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Effects of lidocaine on heart rate, blood pressure, and electrocorticogram in fetal sheep
Effects of IJdocaine on heart rate, blood pressure, and electrocorticogram in fetal sheep K.
TERAMO,
M.D.*~
N. B E N O W I T Z ,
M.D.
HEYMANN,
M.
A.
K.
KAI-IANP)~,
A. S I I M E S ,
M.B.B.CH.** M.D.*
M.D.*
A. M. R U D O L P H ,
M.D.
San Francisco, California
Effects of lidocaine on blood pressure, heart rate, electrocortical activity, pH, and blood gases were studied in chronically catheterized sheep fetuses in utero. Lidocaine infused at a constant rate of less than I rag. • rain.-t • Kg. -1 into a fetal femoral vein did not cause changes in fetal blood pressure, heart rate, pH, or blood gases. Infusion rates above 1 mg. • min. -I • KE. -1 caused sudden, phasic increases in blood pressure in the majority of the fetuses. The heart rate increased in association with each phasic increase in blood pressure. In some fetuses the heart rate decelerated after the initial acceleration. Fetal electrocortical recordings showed that each phasic change in blood pressure and heart rate was secondary to epileptiform activity. The concentration of lidocaine in fetal arterial blood was 11.6 +_3.8 #g per milliliter when the first phasic increase in blood pressure occurred. Tracheal pressure recordings showed deep fetal breathing movements with each epileptiform activity. It is concluded that lidocaine causes convulsions in the fetal sheep and that the cardiovascular changes are due to central stimulation during these convulsions. In newborn lambs lidocaine produced similar epileptiform activity associated with tonic-clonic convulsions and cardiovascular changes. Fetal arterial pH was not affected until the phasic changes occurred, after which the pH fell rapidly in the majority of the fetuses. In three paralyzed fetuses the pH also decreased at the onset of phasic increases in blood pressure. This indicated that muscular activtiy was not the main cause of the acidemia during fetal epilepti[orm activity. Bolus injections of lidocaine in doses of 3.0 to 22.2 rag. per kilogram of fetal weight cau'sed an immediate decrease in blood pressure and heart rate. These changes were related to the dose of lidocaine. The convulsive dose of lidocaine as a bolus injection ranged from 8.0 to 22.2 rng. per kilogram.
From the Cardiovascular Research Institute and the Departments of Pediatrics, Physiology, and Pharmacy, University of California, San Francisco Medical Center, San Francisco, California 94143. Supported by United States Public Health Service Grants HL-06285 and GM-01791. Presented in part before the Society of Gynecological Investigation, Atlanta, Georgia, March 29, 1973. Received for publication August 8, 1973. Revised September 25, 1973. Accepted September 27, 1973.
Reprint requests: A. M. Rudolph, M.D., Cardiovascular Research Institute, University of California, San Francisco Medical Center, San Francisco, California 94143. *Recipients of research fellowship of Bay Area Heart Research Committee, San Francisco. **Recipient of United States Public Health Service Research Career Development Award (HD-35398) from the National Institute of Health and Human Development. ~Present address: Department of Obstetrics and Gynecology, University of Helsinki, 00290 Helsinki 29, Finland.
935
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April 1, 1974 Am. J. Obs~et.Gynecol.
Teramo et al.
T a b l e I. D a t a on 13 fetal lambs that received lidocaine by continuous infusion or as a bolus injection Continuous infusion
Fetus No.
Gestational age (days)
Weight (Gm.)
120 122
2,500
1 2
Days after operation
8 2
126
6
127
7
129
2,550
9
123 124
2,250
5 6
4 5
124 125
2,850 2,000
4 2
6 7
127 130
2,000
5 4
8 9
131 133 133
3,000 2,050
5 5 13
135 133 134
5,030
15 14 15
135 136 138 140 141
4,000
142
2,400
3
10
11 12 13
*N.R. =
3,300 2,600
16 3 5 2 10 11
Rate o[ inlusion (mg. • rain. -I • Kg. -I)
Duration o[ in[usion (min.)
0.1 0.2 0.24 0.31 0.58 0.8 1.0 1.49
101 100 103 102 97 98 94 103
2.33
65
1.17 2.4 0.38 1.36 2.04
79 52 115 100 94
0.2 0.74 1.64
224 70 92
0.64 0.96 2.04 1.98
121 65 48 165
1.25 1.35 0.6 1.28
33 150 91 78 98
1.22
not recorded.
T h e incidence of fetal b r a d y c a r d i a after obstetrical p a r a c e r v i c a l block has been shown to be related to the dose of the local anesthetic agent, 23 suggesting t h a t the anesthetic agent was the causative factor. Several studies have d e m o n s t r a t e d t h a t fetal b r a d y c a r d i a after p a r a c e r v i c a l block is associated with a transient decrease in fetal p H , 1, 23 indicating t h a t the fetus becomes transiently asphyxiated when the b r a d y c a r d i a occurs. However, the mechanisms by which local anesthetics p r o d u c e fetal distress d u r i n g this form of obstetrical anesthesia are still unclear. T h e most commonly held hypothesis is that the local anesthetic agent produces a direct depressant effect on either the fetal
h e a r t or the fetal brain. Local anesthetic agents given in excessive doses are known to cause convulsions a n d severe depression in newborn infants s a n d newborn lambs. 15 T w o studies of the effects of lidocaine on fetal lambs have been reported recentlv? 3' 1~ Both were performed on acute preparations, the m o t h e r being sedated or anesthetized. M o r i s h i m a a n d associates is infused large amounts of lidocaine at a constant rate into the femoral vein of fetal l a m b s until cardiac standstill occurred. M a n n a n d associates 13 gave bolus injections of lidocaine in doses of 14.3 to 36.8 mg. p e r kilogram of fetal weight over 20 to 30 seconds into the fetal j u g u l a r vein. I n both studies fetal b r a d y -
Volume 118
Effects of lidocaine
Number 7
of lidocaine Arterial concentration of lidocaine when first phasic increase in blood pressure (ag/ml.)
Maximal arterial concentration o[ lidocaine (#g/ml.)
--
0.7
--
1.5
937
Bolus injection o] lidocaine
--
1.9
--
2.6
Range of dose (mg./Kg.)
Convulsive dose (mg./Kg.)
8.0-20.0
20.0
8.9-22.2
22.2
3.5-14.0
14.0
10.0-20,0
20.0
4.0-8.0
8.0
3.0-12.1
12.1
4.5
7.0
7.3 10.2 14.7
17.5
28.3
9.2
11.6 22.8 2.2 13.8 21.1
--
---
17.0 --
13.0
0.2 7.1 15.0 4.4
--
5.6
6.8 13.0
15.1 22.4
11.6
N.R.* 6.0
10.5 10.0
7.0 19.7 42.0
cardia was observed but no original tracings of fetal blood pressure or heart rate were published. Mann and associates 13 also observed diminished or isoelectric fetal cortical activity, but no epileptiform activity, after the injections. Our purpose was to study the effects of lidocaine on the cardiovascular and cerebral functions of the fetal lamb in undisturbed intrauterine conditions. We were able to distinguish two different toxic effects of lidocaine on the fetal lamb by administering the drug either by continuous infusion or as a bolus injection. The effects of continuous infusion of lidocaine on newborn lambs were also studied.
Material and methods Thirteen time-dated pregnant ewes with fetuses of gestational ages ranging from 122 to 142 days (term, 150 days), were used for the study. Table I shows the gestational ages, type of experiment, dose of lidocaine, and the weight of each fetus. All 13 fetuses had catheters chronically implanted in a femoral vein, in the trachea, in a femoral or carotid artery, or both. A catheter was also placed in the amniotic cavity in all cases. For the insertion of catheters, the ewes received spinal anesthesia with 2 to 3 ml. of 1 per cent tetracaine, and also small amounts of pentobarbital during the operation when necessary. In eight of the 13 fetuses, two
938
Teramo e t al.
Ap, il I, 1974 Am. J. Obstet. Gynecol.
