120
ANESTH ANALG 1990;71:12C-4
Additive Contribution of Nitrous Oxide to Halothane MAC in Infants and Children David J. Murray,
MD,
Mahesh P. Mehta,
MD,
MURRAY DJ, MEHTA MI', FORBES RB, DULL DL. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990;71:1204.
Fifty-one infants and small children (14.7 5 7.2 mo) were studied to determine the M A C of halothane in 0, (n = 11) and in the presence of three different nitrous oxide (N,O) concentrations (25% In = 131, 50% I n = 131, and 75% [n = 141). In the three N,O groups, after randomly assigning patients to an N 2 0 group, anesthesia was induced with halothane and N 2 0 using a pediatric circle system. After endotracheal intubation, halothane and N 2 0 end-expired concentrations were adjusted to predetermined concentrations. The initial halothane concentrations in each group were based on the assumption that each percent N 2 0 reduced halothane concentrations by 0.01 vol % (assumed halothane M A C = 1 .O vol a). Based on the response of the preceding subject in each group, halothane concentrations were increased or decreased depending on whether the response was to move or not to move, respectively, in response to the surgical incision. The mean duration of
In clinical studies, when two anesthetic drugs are combined anesthetic requirements for both drugs are reduced in a simple additive fashion (1-5). Recently, it has been observed that different nitrous oxide (N20) concentrations may not contribute to enflurane MAC in an additive manner (6). In a rat model, Cole et al. found concentrations of 10%-30% N 2 0 reduced enflurane MAC relatively more than concentrations of 60%-80% N 2 0 . Using multiple N 2 0 concentrations, the study suggested a nonlinear contribution of N,O to enflurane MAC (6). In humans, most studies that concluded that the contribution of N,O to MAC Supported by a grant from the Foundation for Anesthesia Education and Research (FAER), 1988. Received from the Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa. Accepted for publication April 23, 1990. Address correspondence to Dr. Murray, Department of Anesthesia, University of Iowa College of Medicine, Iowa City, IA 52242. 01990 by the International Anesthesia Research Society
Robert B. Forbes,
MD,
and David L. Dull,
MD
constant end-tidal concentrations before skin incision was 10 min. End-tidal gases were sampled and measured from a separate distal sampling port of an endotracheal tube during controlled ventilation (Perkin-Elmer Mass Spectrometer). The M A C value for halothane in 0, was 0.94 2 0.08 vol % (mean SD). The MAC values of halothane in the presence of 25%, 50%, and 75% N 2 0 were 0.78 0.12 vol %, 0.44 0.10 vol %, and 0.29 F 0.06 vol %, respectively. All concentrations of N,O significantly reduced the M A C of halothane. A regression analysis through all four data points yielded a linear relationship (r? = 0.87) with a predicted MAC for N 2 0 of 105 vol % . Unlike halothane and isoflurane, the predicted M A C of N 2 0 in infants and children is similar to that reported by others in adults. Similar to the results of clinical studies in adults, the contribution of N,O to halothane M A C in children is additive.
* *
*
Key Words: ANESTHETICS, GAsEs-nitrous oxide.
ANESTHESIA, PEDIATRIC. POTENCY, ANESTHETIC-nitrous oxide. INTERACTIONS (DRUG), NITROUS OXIDE, HALOTHANE.
is additive have assessed only one N 2 0 concentration (3,7). In a study of adults, the effect of two different N 2 0 concentrations in reducing enflurane MAC suggested a similar additive effect in reducing the MAC of enflurane (8). A clinical study measuring the contribution of multiple N 2 0 concentrations to halothane, isoflurane, or enflurane in humans is not currently available. Although absolute MAC values for N 2 0 in separate age groups are not available, the predicted MAC value of N 2 0 was lower in older adults than in younger adults in a study assessing the contribution of 60% N 2 0 in reducing the MAC of isoflurane (7). Age alters anesthesia requirements for halothane and isoflurane (9-11). With the increased MAC of halothane and isoflurane in infants and children, perhaps the contribution of N 2 0 to halothane anesthesia may be less in this age group than in adults. The purpose of this study was to measure whether anesthetic requirements for N20, like halothane and
ADDITIVE CONTRIBUTION OF N,O TO MAC IN INFANTS
isoflurane, vary with age, and to determine whether the contribution of various concentrations of N 2 0 reduce halothane MAC requirements in a linear or nonlinear fashion in infants and small children.
