasing decade of life, a value similar to the 6% decrease found by Mapleson (2). The correlation is associated with an r2 of 0.85.

 
equation


This relationship suggests that each increasing decade of life is associated with a 6.7% decrease in MAC (Fig. 1), a value similar to the 6% decrease found by Mapleson. The correlation is associated with an r2 of 0.85. For the 47 values that make up Figure 1, the deviation from the values predicted from Equation 1 is 5.0% ± 4.9% (mean ± SD). Three values (one for halothane and two for sevoflurane) (10,25,27) deviate from those predicted by >3 SD. If these are excluded, the deviation is 4.0% ± 3.3%.

Assuming additivity of N2O with the potent anesthetic, the use of Equation 1 permits calculation of the MAC of N2O (MACN2O) at various ages:

equation


where atm N2O is the atmospheres of N2O used in combination with the atmospheres of potent inhaled anesthetic (atm AN) to produce immobility in 50% of patients. MACAN is the MAC (corrected for age) of the potent anesthetic when it is used in the absence of N2O. In effect, this equation states that the fraction of MAC supplied by N2O equals the fraction not supplied by the potent anesthetic. The MAC for N2O from a regression analysis of these data was 1.565 x 10-0.00343age (r2 = 0.32). The MAC for N2O at 40 yr thus would be 1.14 atm. The correlation coefficient for these data was lower than those for the potent inhaled anesthetics. For the 14 values that make up Figure 2, the deviation (absolute values) from the values predicted from the regression analysis for N2O is 17.7% ± 17.3%. The deviation largely is caused by the great variability of data for very young patients. Thus, the accuracy of the values for children from the equation is limited.



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  		Figure 2. As with the potent inhaled anesthetics, the minimum alveolar anesthetic concentration (MAC) of nitrous oxide (determined by studies of the additive effects of nitrous oxide plus a potent inhaled anesthetic) correlates inversely with an increase in the age of patients (note that the ordinate has a logarithmic scale). As with Figure 1, this figure presents the data for nitrous oxide normalized to age 40 yr. The resulting MACNnor40 = 1.378 x 10-0.00347age (r2 = 0.32). The correlation for this determination is poorer than that for the potent anesthetics, primarily because of the large scatter of data for younger patients and the addition of the errors of measurement of both the potent anesthetic MAC and the nitrous oxide contribution to that MAC.

 
Excluding a value for <1 yr of age, each MAC value for N2O at different ages was divided by the MAC for N2O at 40 yr for data from studies of additivity with desflurane (3,4,38), halothane (9,13), isoflurane (17,18), N2O itself (22), and sevoflurane (30,33) (Table 3) (39). Least-squares analysis for these normalized values for N2O (MACNnor40) gave the following regression (Fig. 2) (r2 = 0.32):


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  		Table 3.  Effect of Age on Nitrous Oxide MAC
 
equation


These results suggest that MAC for N2O decreases 7.7% with each decade increase in life.

Age and MAC-Awake
Several studies provide values for MAC-Awake for desflurane (40,41), halothane (42), isoflurane (43,44–46), N2O (43,45), and sevoflurane (31,29,32,44–48) (Table 4) (49). For isoflurane and sevoflurane, MAC-Awake decreases with increasing age, and it does so in a manner parallel to the effect of age on MAC itself. That is, the ratio of MAC-Awake to MAC (estimated from the MAC at age 40 yr [Table 2] and then corrected for age [Equation 1]) does not change with increasing age. We assume that this relationship applies to all inhaled anesthetics. For desflurane, isoflurane, and sevoflurane, MAC-Awake/MAC is 0.343 ± 0.017 (mean ± SD for 18 values). That is, for these three anesthetics, MAC-Awake is a third of MAC. This value is 62% of the 0.55 value for halothane and N2O. As indicated in the legend for Table 4, the values for N2O MAC-Awake may slightly underestimate the correct value. Thus, patients given halothane or N2O need to eliminate less anesthetic to reach a partial pressure that permits appropriate response to command than do patients given desflurane, isoflurane, or sevoflurane. However, MAC-Awake is also close to the anesthetic concentration suppressing memory and learning (43,50–52). That is, desflurane, isoflurane, and sevoflurane are more potent amnestic anesthetics than halothane and N2O (43).