5C--
f
i
4C~
MAXIMAL CONCENTRATION OF LIDOCAINE
3~ %
"
20-o le
10 o o0 oo
%
o
o
I I
1
2
I
3
RATE OF LIDOCAINE INFUSION Jrng.min-l.kg-I I
Fig. 1. Correlation between infusion rate of lidocaine into the femoral vein for more than 50 minutes and maximal concentration of lidoeaine in arterial whole blood during 24 infusions in 11 fetal lambs. Regression line, Y ~- 10.15X - 0.42, r = 0.94, was calculated without the point at arrow. This fetus (No. 13, 142 days' gestational age) became more acidotic than the other fetuses during the infusion of lidocaine: pH dropped from 7.31 to 6.99. The severe acidosis could be due at least in part to a decrease in fetal placental flow and consequent decrease in transfer of lidocaine from the fetus to the mother. Open circles, no fetal cardiovascular change during the infusion of lidocaine; closed circles, phasic increases in fetal blood pressure and heart rate during the infusion. electrodes were fixed with screws through the parietal skull bone for recordings of electrocortical activity. T h e screws were 1.5 cm. apart in the sagittal plane, 0.5 cm. from the midline, and covered with dental cement. All fetal catheters were implanted under local infiltration anesthesia with 0.5 per cent lidocaine. At least two days were allowed for recovery from the operation before the fetal studies. Only fetuses with a p H of 7.30 or higher at the time of study are included here. We also studied four newborn lambs two to four days after birth. All newborn lambs had catheters implanted in a femoral artery and vein, as well as electrodes for recording of electrocortical activity. Except for local infiltration of lidocaine (maximal amount, 3.0 ml. of 0.5 per cent lidocaine) for the insertion of catheters, no anesthesia was used before or during the studies. T h e lambs were studied on the same day the catheters were inserted. All four had normal p H and blood gas values prior to the studies. Lidocaine hydrochloride (Xylocaine, Astra), 1 or 2 per cent, was infused at a constant rate into a femoral vein in 11 fetuses
and in all four newborn lambs. T h e rate of infusion into the fetuses ranged from 0.1 to 2.4 mg. • rain. -1 • Kg. -~ and in the newborn lambs from 0.4 to 0.75 mg. • rain. -1 - Kg. -~ T h e period of infusion ranged from 33 to 224 minutes (mean, 98 minutes) in the fetal group and from 41 to 116 minutes (mean, 65 minutes) in the neonatal group. In several fetal experiments two infusions of lidocaine were given consecutively at different rates (Table I ) . Serial samples of fetal and neonatal arterial blood were obtained for lidocaine, pH, Po2, and Pco~ estimations. Lidocaine concentrations were determined in arterial whole blood with a gas chromatograph after ether extraction ~; 2-diethylamino-3'-bromo-acetanilide was used as the internal standard. For p H and blood gas measurements fetal arterial blood was drawn into heparinized glass syringes. Fetal, neonatal, and maternal arterial blood pH, Po~, and Pco~ were measured immediately with a Radiometer microelectrode unit type P H A 927b at 39 ° C. The base excess (BE) was calculated from p H and Pco2 with the use of the Siggaard-Andersen alignment nomogram?" Fetal p H was not corrected for temperature or oxygen saturation, Fetal, neonatal, and maternal arterial blood pressures and fetal tracheal and amniotic pressures were continuously monitored with a Statham P~aD pressure transducer and recorded with a Beckman Dynograph multichannel direct-writing oscillograph. Fetal and neonatal heart rates were continuously recorded from the arterial pulse wave by a cardiotachometer. Six of the 13 fetuses received bolus injections of lidocaine into the femoral vein (Table I ) . Electrodes for recording of electrocortical activity were placed in all six fetuses. W h e n both continuous infusions and bolus injections of lidocaine were given to the same fetus they were completed on separate days. Because lidocaine is rapidly cleared from fetus to mother across the placenta (our own unpublished observation), a second bolus injection can be given 30 to 60 minutes after the first, depending on the dose. The volume of each bolus injection ranged from 1 to 3 ml., which was injected
Volum~ 118
Effects of lidocaine
Number7
939
CAROTIDARTERY PRESSURE / (mmHg) 0 ~HEART RATE (beats/min.)
NF
TRACHEAL PRESSURE (mmHg)
t
J t
-
Z5 0
AMNIOTIC PRESSURE (mmHg)
15~ Z5 .,-~ ~--~-Jv'~ ~ ' ~ J " - ' - ~ - r ~ 0 I
I
~-~-----~
I
1
~ ~----~'-~'~ I
I
TIME (minutes)
+ 4 rain.
Fig. 2. Data on fetal lamb No. 10 (134 days' gestational age) and amniotic pressure during infusion of lidocaine. The +4 minutes at arrow indicates the time elapsed since infusion rate was changed from 0.96 to 9.04 mg. • rain. -i • Kg. -i
FEMORAL l : f ARTERIAL PRESSURE {mmHg) Ot I
7:
;
~
LL
1
~
2
:"
.:27 7 :
: :" ?
.:"
HEARTRATE 240r (~'/~i")
TRACHEAL PRESSURE (mmHg)
120 k
[
'
:
~
....
~
'
~
~
20[ 0 ~
-
L
t+
l
69 rain
" I
I
~ I
I
1
I
TIME (minutes)
Fig. 3. Data on fetal lamb No. 7, and amniotic pressure during continuous infusion of lidocaine. The +69 minutes at arrow indicates the time since the infusion rate was changed from 1.36 to 2.04 mg. • rain. -1 • Kg. -~
into the fetal femoral vein over a period of 5 to 10 seconds. T h e a m o u n t of lidocaine injected ranged from 10 to 60 mg., corresponding to 3.0 to 92.2 mg. p e r kilogram of fetal body weight. T h e injections were started with 10, 20, or 30 mg. of lidocaine and increased by 10 mg. increments until the recording of fetal electrocortical activity showed epileptiform waves. F o r the statistical analysis of changes in fetal p H , blood gas values, a n d blood pressure within groups, S t u d e n t ' s p a i r e d t test was used.
Results Continuous infusion of lidocaine into fetal lambs. M a x i m a l concentrations of lidocaine
in fetal arterial blood d u r i n g continuous infusion of the d r u g into the fetus for more t h a n 50 minutes correlated directly with the infusion rate (Fig. 1 ). I n calculating the regression line we excluded the point i n d i c a t e d in Fig. 1 (fetus No. 13, 149 days' gestational a g e ) , because of its highly significant deviation from other points. 2° L i d o c a i n e infusion rates below 1 mg. • rain. "1 • Kg. -1 in eight fetuses (12 infusions) h a d no effect on fetal blood pressure or h e a r t rate. W h e n the infusion rate ranged from 1.0 to 2.4 mg. • min. -1 • Kg. -1, sudden phasic increases in blood pressure (Figs. 2 a n d 3) developed d u r i n g 10 of the 12 infusions. As long as the arterial concentration of lidocaine r e m a i n e d below 7 /zg p e r milliliter, no fetal cardio-
940
T e r a m o et al.
CAROTID ARTERY I
Ap~it 1, 1974
Am. J. Obstet. Gynecol.
~
~
PRESSURE
~
(mmHg)
~
Z]
....
~ 1,.Z
Jl~
......
0L CORTICOGRAM
HEARTRATE
/4V[ - ~ 300~
,(
(beats/rain.)
? ,~
lO0 TRACHEAL
PRESSURE (mmHg) UTERINE
15~ 7.5 0
..... p _
15 V
PRESSURE
7.5~ l
(mmHg)
0
~. ~ . . . . .
~\ . . . .