Methods After the study was approved by the Committee for Human Studies and informed written parental consent was obtained, 51 ASA physical status I or I1 infants and small children (7-30 mo old) who required elective surgery were studied. The infants and small children received no premedicants and fasted for 4-6 h before anesthesia induction. In all infants and children anesthesia was induced by mask with halothane and N,O using a semi-closed circle system. Oxygen saturation, blood pressure, and heart rate by electrocardiogram were monitored during induction and maintenance of anesthesia. Under deep halothane anesthesia, the tracheas were intubated using a 4.0 or 4.5 Sheridan Etco, uncuffed tracheal tube, which contains a secondary lumen for obtaining gas samples from the distaI end of the endotracheal tube. End-tidal and inspired anesthetic concentrations were measured using a Perkin-Elmer mass spectrometer. After endotracheal intubation, anesthetic concentrations were reduced to predetermined N,O and halothane concentrations and maintained constant for as long as possible before skin incision. Ventilation was controlled with tidal volumes of 10-12 mL/kg and respiratory rates were maintained between 16 and 24 breathdmin to maintain end-tidal Pco, at 32 2 5 mm Hg (mean ? SD). The 51 patients were divided into four groups according to the predetermined N,O concentration used during the study period. The first 40 patients were randomly assigned to either 25% ( n = 13), 50% (n = 13), or 75% ( n = 14) N,O groups. The 0% N 2 0 group (n = 11) was studied after the completion of the N,O groups. With a constant level of N,O maintained in each patient, a single halothane concentration was then assessed to determine each child’s response to skin incision. The technique used to determine MAC was adapted from prior MAC studies where the objective was to bracket an end-tidal concentration of halothane that was MAC for the group being studied (3,7-11). Each patient was observed for purposeful movement in the 20-30 s after skin incision. Increases in respiratory rate, coughing, or breath holding after skin incision were not considered to constitute purposeful movement. The initial halothane concentration selected in each group was based on the
ANESTH ANALG 1990;71: 12M
121
assumption that 1%N 2 0 would reduce halothane concentrations by 0.01 vol % because prior studies have determined the MAC of halothane to be 1.0 vol % in infants and children (10). For each subsequent patient, the halothane concentration selected was based on the response of the previous infant or child. The end-tidal halothane concentration was increased or decreased by 0.1 or 0.2 vol % depending on whether the preceding infant or small child studied had moved or not moved after skin incision. A requirement for beginning data collection in a group was an initial paired response of move/no move or vice versa. The data were analyzed by the method described by Dixon for determining quanta1 responses (12). The age, weight, CO,, duration of constant end-tidal values, and halothane MAC were analyzed by oneway analysis of variance to determine differences between the four groups. A regression analysis was applied to the halothane groups to determine the correlation between halothane doses at different N,O concentrations. All results are expressed as mean ? SD.
Results The MAC value for halothane in O2 was 0.94 ? 0.08 vol %. The addition of 25% N,O reduced the MAC value for halothane to 0.78 ? 0.12 vol %. The MAC value of halothane during 50% and 75% N,O was 0.44 5 0.10 and 0.29 _t 0.06 vol %, respectively. The MAC values for halothane were significantly different in each N,O level and, as expected, increasing N,O concentrations progressively reduced anesthetic requirements for halothane. The age, weight, mean expired N,O concentration, and end-tidal CO, are presented in Table 1. Tracheal intubation performed under deep halothane anesthesia occurred a minimum of 15 min and a maximum of 52 min before the assessment of MAC after skin incision. The mean respiratory rate of the infants and children before skin incision was 22.6 t 3 breathdmin. The mean duration of constant endexpired halothane levels was 10 min (range, 6-27 min). The ratio between end-expired halothane and inspired halothane was 0.96 t 0.03 at the time of skin incision. The move/no move responses to skin incision of the infants and children at each study level are presented in Figure 1. Regression analysis was applied to determine the correlation coefficient and slope of the line extrapolated through the data sets. The r value for this line is
122
MURRAY ET AL.
ANESTH ANALG 1990;71: 12G4
Table 1. Summary of Results in Each Group Response to skin incision Move (n)
No move (n)
Mean expired N,O (vol %)
Halothane MAC (vol %)
End-tidal CO, (mm Hg)
2.5
6
5
0 ( n = 11)
0.94 2 0.08
29.9 t 3.5
11.5 t 6.0
9.4 i 2.0
6
7
0.78 i 0.12
30.4 2 4.5
15.7 ? 6.4
11.1 t 2.2
6
7
0.44 i 0.10
29.3 i 3.0
17.2 k 6.9
11.2
7
7
24.8 t 1.4 ( n = 13) 49.9 i 1.4 ( n = 13) 73.3 2 2.8 ( n = 14)
0.29 t 0.06
33.4 2 3.9
Age (mo) 14.4
6.9
Weight (kg) 9.9
Ifr
k
2.5
~
All results are expressed as mean
2 SD.
-
'e
&%i
0 0
. . . W o o % %
.. I
0.00
0.25
0
p
Figure 1 . Response to skin incision (move or no move) in four groups of infants assessed at various halothane concentrations. Each patient is represented by a closed (move) or open (no move) circle.
