ANESTH ANALG

I983;62:9-14

Fetal Anesthetic Requirement (MAC) for Halothane

George A. Gregory, MD, John G. Wade, MD, Diane R. Beihl, MD,
Bill Y . Ong, MD, and Daniel S. Sitar, MD
G. A. GREGORY, J. G. WADE, D. R. BEIHL, B. Y. ONG,
D. S. SITAR: Fetal anesthetic requirement (MAC) for
halothane. Anesth Analg 1983;62:9-14.

We asked whether the anesthetic requirement (MAC)of fetal

lambs is lower than that of pregnant ewes. In five pregnant
ewes anesthetized with a subarachnoid block, a fetal foot
was withdrawn through a hysterotomy. The ewe then breathed
1.5% halothane and a clamp was applied to the fetal foot
at 2-min intervals. W e concomitantly obtained arterial blood
from previously implanted catheters. When fetal movement
in response to clamping the foot ceased, halothane was discontinued and the stimulus and sampling continued until
the fetus began to move. Anesthesia was again resumed and

Eger et al. introduced MAC (minimal alveolar concentration) as a measure of anesthetic potency (1).
Although it is impossible to determine the alveolar
concentration of an anesthetic in fetuses, the term
MAC has been widely applied as a measure of anesthetic potency in extrauterine humans and animals.
Thus, the term MAC is used throughout this paper
despite the fact that we measured blood concentrations of the drug and not alveolar concentrations. We
chose to do this for two reasons: we did not want to
further confuse the reader by introducing another term
for anesthetic potency, and MAC has come to mean
not only the minimal alveolar concentration of an anesthetic, but has also become a generic term for anesthetic potency.
The anesthetic requirement (MAC) of humans and
animals varies with age (2-4), being greatest in the

Received from the Department of Anesthesia, University of

Manitoba, Winnipeg, Manitoba, Canada, and the Departments of
Anesthesia, Pediatrics, and Cardiovascular Research Institute, University of California, San Francisco, California. Presented in part
at the annual meeting of the International Anesthesia Research
Society, Atlanta, Georgia, 1981. Accepted for publication August
18, 1982.
Reprint requests to Dr. Gregory, Department of Anesthesia,
University of California Room S426, Third and Parnassus Avenues,
San Francisco, CA 94143.
0 1983 by the International Anesthesia Research Society

continued until movement stopped. Anesthesia was then

deepened and MAC was determined in the mother (stiinulus-ear clamp). The fetal blood concentrations of halothane at MAC were 48
28 mgiL; they were 133
5
mglL in the mother. This difference was highly significant
'0 < 0.001). Calculated end-tidal concentrations were 0.33%
and 0.69%, respectively. In two animals delivered by cesarean section, M A C increased progressively over the first
12 h of life. Progesterone levels concomitantly decreased.

Key Words: POTENCY, ANESTHETICS: fetal MAC;

ANESTHESIA: obstetric; ANESTHESIA, VOLATILE;
halothane.

neonate and least in the elderly. Because pregnancy

reduces MAC in the mother (5), we wondered whether
MAC also might be reduced in the fetus. Such information would be of value to those studying the effects
of anesthetics on the fetus and to those doing fetal
surgery in humans (6). It also would be useful in the
latter case to know whether an anesthetic concentration sufficient for the mother's needs is also sufficient
for the fetus. Because there is no way at present to
obtain these data in humans, we determined MAC in
lamb fetuses and in their mothers and compared our
data with those obtained in 1- to 7-day-old lambs (4).

Methods
MAC was determined in five pregnant ewes and their
seven fetuses (gestation 130-135 days), which included two sets of twins and three singletons. The
mothers were anesthetized with halothane; through
a hysterotomy, catheters were inserted into an axillary
artery and a femoral vein of the fetus. At postmortem
examination, the tip of the arterial catheter was always proximal to the ductus arteriosus. Catheters also
were inserted into a femoral artery and a vein of the
mother. The incisions were closed and the mother
and fetus allowed to recover for at least 48 h. On the
day of the study after determining that the fetal and

10

GREGORY ET AL.