~_r . ... I I
+ 40 min
I I TIME (minutes)
_~
Fig. 4. Data on fetal lamb No. 10 (135 days' ges-
tational age) and amniotic pressure during infusion of lidocaine (1.98 mg. • min. -1 • Kg.-1 The +40 minutes indicates the time from the beginning of the infusion. The fetus had been paralyzed with 7.5 rag. of succinylcholine. Note the absence of respiratory movements on the tracheal pressure tracing (compare with Fig. 2).
i
~
C
~_
D
~
A~'A
.~.~,~.~.5/~, ~
•]
lO0.uV
1 SEC
Fig. 5. Fetal electrocorticogram immediately before (A), during (B), and 13 (C) and 43 minutes (D) after continuous infusion of lidocaine (1.25 rag. • rain.-1 • Kg.-1) into the femoral vein of fetus No. 11 (138 days' gestational age). vascular changes were observed, with one exception. In one fetus (No. 10, 134 days' gestational age), sudden phasic increases in blood pressure occurred for the first time at a lidocaine concentration of 6.8/~g per milliliter in arterial blood. In the eight fetuses in which phasic increases in blood pressure oc-
curred during infusion of lidocaine, the mean (±S.D.) concentration of lidocaine in arterial blood was 11.6 _+ 3.8 /~g per milliliter (range, 6.8 to 17.5 /~g per milliliter) when the first blood pressure change occurred. In the fetuses with no cardiovascular changes during the infusion, the maximal concentration of lidocaine in arterial blood was 13.8 ~g per milliliter. Associated with the very first phasic response in blood pressure, the mean increase in the systolic pressure was 33.6 + 13.8 mm. Hg and in the diastolic pressure 21.3 + 6.6 mm. Hg. Both increases are highly significant (p < 0.001 ). The phasic increases in fetal blood pressure became less pronounced as the lidocaine infusion was continued, but the blood pressure between the phasic increases rose slowly during the infusion. When the infusion was discontinued, the phasic increases stopped immediately and fetal blood pressure gradually decreased. Between 20 to 40 minutes after the end of the lidocaine infusion, fetal blood pressure had returned to the preinfusion level. The heart rate increased with each phasic increase in blood pressure (Fig. 2) ; in some fetuses a transient deceleration occurred after the initial acceleration (Fig. 3). The basal fetal heart rate slowly increased after the first phasic increase in blood pressure had occurred. When the infusion of lidocaine was discontinued, the phasic changes in heart rate also stopped, in association with the cessation of the phasic increases in blood pressure. After the infusion, the basal fetal heart rate gradually returned to the preinfusion level. Tracheal pressure reflected deep respiratory movements in association with each phasic increase in fetal blood pressure (Figs. 2 and 3). The amniotic pressure, as well as the maternal arterial pressure, remained unchanged during the phasic cardiovascular changes in the fetuses. In four of the six fetuses with implanted cortical electrodes, epileptiform high-voltage activity was observed in association with each phasic increase in blood pressure dur-
Volume 118 Number 7
Effects of lidocaine
100~_50r(mmHg)
, , ¢ , , . ,'
.........
50 -
PRESSURE
941
, i t'',
,.,
:i
,
0 L.
CORT,COGRAM ~V[ HEART RATE 200 300I (beats/rain.) 100
~'~'-'~-'------~"
15~ 7.5 0
TRACHEAL PRESSURE
(mrnHg)
I
t
I
I
I
I
r
J
I
I
I
I
I
I
i
i
]
I
L
[
i
~ l
I
L I
I
I
i
]
TIME (seconds)
36 mm
Fig. 6. Fetal arterial pressure and heart rate during one epileptiform burst during fetal infusion of lidocaine (fetus No. 10, 135 days' gestational age). The epileptiform acdvity precedes increases in blood pressure and heart rate by approximately 2 seconds. The fetus had been paralyzed with succinylcholine. The +36 minutes indicates the time from the beginning of the infusion.
LIDOCAINE INFUSION STARTED
pH(units) 750
I
I I
7.40
7.30
720
7.10
7 O0 0~
lO
I
-120
I
-60
I I I I I II
0
1
60
I- __
120
I
180
I
- 240
~
300
"TIME (minutes)
Fig. 7. Arterial blood pH before, during, and after infusion of lidocaine in six fetal lambs (seven infusions) with no cardiovascular changes during infusion. The termination of infusions is not indicated because of a different infusion dme in each fetus.
ing the infusion of lidocaine (Fig. 4). I n the other two fetuses epileptiform cortical activity was seen three minutes (fetus No. 7, Fig. 3) and 10 minutes after the first phasic increase. Fig. 5 shows the electrocortical
activity before infusion of lidocaine, during one epileptiform burst during the infusion, and during the recovery phase. T h e duration of each epileptiform discharge varied from 5 to 45 seconds. It consisted of clusters of
942
Teramo e t al.
April 1, 1974 Am. J. Obstet. Gynec.ol.
FIRST ACUTE BLOOD PRESSURE~INCREASE
pH (units) 7.50 -
~'~
I 7.40 -
J
7.30
7.20
7.10 -
7.00C.-
:
-240
I -180
l -120
[
-60
0
I
[
I
I
60
120
180
240
TIME (minutes)
Fig. 8. Arterial blood pH before, during, and after infusion of lidocaine in eight fetal lambs (10 infusions) with phasic increases in blood pressure during the infusion. The dotted line indicates the occurrence of the first phasic increase in blood pressure in each study.
polyspikes of high amplitude, less than 80 msec. in duration, with a mean frequency of 3 to 4 cycles per second (Fig. 5). These epileptiform bursts preceded the increases in blood pressure and heart rate by approximately 2 seconds (Fig. 6). The cortical epileptiform activity and the phasic cardiovascular changes were closely correlated (Figs. 2 to 4). When the epileptiform bursts were rapidly repeated, a second increase occurred in fetal blood pressure and heart rate. The epileptiform bursts and the corresponding cardiovascular changes usually occurred at a rate of one to four per minute. After each epileptiform activity the fetal electrocortical tracing became isoelectric (Figs. 3 to 5). The epileptiform activity and the phasic cardiovascular changes were not altered when the fetus was paralyzed with succinylcholine (Fig. 4) or gallamine. Fetal respiratory movements stopped promptly when the fetus was paralyzed. Intravenous injection of sodium pentobarbital, 10 mg., into one fetus during the infusion of lidocaine stopped the epileptiform bursts and corresponding phasic
cardiovascular changes for approximately 10 minutes. In all fetuses epileptiform activity stopped rapidly after the infusion of lidocaine was discontinued and cortical activity slowly returned to preinfusion levels (Fig. 5). In six fetuses in which no cardiovascular changes occurred during the infusion of lidocaine, arterial pH was stable (Fig. 7). In the eight fetuses with phasic increases in blood pressure during the infusion, pH remained unchanged until the phasic changes occurred, after which it began to fall rapidly except in one fetus (Fig. 8). This fetus (No. 5) was the youngest in this group (gestation 125 days). Table II shows the mean values for fetal pH, Po2, Pco.2, and base excess (BE) during infusion of lidocaine in the eight fetuses (10 experiments) with phasic cardiovascular changes. In this group the mean decreases in the pH and BE of fetal arterial blood were statistically significant after the phasic increases in blood pressure had commenced. During the infusion of lidocaine, but before the first phasic increase in blood pressure, the decrease in fetal pH was of
Effects of lidocaine
Volume I18 Number 7
943
pH (units ~, LIDOCAINE 2.0 mg.min 1.kg-I
750 SUCCINYLCHOLINE
I I
~ I-~-FIRST PHASIC
7.5 mg
//BLOOD ~',Jr
PRESSURE I
INCREASE
I
Pco2 Po2 (mmHg) (mmHg) Z~ O
7.40
r
50
30
40
2O
20
10
t
I 730
0---
72C
I l 0 100 200 300 TIME (minutes) Fig. 9. pH, Po=, and Pco.. of fetal arterial blood before, during, and after infusion of lidocaine into the fetal femoral vein (fetus No. 10, 135 days' gestational age). Fetal acidosis developed after phasic increases in fetal blood pressure although the fetus was paralyzed with succinylcholine eight minutes before the first phasic increase in blood pressure. I
-200
-100
0
30
DECREASE IN SYSTOLIC PRESSURE (mm Hg)
3C
20
DECREASE iN DIASTOLIC PRESSURE (mm Hg)
./: ../ I
8
I
16
I
2G
10
0
0 DOSE OF LIDOCAiNE(mg/kg) 24
I
8
I
16
J
24
Fig. 10. Dose-response curves of decreases in systolic and diastolic pressures after bolus injections of lidocaine into the femoral vein in six fetal lambs. The highest dose of lidocaine produced epileptiform activity in each fetus.
borderline significance (p < 0.05). T h e mean increase in Pco2 was also statistically significant. The Po2 decreased significantly (p < 0.05) two to eight minutes after the first phasic increase in blood pressure. The maximal changes in the mean Po2 and Pco2 were observed two to eight minutes after the first phasic increase in blood pressure,
whereas the mean values for p H and BE fell continuously after the phasic changes had begun. T h e mean levels of fetal arterial pH, Po2, Pco2, and BE returned partially or completely to the preinfusion levels after the infusion was discontinued (Table I I ) . Fetal acidemia was not prevented by muscle paralysis in the three fetuses given succinyl-
944
T e r a m o et al.