0 0 0
I
I
0.75
1 .oo
I
0.50
m v E N O m v E
0
HALOTHANE VOL Yo
0.934 with an Y' value of 0.87 (Figure 2). The value for 1 MAC N,O predicted from extending the linear regression line is 105% (Figure 2).
Discussion End-expired halothane concentrations were used to reflect central nervous system concentrations of halothane (13,14). The measurement of end-expired halothane assumes that these concentrations reflect end-tidal anesthetic levels. Arterial anesthetic concentrations were assumed to be equivalent to levels of halothane in the central nervous system. For halothane concentrations: end-expired endtidal ~4 alveolar a arterial a central nervous system. Entrainment of inspired gas could limit the accuracy of end-tidal values in reflecting alveolar halothane concentration, particularly when respiratory rates are rapid and tidal volumes are small. For this
reason, distal tracheal gas sampling from an endotracheal tube in infants was used to measure alveolar gas samples (15,16). Alveolar anesthetic levels reach equilibrium with anesthetic levels in the brain over a period of time. A soluble anesthetic such as halothane requires more time to achieve equilibrium with vessel-rich tissue groups than does N,O. In infants the time constant of equilibrium for halothane concentrations in the central nervous system to reach equilibrium with end-tidal halothane concentrations is shorter than in adults (14). A minimum of two to three constants would be required to assure that brain concentrations are equivalent to alveolar levels (13,14). Before the assessment of MAC, anesthetic concentrations were unchanged for a period of time equivalent to three to four time constants (10 min). Tracheal intubation was performed under deeper levels of halothane anesthesia without muscle relaxants, and then halothane concentrations were reduced to the end-tidal halothane concentrations that
ADDITIVE CONTRIBUTION OF N,O TO MAC IN INFANTS
ANESTH ANALG 1990;71:12&4
123
HALOTHANE VOL % 1.oo
Figure 2. Regression analysis of four data voints. The halothane MAC at dikerent N,O concentrations are plotted, and the line represents the regression analysis through all four data points. “ A ‘ indicates predicted MAC of N,O.
i1
0.75
0.50
-
0.25-
0.00
!
I
I
0.0
25.0
\ 50.0
%N20
were assessed at skin incision. For this reason, small differences between alveolar and inspired halothane concentrations were measured at the time of skin incision (13). The MAC of halothane in this study was similar to the values reported by Gregory et al. in a study of infants of similar age (10). In prior studies in adults, when N 2 0 was added to halothane, enflurane, or isoflurane the contribution to MAC was additive (3,7,8). We found a similar additive effect at three N 2 0 concentrations (25%, 50%, and 75%) during halothane anesthesia. When six different concentrations of N,O were assessed, Cole et al. suggested that higher N,O concentrations (60%-80%) contributed proportionately less to the MAC of enflurane in rats than lower concentrations (10%-30%) ( 6 ) . In an editorial that accompanied this article, Eger suggested the data presented by Cole et al. could have been interpreted to indicate an additive effect of N,O (1). In a letter to the editor, Cole et al. suggest that perhaps higher N,O concentrations by increasing sympathetic activity may alter anesthetic requirements (17). If increases in sympathetic activity during N,O are dose-related, as suggested in clinical studies, and if increases in sympathetic stimulation increase anesthetic requirements, then a nonlinear contribution of N,O might occur with lower N 2 0 concentrations reducing MAC proportionately more than higher N,O concentrations. In infants and children, Hickey et al. and Murray et al. found cardiovascular changes that suggest minimal sympathetic stimulating effect of N,O (18,19). This may explain why a linear contribution of N,O was observed in this study of infants and children but not in the study of Cole et al. A separate clinical study would be required to
75.0
I
100
9 A