ANESTH ANALG
1983;62:9-14

maternal blood pressure, blood gas tensions, and pH

were normal in both the mother and fetus, we anesthetized the mother with spinal anesthesia and reopened the hysterotomy. A foot of the fetus was withdrawn and the uterus was closed around it (Fig. I).
After injecting local anesthetic into the neck of the
mother, we performed a tracheostomy through which
1.5% halothane in oxygen was administered.
A Kocher clamp was applied to the ear of the mother
and to the web between the toes of the fetus while
we concomitantly observed the mother and felt and
observed the leg of the fetus for movement. Blood
samples of 1ml were obtained from the femoral artery
of the mother and the subclavian artery (preductal)
of the fetus every 2 min and stored in gas-tight syringes at 0C for later analysis. When fetal movements
ceased, the anesthetic was discontinued. The foot of
the fetus and ear of the mother again were stimulated
and blood samples were drawn every 2 min until fetal
movement occurred. We then readministered 1.5%
halothane to the mother, stimulated the foot of the
fetus, and tested for movement. When movement
again ceased, the anesthetic concentration was increased. MAC was determined in the mother by
pinching her ear with a Kocher clamp, and measuring
blood and end-tidal concentrations of halothane. We
estimated MAC by plotting the anesthetic concentration in arterial blood and the presence or absence of

movement in response to the stimulus (Fig. 2); we

then averaged the bracketing anesthetic concentrations.
Blood samples were transferred to vials whose
openings were sealed with Teflon caps. One ~1 of
chloroform was added to each sample as an internal
standard before the samples were equilibrated in a
37C water bath. The ratio of peak heights (chloroform
z, halothane) was used to determine the concentration
of halothane in each sample. As long as the samples
were analyzed within 8 h, no halothane was lost from
the samples.
Halothane concentrations were determined with a
flame-ionization detector by the technique of Wolfson
et al. (6). A 3% OV-1 on gas chrome-Q, 5 ft long
times in. stainless steel column was maintained at
40C. A nitrogen carrier gas-flow rate of 40 ml/min
delivered the sample through the column to a flameionization detector at 125"C, which was supplied by
40 ml of hydrogen and 400 ml of air per min. The
samples were injected at ambient pressure.
In two animals, we determined MAC both in utero
and repeatedly during the first 12 h of extrauterine
life to determine how soon after birth MAC changed.
These two animals were delivered by cesarean section; their tracheae were intubated and their lungs
mechanically ventilated to maintain Pacoz between
30 and 35 torr. Halothane was administered from a

Subclavian Artery

Femoral Vein

Figure 1 Catheter placement and incisons for determining MAC in the ewe and fetus The foot of the fetus
was withdrawn through a hysterotomy and stimulated
with a Kocher clamp

FETAL MAC

ANESTH ANALG
1983;62:9-14

MAC Determination In Seven 130-135DayOld Fetuses

MOM

1111I
I1 1

Y I

NO MOVE

MOVE

(X135i5)

Is0

mgiL

22

11

Mothers
Fetuses
Fetuses at maternal MAC

52

No MOVE
MOVE

mr

Is0

MOVE
0

MOVE
0

I II

No MOVE

2
2

5
28
21

0.69 i- 0.25
0.33 t 0.29
0.54 t 0.14

130

40

I l l

NO MOVE

I 111 I1 I

No MOVE

133
49
82

End-tidal concentrations calculated as described in text.

50

End-tidal
concentration

1
Is0

NO M O M

Blood halothane
concentratiun at MAC

Ill I

NO MOVE

M
O
M

Table 1. Mean Concentrations of Halothane at MAC, and

Theoretical End-Tidal Concentrations of Halothane in the
Mothers and the Fetuses at Maternal MAC.

I30

30

I1

MATERNAL M E

11

I 1

II

133

40

II

I
I

I*

2 0 4 0
60 80
100120
HALOTHANE CONCENTRATION
(mg/L)

140

Figure 2. The relationship of the concentration of halothane in

blood to movement in response to noxious stimuli. The marks
above the line indicate movement; those below, no movement. The
numbers to the right are blood levels of halothane in the mothers
at MAC.