April 1, 1974 Am. J. Obstet. Gynecol,
100 -80DECREASE IN HEART RATE (beats/mln)
60 40
20 0
I 8
I 16
I 24
DOSE OF LIDOCAINE(mg/kg)
Fig. 11. Dose-response curves of decreases in heart rate after bolus injections of lidocaine into the femoral vein in six fetal lambs. The highest close of lidocaine produced epileptiform activity in each fetus.
choline or gallamine. Fig. 9 shows the results of one such experiment. Paralyzing the fetus with 10 mg. of succinylcholine had no effect on fetal acid-base balance. Maternal p H and blood gas values remained stable during fetal infusion of lidocaine in every experiment. Continuous infusion of lidocaine into newborn lambs. In all four newborn lambs, phasic blood pressure increases occurred when lidocaine was infused at a rate of 0.5 to 0.76 rag. • rain. 1 • Kg. -1. In association with each phasic increase in blood pressure, convulsive motor activity was also observed. The first convulsion was associated with the first phasic increase in blood pressure. The recording of electrocortical activity showed high-voltage epileptiform waves similar to those observed during the phasic increases in blood pressure in the fetuses. Although the infusion of lidocaine was discontinued immediately after the first convulsion in three of the four newborn lambs, the phasic convulsions and cardiovascular changes persisted. Diazepam in a dose of I mg. intravenously promptly stopped the convulsions and the phasic cardiovascular changes in three of the four newborn lambs. The remaining newborn lamb, in which the lidocaine infusion was not discontinued, died 10 minutes after the first seizure. The newborn lambs became acidemic after they started to convulse. The mean (_+S.D.) concentration
of lidocaine in arterial whole blood in the four newborn lambs was 15.0 (_+3.1) ~g per milliliter at the time of the first convulsion. Bolus injection of lidocaine into fetal lambs. A bolus injection of lidocaine, 10 to 60 rag. (3.0 to 22.2 rag. per kilogram of body weight), into the femoral vein consistently caused a transient fall in fetal systolic and diastolic pressures and heart rate in all six fetuses. These changes lasted less than 30 seconds with low doses of lidocaine but with high doses the decrease in blood pressure lasted up to 2 minutes t5 seconds and the decrease in heart rate up to 10 minutes. The magnitude of decrease in blood pressure was directly related to the dose of lidocaine in all six fetuses (Fig. 10). The decrease in fetal heart rate after a bolus injection of lidocaine was also directly related to the dose of the drug in five of the ~ix fetuses (Fig. 11). Atropine did not block the fetal hypotension or bradycardia after a bolus injection of lidocaine. With doses of lidocaine below 8 rag. per kilogram of fetal weight, no epileptiform activity was noted on the fetal corticogram. The convulsive dose of lidocaine injected as a bolus ranged from 8.0 to 22.2 rag. per kilogram of fetal weight. A close correlation existed between fetal epileptiform activity and increase in blood pressure; however, the blood pressure rise was small during the first seizure (Fig. 12). In three fetuses it was necessary to increase the dose of lidocaine above 18 mg. per kilogram to produce fetal epileptiform activity. However, above 18 mg. per kilogram of lidocaine no further decrease in the systolic pressure was observed (Fig. 10). Comment
Although it is well known that local anesthetic agents rapidly cross the placenta and can produce fetal asphyxia, the precise mechanisms responsible for the fetal depression have not been delineated. Although some studies about effects of local anesthetic agents on the fetal sheep have recently been published,13, 15 these were performed under
Effects of lidocaine
Volume 118
945
Number 7
LIDOCAINE 50 mg I
FEMORAL ARTERY PRESSURE (mmHg)
I
l~f OL
HEARTRATE (beats/min) 120u" ~ - - ~ - ~ ' ~
......
u
aEaRo- , 100 :::=:===~:- !r~l,
IIII IIII III IIIIIIII IIIIIIIIIll IIIlll I Ill lUlIIIII I l l l III IIII J l l l l lII II IIIIIIIIIIIIII I III II l l l l lI l l l l u l l l l l l H I I I I
I
I
I
[
I
I
I
TIME(seconds] Fig. 12. Effect of 50 mg. (22.2 mg. per kilogram) of lidocaine injected as a bolus into the femoral vein in fetal lamb No. 3 (123 days' gestational age).
T a b l e II. Means of arterial p H , Po2, Pco2, and base excess (BE) before, during, and after infusion of lidocaine in fetuses with phasic increases in blood pressure during the infusion
Be~ore lidocaine pH: X 7.363 S.D. 0.032 N 10 p~* Po2 (mm. Hg) : X 20.5 S.D. 3.5 N 10 p* Pco.. (ram. Hg) : X 41.3 S.D. 4.5 N 10 p* BE (mEq./L.) : X -1.72 S.D. 2.46 N 10 p~
Be/ore first increase in blood pressure
Time (min.) alter first increase in blood pressure
2-8
I
9-25
I 26-6o
Time (rain.) after ending inlusion o/ lidocaine
o-15
I 16-3o
I 46-9o
7.345 0.041 10 < 0.05
7.269 0.081 7 < 0.01
7.261 0.084 9 <( 0.005
7.248 0.097 8 < 0.005
7.171 0.113 6 < 0.01
7.226 0.117 8 < 0.01
7.255 0.113 8 < 0.05
19.3 3.0 10 n.s.
15.4 3.6 7 < 0.05
17.1 4.0 9 n.s.
18.6 4.5 8 n.s.
20.2 1.6 6 n.s.
20.6 4.6 8 n.s.
21.4 3.9 8 n.s.
45.7 7.0 9 ~ 0.05
53.3 11.5 6 ~ 0.05
48.9 8.2 8 ~ 0.005
48.1 7.3 8 ~ 0.005
49.7 5.9 6 < 0.05
45.1 6.8 8 n.s.
45.1 4.0 8 < 0.05
-1.03 2.17 9 n.s.
-3.98 3.78 6 n.s.
-5.64 3.91 8 < 0.05
-6.86 3.34 8 < 0.01
-10.15 5.34 6 < 0.01
-8.41 5.67 8 < 0.01
-6.71 5.68 8 n.s.