assess whether increases in sympathetic activity produced by N,O alter anesthetic requirements. With requirements for halothane and isoflurane concentrations increased 130% and 140% in infants compared to adults, we anticipated that the MAC of N,O might be increased in infants and children, and that the contribution of N,O to halothane anesthesia would be less than in adults. Using a linear regression analysis, the projected N,O concentration required to produce 1.0 MAC in infants and small children was 105%. In adults, using assessments based on the additive contribution of a single N,O concentration to halothane or isoflurane, the MAC of N 2 0 was predicted to be 108%, 11896, 105%, and 110% (3,7,8). The predicted MAC of N,O in this study as well as in prior clinical studies assumes that the contribution of N 2 0 to MAC remains linear at concentrations of greater than 75%. In the only study assessing the MAC of N 2 0 alone under hyperbaric conditions, the MAC of N,O in healthy adult volunteers was 106% (20). Although this study supports the concept of additivity of anesthetic agents in predicting MAC, we found that the MAC of N,O, unlike the volatile anesthetics, was not increased in infants and small children. In a younger (19-30 yr), as well as in an older patient population (>55 yr), the predicted MAC of N,O during isoflurane anesthesia decreased from 116% to 100% (7). The MAC of halothane in 0, in infants was 0.94 vol % compared to 0.78 vol % in adults. The addition of 75% N,O to halothane reduced the MAC of halothane to 0.29 0.06 vol % in infants and children. In adults, the MAC of halothane during 70% N,O is 0.29 vol % (3). When combined with the other properties of N,O, such as its low
*
124
ANESTH ANALG 1990;71:12%4
solubility and minimal cardiovascular effects, the continued use of N,O in children seems warranted because N 2 0 reduces halothane and perhaps isoflurane concentrations required to achieve surgical anesthesia to a greater degree in infants than in adults. In summary, in infants and children, N 2 0 concentrations reduce halothane MAC in a linear additive manner. The predicted MAC of N,O based on a linear regression analysis is similar in infants and adults.
References ~~
1. Eger El 11. Does 1 + 1 = 2? Anesth Analg 1989;68:551-5. 2. Eger EI 11, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:75M13. 3. Saidman LJ, Eger El 11. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology 1964;25:302-6. 4. Quasha AL, Eger EI 11, Tinker JH. Determination and applications of MAC. Anesthesiology 1980;53:31534. 5. Gion H, Saidman LJ. The minimum alveolar concentration of enflurane in man. Anesthesiology 1971;35:361-4. 6. Cole DJ, Kalichman MW, Shapiro HM. The nonlinear contribution of nitrous oxide at sub-MAC ccmcentrations to enflurane MAC in rats. Anesth Analg 1989;68:556-62. 7. Stevens WC, Dolan WM, Gibbons RT, et al. Minimum alveolar concentrations (MAC) of isoflurane with and without oxide in patients of various ages. Anesthesiology 1975;42:197-200. 8. Torri G, Damia C , Fabiani ML. Effect of nitrous oxide on the anaesthetic requirement of enflurane. Br J Anaesth 1974;46: 468-72.
MURRAY ET AL.
9. Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements for halothane in young children 0-1 month and 1 4 months of age. Anesthesiology 1983;59:421-4. 10. Gregory GA, Eger El 11, Munson ES. The relationship between age and halothane requirement in man. Anesthesiology 1969; 30:488-91. 11. Cameron CB, Robinson S, Gregory GA. The minimum anesthetic concentration of isoflurane in children. Anesth Analg 1984;63:418-20. 12. Dixon WJ. Quantal-response experimentation: the up-anddown method. In: McArthur JW, Colton T, eds. Statistics in endocrinology proceedings. Cambridge: MIT Press, 1970:25167. 13. Eger El 11. Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Eger EI 11, ed. Anesthetic uptake and action. Baltimore: Williams & Wilkins, 1974:77-96. 14. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969;30:338-94. 15. Ozanne GM, Young WG, Mazzei WJ, Severinghaus JW. Multipatient anesthetic mass spectrometry: rapid analysis of data stored in long catheters. Anesthesiology 1981;55:62-70. 16. Schieber RA, Namnoum A, Sugden A, Saville AL, Orr RA. Accuracy of expiratory carbon dioxide measurements using the coaxial and circle breathing circuits in small subjects. J Clin Monit 1985;1:149-55. 17. Cole DJ, Kalichman MW, Shapiro HM, Eger El 11. Does 1 + 1 = 2?-a continuing debate. Anesth Analg 1990;70:126-7. 18. Hickey PR, Hansen DD, Stafford M, Thompson SL, Jonas RE, Mayer JE. Pulmonary and systemic hemodynamic effect of nitrous oxide in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1986;65:37&8. 19. Murray DJ, Forbes RB, Murphy K, Mahoney LT. Nitrous oxide: cardiovascular effects in infants and children during halothane and isoflurane anesthesia. Anesth Analg 1988;67: 105944. 20. Hornbein TF, Eger El 11, Winter PM, Smith G, Wctstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982;61:55M.