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  		Table 4.  Age and MACawake
 
Body Temperature and MAC
In animals, and presumably humans, MAC for potent inhaled anesthetics decreases with decreasing body temperature by approximately 4% to 5% per degrees centigrade decrease, doing so in a rectilinear manner (53–55), with complete elimination of the requirement for anesthesia at 20°C (56). However, this relationship does not extend to N2O; MAC for N2O does not change materially with decreasing temperature (57).

Application to Anesthetic Monitors
Some present end-tidal (alveolar) analyzers analyze the end-tidal concentrations of N2O plus a concurrently administered potent inhaled anesthetic and convert these values to nominal MAC values. In the past, these conversions often assumed a single value for MAC for a given anesthetic, the chosen value usually being that for a young to middle-aged adult (20 to 60 yr old). The result is a fair, but limited, approximation to a true MAC. Except for the MAC display in the new Julian Software 3.0® (Dräger Medizintechnik GmbH, Lübeck, Germany), no present monitor provides concurrent information on MAC and MAC-Awake.

The preceding information on the influence of age on MAC and MAC-Awake might be used in a summary manner in the display provided by future anesthetic monitors (see Appendix 1 for details). Because core temperature and end-tidal anesthetic concentrations are usually monitored, incorporation of these measurements would require no action on the part of the anesthetist, who would, however, have to enter the patient’s age. Absent input on age, and perhaps temperature, the monitor would assume a default state of normal temperature and 40 yr of age.

MAC and MAC-Awake conventionally are given as percentage anesthetic at 1 atm or the fraction of MAC, respectively. The anesthesiologist using these values must appreciate that the reference pressure always is 1 atm. Optimally, any device that provided a readout of MAC and MAC-Awake would correct readout values for the ambient pressure.

Some variables are probably too uncertain or difficult to account for in an augmented monitor display. These include the effects of pregnancy (58), increased cerebrospinal fluid sodium (59), and injected depressant drugs (19,30,47,60–62) on MAC and MAC-Awake. Although potential interactions are many, implementation of these into an algorithm would be nearly impossible because the data needed (e.g., the blood concentration of the injected drug) would not be available. Finally, the monitor should indicate that values for MAC and MAC-Awake for patients less than 1 yr old are probably of limited accuracy.


   Appendix 1
Top
 Abstract
 Introduction
 Appendix 1
References
 
We begin with a knowledge of the MAC for a specific potent inhaled anesthetic at age 40 yr (Table 1), termed A. We correct A, by using the fraction obtained from Equation 1, for the fact that the patient is aged B yr, giving us C. That is,

equation


We assume a 5% rectilinear (not logarithmic) correction per degree core temperature decrease from 37°C. Thus, we correct C to give D:

equation


where T is the core temperature (°C). D is the MAC value (atm) corrected for age and temperature. The MAC fraction, E, provided by atm AN (where atm AN is the actual end-tidal partial pressure of potent inhaled anesthetic in atmospheres), thus is

equation


The MAC (F) of N2O is obtained from MAC of N2O at age 40 yr corrected as in Equation 3 for the patient’s age. No correction is made for temperature:

equation


The MAC contribution of N2O (G) then would be

equation


Thus the total MAC for the combination of N2O plus the potent anesthetic is H:

equation


Determination of MAC-Awake follows from the above. For desflurane, isoflurane, sevoflurane, and (possibly) enflurane, MAC-Awake (I) may be calculated as

equation


For halothane, the MAC-Awake value is J:

equation


And for N2O, the MAC-Awake value is K:

equation


The fraction of the MAC-Awake value supplied by the potent inhaled anesthetics desflurane, isoflurane, or sevoflurane (L), then, is

equation


The fraction of the MAC-Awake value supplied by halothane (M) is

equation


and the fraction of the MAC-Awake value supplied by N2O (N) is

equation


Finally, the total fraction (or multiple) of MAC-Awake (O) is

equation


This ignores a slight antagonism of N2O and at least one potent inhaled anesthetic, isoflurane (63).