*The statistical evaluation (paired t t e s t ) w a s done comparing the change of parameters with values obtained immediately before the infusion lidocaine.
circumstances in which fetal physiological functions m ay be compromised. We therefore studied the effects of lidocaine on chronically catheterized sheep fetuses in utero. A direct relationship between the rate of
infusion of lidocaine for more than 50 minutes into the fetus and the concentration of the d r u g in the fetal arterial blood was d e m o n s t r a t e d in the present study. A f t er 50 minutes of infusion there was only a very slow f u r t h er increase in the co n cen t r at i o n of
946
T e r o m o et al.
lidocaine in fetal arterial blood suggesting that a steady state had almost been reached. This also suggests that the total clearance of lidocaine in relation to fetal weight is nearly constant at least over the gestational period and at all rates of lidocaine infusion studied. When lidocaine concentrations were below 7 /ag per milliliter in fetal arterial blood, no fetal cardiovascular changes were observed with one exception. Above 7/~g per milliliter a pattern of phasic changes in blood pressure and heart rate were observed in the majority of the fetuses. The range of fetal arterial concentration of lidocaine (6.8 to 17.5 t~g per milliliter) at the time of the first phasic increase in blood pressure is rather large. The reason for this is not clear. Electrocortical recordings showed that the phasic increases in the blood pressure of the fetuses were due to epileptiform activity during infusion of lidocaine. The reason fetal epileptiform activity was not seen with the first phasic increases in blood pressure during continuous infusion of lidocaine in two of our fetuses may be technical. Our electrodes record electrical activity only in the fetal cortex. It is possible that low concentrations of lidocaine caused seizure activity in deeper parts of the brain resulting in cardiovascular changes, but did not affect the cortex. Cortical epileptiform activity was recorded three and 10 minutes, respectively, after the first increase in blood pressure in the two fetuses. The mean threshold concentration of lidocaine for epiteptiform activity was 11.6 + 3.8 ~g per milliliter during continuous infusion of the drug. Munson and Wagman, 1'~ in studies on adult monkeys, reported 24.5 ~g per milliliter as the mean arterial plasma concentration of lidocaine when the first convulsion occurred during rapid infusion of lidocaine. However, the possibility of species differences in sensitivity to local anesthetics does not allow us to draw conclusions about differences in the toxicity of local anesthetics in fetal and adult animals. Phasic increases in blood pressure observed in our studies were similar to those described
April 1, 1974 Am. J. Obstet, Gynecol.
in both adult man ~, 14 and experimental animals 1",17 during epileptic seizures. Fetal seizures after administration of a local anesthetic, however, have not been previously described. Our results differ from those of Mann and associates, 13 in which the electrocorticogram did not show epileptiform activity in fetal lambs receiving lidocaine intravenously in doses as high as 36.8 mg. per kilogram of fetal weight. The most likely explanation for the lack of epileptiform activity in their study is that these studies were performed in acute sheep preparation under halothane anesthesia. It has been shown that volatile anesthetics, e.g., nitrous oxide," methoxyfluorane, fluoroxene, and halothane, '-'~ increase the seizure threshold to local anesthetics, de Jong and colleagues ~ have also shown that acute operative stress per se probably increases the seizure threshold. Our findings emphasize the importance of studying fetal sheep as nearly as possible under undisturbed conditions. Although we did not actually observe fetal convulsions, since the fetuses were within the uterus, we assume that motor convulsive activity did occur. This is based on the recordings of tracheal pressure, which showed strong respiratory movements in association with electrical epileptiform activity. Also, in similar experiments in newborn lambs, electrocortical epileptiform activity of similar type observed in the fetuses was associated with tonic-clonic movements of the limbs and the body. It is possible, although unlikely, that our fetuses did not have motor activity during epileptiform bursts, because Bernhard and colleagues 4 observed fetal epileptiform activity after electrical and pentylenetetrazole stimulation but no tonic or clonic movements in exteriorized sheep fetuses. They did, however, observe motor reactions in newborn lambs after electrically induced seizures. Why these investigators did not observe fetal motor reactions with seizure activity remains unclear. One possibility is that their fetuses were asphyxiated, since exteriorization considerably decreases placental blood flow in the sheep. 11 Bernhard
Volume118
Effects of lidocaine 947
Number 7
and colleagues 4 did not include data on fetal cardiovascular functions or blood gases in their report. In most fetuses with an intact placenta acute increases in blood pressure are buffered by a low resistance in the placenta. The magnitude of the increase in fetal blood pressure in association with epileptiform activity in our fetuses was therefore surprisingly large. We think that the acute pressure increases during lidocaine infusion were due to central stimulation of the autonomic nervous system, resulting in transient peripheral vasoconstriction. The concomitant increase in the fetal heart rate was probably also attributable to central stimulation. The deceleration following the acceleration may be a baroreflex response resulting from the acute pressure increase, but this response was not studied in more detail. Another possible explanation for the deceleration of fetal heart rate would be that fetal arterial Po2 decreases acutely during an epileptiform burst. However, the rapidity of the changes both in blood pressure and heart rate suggests that these changes reflect phasic stimulations of the vasomotor centers of the brain. The gradual increases in blood pressure and heart rate between the phasic increases could be due to catecholamine release from adrenals following central nervous stimulation during the seizures. Fetal pH was stable during the infusion of lidocaine until the phasic increases in fetal blood pressure had occurred. In all but one fetus the pH then fell rapidly; it is of interest that this fetus was the youngest (124 days of gestation) in the group. The fetal acidemia was mixed respiratory and metabolic. Metabolic acidemia both in arterial blood and in brain tissue has been shown to develop during induced seizures in experimental animals.9, 1~ This metabolic acidosis appeared to be due mainly to respiratory failure, since it could be prevented by adequate ventilation of the animal. 3, 16 The mechanisms of the fetal acidosis during the electroencephalographic and phasic cardiovascular changes remains unclear.
Paralyzing the fetus with neuromuscular blocking agents did not prevent acidosis, which excludes excessive muscle movements as the main causative factor. The number of fetuses in our study is too small to allow any comparison of acid-base balance between groups paralyzed and not paralyzed during lidocaine-induced seizures. It is possible that fetal cardiac output fell during the phasic cardiovascular changes, resulting in hypoperfusion of fetal tissues and decreased umbilical flow. Also, marked fetal peripheral vasoconstriction during epileptiform activity could have been a contributory factor by interfering with local flow and thus resulting in tissue hypoxia and increased anaerobic metabolism. It has been shown that local anesthetic agents depress oxidative metabolism in cell culture. 7 It is possible that enzyme systems can be affected by local anesthetics in vivo, but no information on this is available. The results of bolus injections of lidocaine into the femoral vein of our fetuses showed that lidocaine has, at least in fetal sheep, two different toxic effects. With all doses studied, an immediate transient bradycardia and hypotension was observed after a bolus injection. Both changes correlated directly with the dose of lidocaine. With larger doses of lidocaine, epileptiform cortical activity was also seen. If the epileptic burst occurred during maximal hypotension and bradycardia, minimal or no increases in blood pressure and heart rate were observed, but if the epileptiform activity occurred during the recovery phase, moderate increases occurred in both arterial pressure and heart rate. Since the hypotension and bradycardia were not blocked by atropine, these changes were not due to an increase in vagal tone. We conclude from the bolus injection studies that lidocaine probably has a direct depressant effect on the fetal heart. This is in accordance with studies which showed similar myocardial depression after intravenous bolus injections of lidocaine to adult dogs. ~s In our studies, during continuous infusion of lidocaine, cardiovascular changes were observed
948
Teramo et al.
only secondary to epileptiform activity. It is possible that lidocaine diffuses more slowly into the fetal brain than into the fetal heart, which would explain why only high doses of lidocaine caused epileptiform activity in the fetal sheep. We have previously described the effect of a bolus injection of 6.7 mg. per kilogram of mepivacaine directly into the umbilical vein of a h u m a n fetus of 20 weeks' gestational age? ° The injection caused immediate bradycardia and arterial hypotension in the fetus. I n the present study bolus injections of lidocaine into the femoral veins resulted in an identical response in fetal lambs. The effects of obstetrical paracervical blockade on the fetal heart rate and fetal intravenous injection of lidocaine are similar. Both produce fetal bradycardia related to the dose of the local anesthetic agent. Direct measurements of the concentrations of the local anesthetic agent in fetal scalp blood after paracervical blocks have shown a relationship between the concentration of the drug and the incidence of fetal bradycardia and acidosis?, ~2 T h e effect of a bolus injection of lidocaine into a fetal femoral vein on the arterial blood pressure and heart rate was rather brief. This can probably be explained by the short half-life of lidocaine in the fetal sheep due to the rapid placental transfer of the drug.
REFERENCES
1. Asling, J. H., Shnider, S. M., Margolis, A. J., Wilkinson, G. L., and Way, E. L.: AM. J. OBSTET. GYNECOL. 107: 626, 1970. 2. Benowitz, N., and Rowland, M.: Anesthesiology. In press. 3. Beresford, H. K., Posner, J. B., and Plum, F.: Arch. Neurol. 20: 243, 1969. 4. Bernhard, C. G., Kaiser, I. H., and Kolmodin, G. M.: Acta Physiol. Scan& 47: 333, 1959. 5. Brown, M. L., Huston, P. E., Hines, H. M., and Brown, G. W.: Arch. Neurol. Psychol. 69: 601, 1953. 6. de Jong, R. H., Heavner, P. E., and de Oliveira, L. F.: Exp. Neurol. 35: 558, 1972. 7. Fink, B. R., Kenny, G. E., and Simpson, W. E.: Anesthesiology 30: 150, 1967.