ANESTH ANALG 1990;71:12C-4
Additive Contribution of Nitrous Oxide to Halothane MAC in Infants and Children David J. Murray,
MD,
Mahesh P. Mehta,
MD,
MURRAY DJ, MEHTA MI', FORBES RB, DULL DL. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990;71:1204.
Fifty-one infants and small children (14.7 5 7.2 mo) were studied to determine the M A C of halothane in 0, (n = 11) and in the presence of three different nitrous oxide (N,O) concentrations (25% In = 131, 50% I n = 131, and 75% [n = 141). In the three N,O groups, after randomly assigning patients to an N 2 0 group, anesthesia was induced with halothane and N 2 0 using a pediatric circle system. After endotracheal intubation, halothane and N 2 0 end-expired concentrations were adjusted to predetermined concentrations. The initial halothane concentrations in each group were based on the assumption that each percent N 2 0 reduced halothane concentrations by 0.01 vol % (assumed halothane M A C = 1 .O vol a). Based on the response of the preceding subject in each group, halothane concentrations were increased or decreased depending on whether the response was to move or not to move, respectively, in response to the surgical incision. The mean duration of
In clinical studies, when two anesthetic drugs are combined anesthetic requirements for both drugs are reduced in a simple additive fashion (1-5). Recently, it has been observed that different nitrous oxide (N20) concentrations may not contribute to enflurane MAC in an additive manner (6). In a rat model, Cole et al. found concentrations of 10%-30% N 2 0 reduced enflurane MAC relatively more than concentrations of 60%-80% N 2 0 . Using multiple N 2 0 concentrations, the study suggested a nonlinear contribution of N,O to enflurane MAC (6). In humans, most studies that concluded that the contribution of N,O to MAC Supported by a grant from the Foundation for Anesthesia Education and Research (FAER), 1988. Received from the Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa. Accepted for publication April 23, 1990. Address correspondence to Dr. Murray, Department of Anesthesia, University of Iowa College of Medicine, Iowa City, IA 52242. 01990 by the International Anesthesia Research Society
Robert B. Forbes,
MD,
and David L. Dull,
MD
constant end-tidal concentrations before skin incision was 10 min. End-tidal gases were sampled and measured from a separate distal sampling port of an endotracheal tube during controlled ventilation (Perkin-Elmer Mass Spectrometer). The M A C value for halothane in 0, was 0.94 2 0.08 vol % (mean SD). The MAC values of halothane in the presence of 25%, 50%, and 75% N 2 0 were 0.78 0.12 vol %, 0.44 0.10 vol %, and 0.29 F 0.06 vol %, respectively. All concentrations of N,O significantly reduced the M A C of halothane. A regression analysis through all four data points yielded a linear relationship (r? = 0.87) with a predicted MAC for N 2 0 of 105 vol % . Unlike halothane and isoflurane, the predicted M A C of N 2 0 in infants and children is similar to that reported by others in adults. Similar to the results of clinical studies in adults, the contribution of N,O to halothane M A C in children is additive.
* *
*
Key Words: ANESTHETICS, GAsEs-nitrous oxide.
ANESTHESIA, PEDIATRIC. POTENCY, ANESTHETIC-nitrous oxide. INTERACTIONS (DRUG), NITROUS OXIDE, HALOTHANE.
is additive have assessed only one N 2 0 concentration (3,7). In a study of adults, the effect of two different N 2 0 concentrations in reducing enflurane MAC suggested a similar additive effect in reducing the MAC of enflurane (8). A clinical study measuring the contribution of multiple N 2 0 concentrations to halothane, isoflurane, or enflurane in humans is not currently available. Although absolute MAC values for N 2 0 in separate age groups are not available, the predicted MAC value of N 2 0 was lower in older adults than in younger adults in a study assessing the contribution of 60% N 2 0 in reducing the MAC of isoflurane (7). Age alters anesthesia requirements for halothane and isoflurane (9-11). With the increased MAC of halothane and isoflurane in infants and children, perhaps the contribution of N 2 0 to halothane anesthesia may be less in this age group than in adults. The purpose of this study was to measure whether anesthetic requirements for N20, like halothane and
ADDITIVE CONTRIBUTION OF N,O TO MAC IN INFANTS
isoflurane, vary with age, and to determine whether the contribution of various concentrations of N 2 0 reduce halothane MAC requirements in a linear or nonlinear fashion in infants and small children.