Fluotec vaporizer. End-tidal concentrations of halothane were measured with a Beckman LB-2 halothane
analyzer that was calibrated periodically with gases
containing known concentrations of halothane. Blood
and end-tidal concentrations of halothane were determined at 2-4 h intervals. In these two animals,
serum progesterone levels were determined shortly
after birth and at 4 h and 8 h of age to determine
whether the progesterone levels decreased as the MAC
for halothane increased after birth. In three other fetuses, we infused naloxone (15 mg/kg) intravenously
after the mothers had breathed 1.5% halothane for
10-12 min, which is the average time it took the fetuses to reach MAC. We did this to determine whether
endorphins were the cause of the decreased anesthetic requirement in the fetus.

Results
MAC, as determined by blood levels of anesthetic,
was much lower in the fetuses (48 2 29 mg/L) than
in the ewes (133 k 5 mg/L). (Table 1; Fig. 2). These
differences were highly significant ( P < 0.001) by unpaired t-tests. The concentration of halothane in the
blood required to produce MAC varied more among

the fetuses than among their mothers. For one set of

twins, MAC occurred at 90 mg/L; in the remaining
fetuses, it occurred between 22 and 40 mg/L. In contrast, MAC occurred in the mothers between 130 and
142 mg/L. Simultaneously measured end-tidal halothane concentrations in the mother were 0.69 ? 0.03%
at MAC.
The two animals delivered by cesarean section and
studied over the next 12 h of life had a progressive
increase in the end-tidal concentration of halothane
required to produce MAC. In both animals the concentration of progesterone progressively decreased.
In one animal it decreased from 735 ng/L at birth to
303 ng/L, and in the other from 700 ng/L to 350 ng/L
by 12 h of age (Fig. 3).
The three animals given intravenous naloxone in
utero did not move despite repeated stimulation with
a Kocher clamp for 5 min after the injection.
Figure 4 shows the relationship between MAC and
fetal and maternal systolic blood pressures. At 1 MAC,
blood pressures decreased 7% from control in the fetus and 24% in the mother. These differences were
not significant in the neonate, but were significant in
the mother (analysis of variance) between control and
1 MAC. There was no significant difference between
the control state and fetal MAC or fetal MAC and
maternal MAC.

Discussion
MAC was defined originally as the alveolar (end-tidal)
anesthetic concentration (1,7). However, MAC also
has come to be used as a measure of anesthetic potency regardless of how the anesthetic concentration
is measured (Eger, EI, 11; personal communication).
Because it is not possible to obtain end-tidal gas samples in the fetus, the theoretic concentrations of these
gases had the animals been breathing gas were calculated from the blood concentrations of halothane.
The approach we used to define MAC in the fetus

GREGORY ET AL.

ANESTH ANALG

12

1983;62:9-14

1.25

~1000

NEWBORNS

1.00

0.75

Figure 3. The relationship of time after birth and

MAC for two animals. Over the first 8 h of extrauterine life, MAC increased and serum progesterone level concomitantly decreased.

. :-0
-0 PROGESTERONE

0.25

0.00
__ L
Birth

6
8
10
TIME AFTER BIRTH
(hours)

12

14

did not produce the steady-state conditions usually

obtained in gas-breathing subjects. Consequently, our
values contain an element of hysteresis that increases
variability of the MAC values. That is, the blood concentration of halothane probably was lower than that
in the brain when movement occurred in response to
our stimulus while changing from a high to a low

Figure 4. The relationship of systolic blood pressure to MAC in

five ewes and their seven fetuses. The blood pressure of the mother
decreased significantly at MAC while that of the fetus did not.

140

MEAN +- S.E.

3
120
I
E
E

- too
2
3
% 80
2
a
60

MOTHERS

8
z

.-- 40
0

u)