April 1, 1974
Am. J. Obstet. Gynecol,
We do not know whether local anesthetics cause convulsions in the h u m a n fetus after paracervical blockades. O u r results with sheep fetuses do not support this possibility, since the mean concentration of lidocaine at the time of the first convulsions was 11.6 txg per milliliter. Fetal concentrations after administration of mepivacaine, 300 to 400 rag., for paracervical block ranged from 1.l to 8.3 ~tg per milliliter in the plasma (scalp capillary blood) of h u m a n terra fetuses. 2~ It is possible that the h u m a n fetal brain is more sensitive to local anesthetic agents than that of the lamb. Also, differences in the prenatal development of the brain m these two species and within the same species may alter the toxic effect of local anesthetics on the central nervous system. It is evident from our results that fetal seizures induced by lidocaine are harmful to the fetus. Electroencephalographic studies of the h u m a n fetus during obstetrical paracervical block are needed if we are to continue using this form of obstetrical anesthesia. We are grateful to Dr. J. E. Hoffman for his recommendations concerning the statistical analyses, to Dr. J. P. Spier for his interpretation of electrocorticograms, and to Dr. M. Rowland for his technical guidance concerning the lidocaine assay.
8. Finster, M., Poppers, P. J., Sinclair, J. C., Morishima, H. O., and Daniel, S. S.: AM. J. OBSTET. GYNECOL.92: 922, 1965. 9. Hamilton, R. W., and Schoolman, A.: Neurology 15: 444, 1965. 10. Heymann, M. A.: Fed. Proc. 31: 44, 1972. 11. Heymann, M. A., and Rudolph, A. M.: Circ. Res. 21: 741, 1967. 12. King, L. J., Lowry, O. H., Passonneau, J. V., and Venson, V.: J. Neurochem. 14: 599, 1967. 13. Mann, L. I., Bailey, C., Carmichael, A,, and Duchin, S.: AM. J. OBSTET. GYNECOL. 112: 789, 1972. 14. Meyer, J. S., Gotoh, F., and Favaie, E.: Electroencephalogr. Clin. NeurophysioI. 2I: 10, 1966. 15. Morishima, H. O., Heymann, M. A., Ru-
11~ Number 7
Voh, m,"
16. 17. 18. 19.
dolph, A. M., and Barrett, C. T.: AM. J. OBSTET. GYNECOL. 112: 72, 1972. Munson, E. S., and Wagman, I. H.: Arch. Neurol. 20: 406, 1969. Plum, F., Posner, J. B., and Troy, B.: Arch. Neurol. 18: 1, 1968. Robinson, S. L., Schroll, M., and Harrison, D. C.: Am. J. Med. Sci. 258: 260, 1969. Siggaard-Andersen, O.: Scand. J. Clin. Lab. Invest. 15: 211, 1963.
Effects of lidocaine
949
20. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, ed. 6, Ames, Iowa, 1971, The Iowa State University Press, p. 157. 21. Staniweski, J. A., and Aldrete, J. A.: Can. Anaesth. Soc. J. 17: 602, 1970. 22. Teramo, K., and Rajam~iki, A.: Br. J. Anaesth. 43: 300, 1971. 23. Teramo, K., and Widholm, O.: Acta Obstet. Gynecol. Scand. 46: Suppl. 2, 1967.
TERAMO,
M.D.*~
N. B E N O W I T Z ,
M.D.
HEYMANN,
M.
A.
K.
KAI-IANP)~,
A. S I I M E S ,
M.B.B.CH.** M.D.*
M.D.*
A. M. R U D O L P H ,
M.D.
San Francisco, California
Effects of lidocaine on blood pressure, heart rate, electrocortical activity, pH, and blood gases were studied in chronically catheterized sheep fetuses in utero. Lidocaine infused at a constant rate of less than I rag. • rain.-t • Kg. -1 into a fetal femoral vein did not cause changes in fetal blood pressure, heart rate, pH, or blood gases. Infusion rates above 1 mg. • min. -I • KE. -1 caused sudden, phasic increases in blood pressure in the majority of the fetuses. The heart rate increased in association with each phasic increase in blood pressure. In some fetuses the heart rate decelerated after the initial acceleration. Fetal electrocortical recordings showed that each phasic change in blood pressure and heart rate was secondary to epileptiform activity. The concentration of lidocaine in fetal arterial blood was 11.6 +_3.8 #g per milliliter when the first phasic increase in blood pressure occurred. Tracheal pressure recordings showed deep fetal breathing movements with each epileptiform activity. It is concluded that lidocaine causes convulsions in the fetal sheep and that the cardiovascular changes are due to central stimulation during these convulsions. In newborn lambs lidocaine produced similar epileptiform activity associated with tonic-clonic convulsions and cardiovascular changes. Fetal arterial pH was not affected until the phasic changes occurred, after which the pH fell rapidly in the majority of the fetuses. In three paralyzed fetuses the pH also decreased at the onset of phasic increases in blood pressure. This indicated that muscular activtiy was not the main cause of the acidemia during fetal epilepti[orm activity. Bolus injections of lidocaine in doses of 3.0 to 22.2 rag. per kilogram of fetal weight cau'sed an immediate decrease in blood pressure and heart rate. These changes were related to the dose of lidocaine. The convulsive dose of lidocaine as a bolus injection ranged from 8.0 to 22.2 rng. per kilogram.
From the Cardiovascular Research Institute and the Departments of Pediatrics, Physiology, and Pharmacy, University of California, San Francisco Medical Center, San Francisco, California 94143. Supported by United States Public Health Service Grants HL-06285 and GM-01791. Presented in part before the Society of Gynecological Investigation, Atlanta, Georgia, March 29, 1973. Received for publication August 8, 1973. Revised September 25, 1973. Accepted September 27, 1973.
Reprint requests: A. M. Rudolph, M.D., Cardiovascular Research Institute, University of California, San Francisco Medical Center, San Francisco, California 94143. *Recipients of research fellowship of Bay Area Heart Research Committee, San Francisco. **Recipient of United States Public Health Service Research Career Development Award (HD-35398) from the National Institute of Health and Human Development. ~Present address: Department of Obstetrics and Gynecology, University of Helsinki, 00290 Helsinki 29, Finland.
935
936
April 1, 1974 Am. J. Obs~et.Gynecol.
Teramo et al.
T a b l e I. D a t a on 13 fetal lambs that received lidocaine by continuous infusion or as a bolus injection Continuous infusion
Fetus No.
Gestational age (days)
Weight (Gm.)
120 122
2,500
1 2
Days after operation
8 2
126
6
127
7
129
2,550
9
123 124
2,250
5 6
4 5
124 125
2,850 2,000
4 2
6 7
127 130
2,000
5 4
8 9
131 133 133
3,000 2,050
5 5 13
135 133 134
5,030
15 14 15
135 136 138 140 141
4,000
142
2,400
3
10
11 12 13
*N.R. =
3,300 2,600
16 3 5 2 10 11
Rate o[ inlusion (mg. • rain. -I • Kg. -I)
Duration o[ in[usion (min.)
0.1 0.2 0.24 0.31 0.58 0.8 1.0 1.49
101 100 103 102 97 98 94 103
2.33
65
1.17 2.4 0.38 1.36 2.04
79 52 115 100 94
0.2 0.74 1.64
224 70 92
0.64 0.96 2.04 1.98
121 65 48 165
1.25 1.35 0.6 1.28
33 150 91 78 98
1.22
not recorded.