Methods After the study was approved by the Committee for Human Studies and informed written parental consent was obtained, 51 ASA physical status I or I1 infants and small children (7-30 mo old) who required elective surgery were studied. The infants and small children received no premedicants and fasted for 4-6 h before anesthesia induction. In all infants and children anesthesia was induced by mask with halothane and N,O using a semi-closed circle system. Oxygen saturation, blood pressure, and heart rate by electrocardiogram were monitored during induction and maintenance of anesthesia. Under deep halothane anesthesia, the tracheas were intubated using a 4.0 or 4.5 Sheridan Etco, uncuffed tracheal tube, which contains a secondary lumen for obtaining gas samples from the distaI end of the endotracheal tube. End-tidal and inspired anesthetic concentrations were measured using a Perkin-Elmer mass spectrometer. After endotracheal intubation, anesthetic concentrations were reduced to predetermined N,O and halothane concentrations and maintained constant for as long as possible before skin incision. Ventilation was controlled with tidal volumes of 10-12 mL/kg and respiratory rates were maintained between 16 and 24 breathdmin to maintain end-tidal Pco, at 32 2 5 mm Hg (mean ? SD). The 51 patients were divided into four groups according to the predetermined N,O concentration used during the study period. The first 40 patients were randomly assigned to either 25% ( n = 13), 50% (n = 13), or 75% ( n = 14) N,O groups. The 0% N 2 0 group (n = 11) was studied after the completion of the N,O groups. With a constant level of N,O maintained in each patient, a single halothane concentration was then assessed to determine each child’s response to skin incision. The technique used to determine MAC was adapted from prior MAC studies where the objective was to bracket an end-tidal concentration of halothane that was MAC for the group being studied (3,7-11). Each patient was observed for purposeful movement in the 20-30 s after skin incision. Increases in respiratory rate, coughing, or breath holding after skin incision were not considered to constitute purposeful movement. The initial halothane concentration selected in each group was based on the
ANESTH ANALG 1990;71: 12M
121
assumption that 1%N 2 0 would reduce halothane concentrations by 0.01 vol % because prior studies have determined the MAC of halothane to be 1.0 vol % in infants and children (10). For each subsequent patient, the halothane concentration selected was based on the response of the previous infant or child. The end-tidal halothane concentration was increased or decreased by 0.1 or 0.2 vol % depending on whether the preceding infant or small child studied had moved or not moved after skin incision. A requirement for beginning data collection in a group was an initial paired response of move/no move or vice versa. The data were analyzed by the method described by Dixon for determining quanta1 responses (12). The age, weight, CO,, duration of constant end-tidal values, and halothane MAC were analyzed by oneway analysis of variance to determine differences between the four groups. A regression analysis was applied to the halothane groups to determine the correlation between halothane doses at different N,O concentrations. All results are expressed as mean ? SD.
Results The MAC value for halothane in O2 was 0.94 ? 0.08 vol %. The addition of 25% N,O reduced the MAC value for halothane to 0.78 ? 0.12 vol %. The MAC value of halothane during 50% and 75% N,O was 0.44 5 0.10 and 0.29 _t 0.06 vol %, respectively. The MAC values for halothane were significantly different in each N,O level and, as expected, increasing N,O concentrations progressively reduced anesthetic requirements for halothane. The age, weight, mean expired N,O concentration, and end-tidal CO, are presented in Table 1. Tracheal intubation performed under deep halothane anesthesia occurred a minimum of 15 min and a maximum of 52 min before the assessment of MAC after skin incision. The mean respiratory rate of the infants and children before skin incision was 22.6 t 3 breathdmin. The mean duration of constant endexpired halothane levels was 10 min (range, 6-27 min). The ratio between end-expired halothane and inspired halothane was 0.96 t 0.03 at the time of skin incision. The move/no move responses to skin incision of the infants and children at each study level are presented in Figure 1. Regression analysis was applied to determine the correlation coefficient and slope of the line extrapolated through the data sets. The r value for this line is
122
MURRAY ET AL.
ANESTH ANALG 1990;71: 12G4
Table 1. Summary of Results in Each Group Response to skin incision Move (n)
No move (n)
Mean expired N,O (vol %)
Halothane MAC (vol %)
End-tidal CO, (mm Hg)
2.5
6
5
0 ( n = 11)
0.94 2 0.08
29.9 t 3.5
11.5 t 6.0
9.4 i 2.0
6
7
0.78 i 0.12
30.4 2 4.5
15.7 ? 6.4
11.1 t 2.2
6
7
0.44 i 0.10
29.3 i 3.0
17.2 k 6.9
11.2
7
7
24.8 t 1.4 ( n = 13) 49.9 i 1.4 ( n = 13) 73.3 2 2.8 ( n = 14)
0.29 t 0.06
33.4 2 3.9
Age (mo) 14.4
6.9
Weight (kg) 9.9
Ifr
k
2.5
~
All results are expressed as mean
2 SD.
-
'e
&%i
0 0
. . . W o o % %
.. I
0.00
0.25
0
p
Figure 1 . Response to skin incision (move or no move) in four groups of infants assessed at various halothane concentrations. Each patient is represented by a closed (move) or open (no move) circle.