   Acknowledgments
 
Dr. Eger is a paid consultant to Baxter Healthcare Corp. and to Agilent Technologies. This work was supported in part by NIH Grant 1P01GM47818-04.

I gratefully acknowledge and appreciate the several detailed comments and suggestions made by Professor William W. Mapleson.


   References
Top
 Abstract
 Introduction
 Appendix 1
 References
 

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Accepted for publication May 23, 2001.




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R. E. McKay, A. Bostrom, M. C. Balea, and W. R. McKay
Airway Responses During Desflurane Versus Sevoflurane Administration via a Laryngeal Mask Airway in Smokers
Anesth. Analg., November 1, 2006; 103(5): 1147 - 1154.
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D. J. Castanelli, W. M. Splinter, and N. A. Clavel
Remifentanil decreases sevoflurane requirements in children: [Le remifentanil diminue les besoins de sevoflurane chez les enfants]
Can J Anesth, December 1, 2005; 52(10): 1064 - 1070.
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V. Erden, Z. Yangin, K. Erkalp, H. Delatioglu, F. Bahceci, and A. Seyhan
Increased Progesterone Production During the Luteal Phase of Menstruation May Decrease Anesthetic Requirement
Anesth. Analg., October 1, 2005; 101(4): 1007 - 1011.
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M. J. Laster and E. I. Eger II
Temperatures in Soda Lime During Degradation of Desflurane, Isoflurane, and Sevoflurane by Desiccated Soda Lime
Anesth. Analg., September 1, 2005; 101(3): 753 - 757.
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R. E. Mckay, M. J. C. Large, M. C. Balea, and W. R. Mckay
Airway Reflexes Return More Rapidly After Desflurane Anesthesia Than After Sevoflurane Anesthesia
Anesth. Analg., March 1, 2005; 100(3): 697 - 700.
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H. S. Schwab, M. D. Seeberger, E. I Eger II, C. H. Kindler, and M. Filipovic
Sevoflurane Decreases Bispectral Index Values More than Does Halothane at Equal MAC Multiples
Anesth. Analg., December 1, 2004; 99(6): 1723 - 1727.
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E. M. Strum, J. Szenohradszki, W. A. Kaufman, G. J. Anthone, I. L. Manz, and P. D. Lumb
Emergence and Recovery Characteristics of Desflurane Versus Sevoflurane in Morbidly Obese Adult Surgical Patients: A Prospective, Randomized Study
Anesth. Analg., December 1, 2004; 99(6): 1848 - 1853.
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M. Laster, P. Roth, and E. I Eger II
Fires from the Interaction of Anesthetics with Desiccated Absorbent
Anesth. Analg., September 1, 2004; 99(3): 769 - 774.
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J. G. C. Lerou
Nomogram to estimate age-related MAC
Br. J. Anaesth., August 1, 2004; 93(2): 288 - 291.
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L. Dimpel and M. Enlund
Use of nitrous oxide in anaesthesia
Br. J. Anaesth., October 1, 2003; 91(4): 605 - 606.
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 Br J AnaesthHome page
D. White
Uses of MAC
Br. J. Anaesth., August 1, 2003; 91(2): 167 - 169.
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R. W. D. Nickalls and W. W. Mapleson
Age-related iso-MAC charts for isoflurane, sevoflurane and desflurane in man
Br. J. Anaesth., August 1, 2003; 91(2): 170 - 174.
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R. W. Eshima, A. Maurer, T. King, B.-K. Lin, J. E. Heavner, M. S. Bogetz, and A. D. Kaye
A Comparison of Airway Responses During Desflurane and Sevoflurane Administration via a Laryngeal Mask Airway for Maintenance of Anesthesia
Anesth. Analg., March 1, 2003; 96(3): 701 - 705.
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T. Engelhardt, P.R. Lowe, and E. I. Eger II
MAC Does Not Matter to the Patient * Response
Anesth. Analg., August 1, 2002; 95(2): 499 - 499.
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