T h e incidence of fetal b r a d y c a r d i a after obstetrical p a r a c e r v i c a l block has been shown to be related to the dose of the local anesthetic agent, 23 suggesting t h a t the anesthetic agent was the causative factor. Several studies have d e m o n s t r a t e d t h a t fetal b r a d y c a r d i a after p a r a c e r v i c a l block is associated with a transient decrease in fetal p H , 1, 23 indicating t h a t the fetus becomes transiently asphyxiated when the b r a d y c a r d i a occurs. However, the mechanisms by which local anesthetics p r o d u c e fetal distress d u r i n g this form of obstetrical anesthesia are still unclear. T h e most commonly held hypothesis is that the local anesthetic agent produces a direct depressant effect on either the fetal
h e a r t or the fetal brain. Local anesthetic agents given in excessive doses are known to cause convulsions a n d severe depression in newborn infants s a n d newborn lambs. 15 T w o studies of the effects of lidocaine on fetal lambs have been reported recentlv? 3' 1~ Both were performed on acute preparations, the m o t h e r being sedated or anesthetized. M o r i s h i m a a n d associates is infused large amounts of lidocaine at a constant rate into the femoral vein of fetal l a m b s until cardiac standstill occurred. M a n n a n d associates 13 gave bolus injections of lidocaine in doses of 14.3 to 36.8 mg. p e r kilogram of fetal weight over 20 to 30 seconds into the fetal j u g u l a r vein. I n both studies fetal b r a d y -
Volume 118
Effects of lidocaine
Number 7
of lidocaine Arterial concentration of lidocaine when first phasic increase in blood pressure (ag/ml.)
Maximal arterial concentration o[ lidocaine (#g/ml.)
--
0.7
--
1.5
937
Bolus injection o] lidocaine
--
1.9
--
2.6
Range of dose (mg./Kg.)
Convulsive dose (mg./Kg.)
8.0-20.0
20.0
8.9-22.2
22.2
3.5-14.0
14.0
10.0-20,0
20.0
4.0-8.0
8.0
3.0-12.1
12.1
4.5
7.0
7.3 10.2 14.7
17.5
28.3
9.2
11.6 22.8 2.2 13.8 21.1
--
---
17.0 --
13.0
0.2 7.1 15.0 4.4
--
5.6
6.8 13.0
15.1 22.4
11.6
N.R.* 6.0
10.5 10.0
7.0 19.7 42.0
cardia was observed but no original tracings of fetal blood pressure or heart rate were published. Mann and associates 13 also observed diminished or isoelectric fetal cortical activity, but no epileptiform activity, after the injections. Our purpose was to study the effects of lidocaine on the cardiovascular and cerebral functions of the fetal lamb in undisturbed intrauterine conditions. We were able to distinguish two different toxic effects of lidocaine on the fetal lamb by administering the drug either by continuous infusion or as a bolus injection. The effects of continuous infusion of lidocaine on newborn lambs were also studied.
Material and methods Thirteen time-dated pregnant ewes with fetuses of gestational ages ranging from 122 to 142 days (term, 150 days), were used for the study. Table I shows the gestational ages, type of experiment, dose of lidocaine, and the weight of each fetus. All 13 fetuses had catheters chronically implanted in a femoral vein, in the trachea, in a femoral or carotid artery, or both. A catheter was also placed in the amniotic cavity in all cases. For the insertion of catheters, the ewes received spinal anesthesia with 2 to 3 ml. of 1 per cent tetracaine, and also small amounts of pentobarbital during the operation when necessary. In eight of the 13 fetuses, two
938
Teramo e t al.
Ap, il I, 1974 Am. J. Obstet. Gynecol.
5C--
f
i
4C~
MAXIMAL CONCENTRATION OF LIDOCAINE
3~ %
"
20-o le
10 o o0 oo
%
o
o
I I
1
2
I
3
RATE OF LIDOCAINE INFUSION Jrng.min-l.kg-I I
Fig. 1. Correlation between infusion rate of lidocaine into the femoral vein for more than 50 minutes and maximal concentration of lidoeaine in arterial whole blood during 24 infusions in 11 fetal lambs. Regression line, Y ~- 10.15X - 0.42, r = 0.94, was calculated without the point at arrow. This fetus (No. 13, 142 days' gestational age) became more acidotic than the other fetuses during the infusion of lidocaine: pH dropped from 7.31 to 6.99. The severe acidosis could be due at least in part to a decrease in fetal placental flow and consequent decrease in transfer of lidocaine from the fetus to the mother. Open circles, no fetal cardiovascular change during the infusion of lidocaine; closed circles, phasic increases in fetal blood pressure and heart rate during the infusion. electrodes were fixed with screws through the parietal skull bone for recordings of electrocortical activity. T h e screws were 1.5 cm. apart in the sagittal plane, 0.5 cm. from the midline, and covered with dental cement. All fetal catheters were implanted under local infiltration anesthesia with 0.5 per cent lidocaine. At least two days were allowed for recovery from the operation before the fetal studies. Only fetuses with a p H of 7.30 or higher at the time of study are included here. We also studied four newborn lambs two to four days after birth. All newborn lambs had catheters implanted in a femoral artery and vein, as well as electrodes for recording of electrocortical activity. Except for local infiltration of lidocaine (maximal amount, 3.0 ml. of 0.5 per cent lidocaine) for the insertion of catheters, no anesthesia was used before or during the studies. T h e lambs were studied on the same day the catheters were inserted. All four had normal p H and blood gas values prior to the studies. Lidocaine hydrochloride (Xylocaine, Astra), 1 or 2 per cent, was infused at a constant rate into a femoral vein in 11 fetuses
and in all four newborn lambs. T h e rate of infusion into the fetuses ranged from 0.1 to 2.4 mg. • rain. -1 • Kg. -~ and in the newborn lambs from 0.4 to 0.75 mg. • rain. -1 - Kg. -~ T h e period of infusion ranged from 33 to 224 minutes (mean, 98 minutes) in the fetal group and from 41 to 116 minutes (mean, 65 minutes) in the neonatal group. In several fetal experiments two infusions of lidocaine were given consecutively at different rates (Table I ) . Serial samples of fetal and neonatal arterial blood were obtained for lidocaine, pH, Po2, and Pco~ estimations. Lidocaine concentrations were determined in arterial whole blood with a gas chromatograph after ether extraction ~; 2-diethylamino-3'-bromo-acetanilide was used as the internal standard. For p H and blood gas measurements fetal arterial blood was drawn into heparinized glass syringes. Fetal, neonatal, and maternal arterial blood pH, Po~, and Pco~ were measured immediately with a Radiometer microelectrode unit type P H A 927b at 39 ° C. The base excess (BE) was calculated from p H and Pco2 with the use of the Siggaard-Andersen alignment nomogram?" Fetal p H was not corrected for temperature or oxygen saturation, Fetal, neonatal, and maternal arterial blood pressures and fetal tracheal and amniotic pressures were continuously monitored with a Statham P~aD pressure transducer and recorded with a Beckman Dynograph multichannel direct-writing oscillograph. Fetal and neonatal heart rates were continuously recorded from the arterial pulse wave by a cardiotachometer. Six of the 13 fetuses received bolus injections of lidocaine into the femoral vein (Table I ) . Electrodes for recording of electrocortical activity were placed in all six fetuses. W h e n both continuous infusions and bolus injections of lidocaine were given to the same fetus they were completed on separate days. Because lidocaine is rapidly cleared from fetus to mother across the placenta (our own unpublished observation), a second bolus injection can be given 30 to 60 minutes after the first, depending on the dose. The volume of each bolus injection ranged from 1 to 3 ml., which was injected
Volum~ 118
Effects of lidocaine
Number7
939
CAROTIDARTERY PRESSURE / (mmHg) 0 ~HEART RATE (beats/min.)
NF
TRACHEAL PRESSURE (mmHg)
t
J t
-
Z5 0
AMNIOTIC PRESSURE (mmHg)
15~ Z5 .,-~ ~--~-Jv'~ ~ ' ~ J " - ' - ~ - r ~ 0 I
I
~-~-----~
I
1
~ ~----~'-~'~ I
I
TIME (minutes)
+ 4 rain.