0 0 0
I
I
0.75
1 .oo
I
0.50
m v E N O m v E
0
HALOTHANE VOL Yo
0.934 with an Y' value of 0.87 (Figure 2). The value for 1 MAC N,O predicted from extending the linear regression line is 105% (Figure 2).
Discussion End-expired halothane concentrations were used to reflect central nervous system concentrations of halothane (13,14). The measurement of end-expired halothane assumes that these concentrations reflect end-tidal anesthetic levels. Arterial anesthetic concentrations were assumed to be equivalent to levels of halothane in the central nervous system. For halothane concentrations: end-expired endtidal ~4 alveolar a arterial a central nervous system. Entrainment of inspired gas could limit the accuracy of end-tidal values in reflecting alveolar halothane concentration, particularly when respiratory rates are rapid and tidal volumes are small. For this
reason, distal tracheal gas sampling from an endotracheal tube in infants was used to measure alveolar gas samples (15,16). Alveolar anesthetic levels reach equilibrium with anesthetic levels in the brain over a period of time. A soluble anesthetic such as halothane requires more time to achieve equilibrium with vessel-rich tissue groups than does N,O. In infants the time constant of equilibrium for halothane concentrations in the central nervous system to reach equilibrium with end-tidal halothane concentrations is shorter than in adults (14). A minimum of two to three constants would be required to assure that brain concentrations are equivalent to alveolar levels (13,14). Before the assessment of MAC, anesthetic concentrations were unchanged for a period of time equivalent to three to four time constants (10 min). Tracheal intubation was performed under deeper levels of halothane anesthesia without muscle relaxants, and then halothane concentrations were reduced to the end-tidal halothane concentrations that
ADDITIVE CONTRIBUTION OF N,O TO MAC IN INFANTS
ANESTH ANALG 1990;71:12&4
123
HALOTHANE VOL % 1.oo
Figure 2. Regression analysis of four data voints. The halothane MAC at dikerent N,O concentrations are plotted, and the line represents the regression analysis through all four data points. “ A ‘ indicates predicted MAC of N,O.
i1
0.75
0.50
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0.25-
0.00
!
I
I
0.0
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were assessed at skin incision. For this reason, small differences between alveolar and inspired halothane concentrations were measured at the time of skin incision (13). The MAC of halothane in this study was similar to the values reported by Gregory et al. in a study of infants of similar age (10). In prior studies in adults, when N 2 0 was added to halothane, enflurane, or isoflurane the contribution to MAC was additive (3,7,8). We found a similar additive effect at three N 2 0 concentrations (25%, 50%, and 75%) during halothane anesthesia. When six different concentrations of N,O were assessed, Cole et al. suggested that higher N,O concentrations (60%-80%) contributed proportionately less to the MAC of enflurane in rats than lower concentrations (10%-30%) ( 6 ) . In an editorial that accompanied this article, Eger suggested the data presented by Cole et al. could have been interpreted to indicate an additive effect of N,O (1). In a letter to the editor, Cole et al. suggest that perhaps higher N,O concentrations by increasing sympathetic activity may alter anesthetic requirements (17). If increases in sympathetic activity during N,O are dose-related, as suggested in clinical studies, and if increases in sympathetic stimulation increase anesthetic requirements, then a nonlinear contribution of N,O might occur with lower N 2 0 concentrations reducing MAC proportionately more than higher N,O concentrations. In infants and children, Hickey et al. and Murray et al. found cardiovascular changes that suggest minimal sympathetic stimulating effect of N,O (18,19). This may explain why a linear contribution of N,O was observed in this study of infants and children but not in the study of Cole et al. A separate clinical study would be required to
75.0
I
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9 A