6? 20
0

Control

Fetal

MAC

Maternal
MAC

10
16

anesthetic concentration. The opposite would be true

when going from a lower to a higher anesthetic concentration. The anesthetic concentration in blood
probably was higher than that in the brain. However,
because both the upward and downward movement
of anesthetic concentrations were impaired, the effect
of hysteresis on the average value should be minimized.
Our previous work in newborn humans (2) and
sheep (4) determined MAC by measuring end-tidal
concentrations of halothane. To compare our present
findings with those of the neonate, we converted concentrations of halothane in the blood to their alveolar
gas equivalents, using the blood gas partition coefficients determined by Gibbs et al. (8).We determined
the blood gas-partition coefficients in the blood of two
fetal animals and found them to be 1.93 and 1.94,
which is similar to those determined by Gibbs et al.
Therefore, we used their values to calculate alveolar
concentrations.
To convert the halothane in the blood to alveolar
concentrations, we divided the concentration (mg/L)
in the blood by the blood gas-partition coefficient (1.93
for fetal blood and 2.50 for maternal blood) (8). The
resulting number was divided by the molecular weight
of halothane and the result was multiplied by Avogadros number (22.4 L). This theoretic concentration
of halothane in alveolar gas was then corrected to
body temperature (39C).
The resulting alveolar concentration of halothane is significantly lower at MAC for the fetus than
for the mothers and also for 0.5- to 7-day-old lambs
(4). In the fetus, MAC would occur at an end-tidal
halothane concentration of 0.33%. This is about onehalf as high as the mothers (0.69%), and about onefourth as high as a neonatal lambs (1.15%)MAC (4).
The 0.69% end-tidal halothane concentration calcu-

FETAL MAC

lated for the ewes in the present study is close to the

0.73 + 0.07% end-tidal concentration reported by Palahniuk et al. for MAC in pregnant sheep (5). Our
data indicate that MAC in the fetus is only 47% that
of the mother and 29% that of 0.5- to 7-day-old lambs
(4).
The reason(s) why MAC is so much lower in the
fetus is unknown; however, there are several possible
contributing factors. The lower MAC may be related
in part to the high levels of progesterone in the fetus.
When administered in pharmacologic doses, progesterone is anesthetic (9). In rats, progesterone increases
the pain threshold (lo), accumulates in the reticular
activating system (ll),and causes somnolence. That
progesterone may be partially responsible for changes
in MAC during the first few hours of extrauterine life
is suggested by the increase in concentration of halothane required for MAC, and also the progressive
decrease in the amount of progesterone in the serum
after birth in both animals we studied. However, it
is unlikely that increase in MAC is due solely to the
falling levels of progesterone (5).
Increased metabolic rate and oxygen consumption
may increase the anesthetic requirement after birth.
In previous studies, we demonstrated that MAC is
highest at birth and puberty when metabolism is highest, and lowest in elderly patients (1-3). One might
expect, therefore, that the MAC of the fetus might be
lower than after birth because fetal metabolism is low.
Metabolism increases after birth (12,13)partly because
of an increase in the secretion of thyroid hormone

(14).
It also is possible that endorphins decrease the anesthetic requirement of the fetus. Whether these compounds are anesthetic is controversial (15-18). When
we infused naloxone (15 mg/kg) into the femoral vein
of the fetus after the mother breathed 1.5%halothane
for 10-12 min (the average time required for the fetus
to reach MAC), we saw no change in the response of
the fetus to our stimulus. We conclude that endorphins do not contribute significantly to anesthesia in
the fetal lamb.
Halothane decreases the arterial blood pressure of
newborn humans and animals more than it does that
of adults (2,3); this did not occur in the fetuses. Their
arterial blood pressure at MAC did not differ significantly from that during the control period. However,
stability of arterial pressure changes after birth (3,4);
in 0.5- to 7-day-old lambs, 1MAC halothane decreases
systolic blood pressure almost 30% (4). This difference
may be the result of lower absolute halothane concentrations required to produce MAC in the fetus.
In summary, we have demonstrated that the anesthetic requirement of the fetal lamb is much lower

ANESTH ANALG
1983;62:9-14

13

than that of its mother and of 0.5- to 7-day-old lambs.

We have also shown that MAC increases over the first
12 h of extrauterine life with a reciprocal decrease in
the serum progesterone level and that endorphins
are not responsible for the reduction in MAC. In addition, we have shown that 1 MAC halothane causes
less blood pressure depression in fetal lambs than it
does in neonatal lambs.

The authors thank Ms. Maureen Cummings and Mr. Wayne Pucci
for their excellent technical assistance, and Dr. E.I. Eger, I1 and
Mrs. Pauline Snider for their editorial help with the manuscript.

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1983:62:9-14

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GREGORY ET AL.

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