assess whether increases in sympathetic activity produced by N,O alter anesthetic requirements. With requirements for halothane and isoflurane concentrations increased 130% and 140% in infants compared to adults, we anticipated that the MAC of N,O might be increased in infants and children, and that the contribution of N,O to halothane anesthesia would be less than in adults. Using a linear regression analysis, the projected N,O concentration required to produce 1.0 MAC in infants and small children was 105%. In adults, using assessments based on the additive contribution of a single N,O concentration to halothane or isoflurane, the MAC of N 2 0 was predicted to be 108%, 11896, 105%, and 110% (3,7,8). The predicted MAC of N,O in this study as well as in prior clinical studies assumes that the contribution of N 2 0 to MAC remains linear at concentrations of greater than 75%. In the only study assessing the MAC of N 2 0 alone under hyperbaric conditions, the MAC of N,O in healthy adult volunteers was 106% (20). Although this study supports the concept of additivity of anesthetic agents in predicting MAC, we found that the MAC of N,O, unlike the volatile anesthetics, was not increased in infants and small children. In a younger (19-30 yr), as well as in an older patient population (>55 yr), the predicted MAC of N,O during isoflurane anesthesia decreased from 116% to 100% (7). The MAC of halothane in 0, in infants was 0.94 vol % compared to 0.78 vol % in adults. The addition of 75% N,O to halothane reduced the MAC of halothane to 0.29 0.06 vol % in infants and children. In adults, the MAC of halothane during 70% N,O is 0.29 vol % (3). When combined with the other properties of N,O, such as its low
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ANESTH ANALG 1990;71:12%4
solubility and minimal cardiovascular effects, the continued use of N,O in children seems warranted because N 2 0 reduces halothane and perhaps isoflurane concentrations required to achieve surgical anesthesia to a greater degree in infants than in adults. In summary, in infants and children, N 2 0 concentrations reduce halothane MAC in a linear additive manner. The predicted MAC of N,O based on a linear regression analysis is similar in infants and adults.
References ~~
1. Eger El 11. Does 1 + 1 = 2? Anesth Analg 1989;68:551-5. 2. Eger EI 11, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:75M13. 3. Saidman LJ, Eger El 11. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology 1964;25:302-6. 4. Quasha AL, Eger EI 11, Tinker JH. Determination and applications of MAC. Anesthesiology 1980;53:31534. 5. Gion H, Saidman LJ. The minimum alveolar concentration of enflurane in man. Anesthesiology 1971;35:361-4. 6. Cole DJ, Kalichman MW, Shapiro HM. The nonlinear contribution of nitrous oxide at sub-MAC ccmcentrations to enflurane MAC in rats. Anesth Analg 1989;68:556-62. 7. Stevens WC, Dolan WM, Gibbons RT, et al. Minimum alveolar concentrations (MAC) of isoflurane with and without oxide in patients of various ages. Anesthesiology 1975;42:197-200. 8. Torri G, Damia C , Fabiani ML. Effect of nitrous oxide on the anaesthetic requirement of enflurane. Br J Anaesth 1974;46: 468-72.
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9. Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements for halothane in young children 0-1 month and 1 4 months of age. Anesthesiology 1983;59:421-4. 10. Gregory GA, Eger El 11, Munson ES. The relationship between age and halothane requirement in man. Anesthesiology 1969; 30:488-91. 11. Cameron CB, Robinson S, Gregory GA. The minimum anesthetic concentration of isoflurane in children. Anesth Analg 1984;63:418-20. 12. Dixon WJ. Quantal-response experimentation: the up-anddown method. In: McArthur JW, Colton T, eds. Statistics in endocrinology proceedings. Cambridge: MIT Press, 1970:25167. 13. Eger El 11. Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Eger EI 11, ed. Anesthetic uptake and action. Baltimore: Williams & Wilkins, 1974:77-96. 14. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969;30:338-94. 15. Ozanne GM, Young WG, Mazzei WJ, Severinghaus JW. Multipatient anesthetic mass spectrometry: rapid analysis of data stored in long catheters. Anesthesiology 1981;55:62-70. 16. Schieber RA, Namnoum A, Sugden A, Saville AL, Orr RA. Accuracy of expiratory carbon dioxide measurements using the coaxial and circle breathing circuits in small subjects. J Clin Monit 1985;1:149-55. 17. Cole DJ, Kalichman MW, Shapiro HM, Eger El 11. Does 1 + 1 = 2?-a continuing debate. Anesth Analg 1990;70:126-7. 18. Hickey PR, Hansen DD, Stafford M, Thompson SL, Jonas RE, Mayer JE. Pulmonary and systemic hemodynamic effect of nitrous oxide in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1986;65:37&8. 19. Murray DJ, Forbes RB, Murphy K, Mahoney LT. Nitrous oxide: cardiovascular effects in infants and children during halothane and isoflurane anesthesia. Anesth Analg 1988;67: 105944. 20. Hornbein TF, Eger El 11, Winter PM, Smith G, Wctstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982;61:55M.