Fig. 2. Data on fetal lamb No. 10 (134 days' gestational age) and amniotic pressure during infusion of lidocaine. The +4 minutes at arrow indicates the time elapsed since infusion rate was changed from 0.96 to 9.04 mg. • rain. -i • Kg. -i
FEMORAL l : f ARTERIAL PRESSURE {mmHg) Ot I
7:
;
~
LL
1
~
2
:"
.:27 7 :
: :" ?
.:"
HEARTRATE 240r (~'/~i")
TRACHEAL PRESSURE (mmHg)
120 k
[
'
:
~
....
~
'
~
~
20[ 0 ~
-
L
t+
l
69 rain
" I
I
~ I
I
1
I
TIME (minutes)
Fig. 3. Data on fetal lamb No. 7, and amniotic pressure during continuous infusion of lidocaine. The +69 minutes at arrow indicates the time since the infusion rate was changed from 1.36 to 2.04 mg. • rain. -1 • Kg. -~
into the fetal femoral vein over a period of 5 to 10 seconds. T h e a m o u n t of lidocaine injected ranged from 10 to 60 mg., corresponding to 3.0 to 92.2 mg. p e r kilogram of fetal body weight. T h e injections were started with 10, 20, or 30 mg. of lidocaine and increased by 10 mg. increments until the recording of fetal electrocortical activity showed epileptiform waves. F o r the statistical analysis of changes in fetal p H , blood gas values, a n d blood pressure within groups, S t u d e n t ' s p a i r e d t test was used.
Results Continuous infusion of lidocaine into fetal lambs. M a x i m a l concentrations of lidocaine
in fetal arterial blood d u r i n g continuous infusion of the d r u g into the fetus for more t h a n 50 minutes correlated directly with the infusion rate (Fig. 1 ). I n calculating the regression line we excluded the point i n d i c a t e d in Fig. 1 (fetus No. 13, 149 days' gestational a g e ) , because of its highly significant deviation from other points. 2° L i d o c a i n e infusion rates below 1 mg. • rain. "1 • Kg. -1 in eight fetuses (12 infusions) h a d no effect on fetal blood pressure or h e a r t rate. W h e n the infusion rate ranged from 1.0 to 2.4 mg. • min. -1 • Kg. -1, sudden phasic increases in blood pressure (Figs. 2 a n d 3) developed d u r i n g 10 of the 12 infusions. As long as the arterial concentration of lidocaine r e m a i n e d below 7 /zg p e r milliliter, no fetal cardio-
940
T e r a m o et al.
CAROTID ARTERY I
Ap~it 1, 1974
Am. J. Obstet. Gynecol.
~
~
PRESSURE
~
(mmHg)
~
Z]
....
~ 1,.Z
Jl~
......
0L CORTICOGRAM
HEARTRATE
/4V[ - ~ 300~
,(
(beats/rain.)
? ,~
lO0 TRACHEAL
PRESSURE (mmHg) UTERINE
15~ 7.5 0
..... p _
15 V
PRESSURE
7.5~ l
(mmHg)
0
~. ~ . . . . .
~\ . . . .
~_r . ... I I
+ 40 min
I I TIME (minutes)
_~
Fig. 4. Data on fetal lamb No. 10 (135 days' ges-
tational age) and amniotic pressure during infusion of lidocaine (1.98 mg. • min. -1 • Kg.-1 The +40 minutes indicates the time from the beginning of the infusion. The fetus had been paralyzed with 7.5 rag. of succinylcholine. Note the absence of respiratory movements on the tracheal pressure tracing (compare with Fig. 2).
i
~
C
~_
D
~
A~'A
.~.~,~.~.5/~, ~
•]
lO0.uV
1 SEC
Fig. 5. Fetal electrocorticogram immediately before (A), during (B), and 13 (C) and 43 minutes (D) after continuous infusion of lidocaine (1.25 rag. • rain.-1 • Kg.-1) into the femoral vein of fetus No. 11 (138 days' gestational age). vascular changes were observed, with one exception. In one fetus (No. 10, 134 days' gestational age), sudden phasic increases in blood pressure occurred for the first time at a lidocaine concentration of 6.8/~g per milliliter in arterial blood. In the eight fetuses in which phasic increases in blood pressure oc-
curred during infusion of lidocaine, the mean (±S.D.) concentration of lidocaine in arterial blood was 11.6 _+ 3.8 /~g per milliliter (range, 6.8 to 17.5 /~g per milliliter) when the first blood pressure change occurred. In the fetuses with no cardiovascular changes during the infusion, the maximal concentration of lidocaine in arterial blood was 13.8 ~g per milliliter. Associated with the very first phasic response in blood pressure, the mean increase in the systolic pressure was 33.6 + 13.8 mm. Hg and in the diastolic pressure 21.3 + 6.6 mm. Hg. Both increases are highly significant (p < 0.001 ). The phasic increases in fetal blood pressure became less pronounced as the lidocaine infusion was continued, but the blood pressure between the phasic increases rose slowly during the infusion. When the infusion was discontinued, the phasic increases stopped immediately and fetal blood pressure gradually decreased. Between 20 to 40 minutes after the end of the lidocaine infusion, fetal blood pressure had returned to the preinfusion level. The heart rate increased with each phasic increase in blood pressure (Fig. 2) ; in some fetuses a transient deceleration occurred after the initial acceleration (Fig. 3). The basal fetal heart rate slowly increased after the first phasic increase in blood pressure had occurred. When the infusion of lidocaine was discontinued, the phasic changes in heart rate also stopped, in association with the cessation of the phasic increases in blood pressure. After the infusion, the basal fetal heart rate gradually returned to the preinfusion level. Tracheal pressure reflected deep respiratory movements in association with each phasic increase in fetal blood pressure (Figs. 2 and 3). The amniotic pressure, as well as the maternal arterial pressure, remained unchanged during the phasic cardiovascular changes in the fetuses. In four of the six fetuses with implanted cortical electrodes, epileptiform high-voltage activity was observed in association with each phasic increase in blood pressure dur-
Volume 118 Number 7
Effects of lidocaine
100~_50r(mmHg)
, , ¢ , , . ,'
.........
50 -
PRESSURE
941
, i t'',
,.,
:i
,
0 L.
CORT,COGRAM ~V[ HEART RATE 200 300I (beats/rain.) 100
~'~'-'~-'------~"
15~ 7.5 0
TRACHEAL PRESSURE
(mrnHg)
I
t
I
I
I
I
r
J
I
I
I
I
I
I
i
i
]
I
L
[
i
~ l
I
L I
I
I
i
]
TIME (seconds)
36 mm
Fig. 6. Fetal arterial pressure and heart rate during one epileptiform burst during fetal infusion of lidocaine (fetus No. 10, 135 days' gestational age). The epileptiform acdvity precedes increases in blood pressure and heart rate by approximately 2 seconds. The fetus had been paralyzed with succinylcholine. The +36 minutes indicates the time from the beginning of the infusion.
LIDOCAINE INFUSION STARTED
pH(units) 750
I
I I
7.40
7.30
720
7.10
7 O0 0~
lO
I
-120
I
-60
I I I I I II
0
1
60
I- __
120
I
180
I
- 240
~
300
"TIME (minutes)
Fig. 7. Arterial blood pH before, during, and after infusion of lidocaine in six fetal lambs (seven infusions) with no cardiovascular changes during infusion. The termination of infusions is not indicated because of a different infusion dme in each fetus.
ing the infusion of lidocaine (Fig. 4). I n the other two fetuses epileptiform cortical activity was seen three minutes (fetus No. 7, Fig. 3) and 10 minutes after the first phasic increase. Fig. 5 shows the electrocortical
activity before infusion of lidocaine, during one epileptiform burst during the infusion, and during the recovery phase. T h e duration of each epileptiform discharge varied from 5 to 45 seconds. It consisted of clusters of
942
Teramo e t al.
April 1, 1974 Am. J. Obstet. Gynec.ol.
FIRST ACUTE BLOOD PRESSURE~INCREASE
pH (units) 7.50 -
~'~
I 7.40 -
J
7.30
7.20
7.10 -
7.00C.-
:
-240
I -180
l -120
[
-60
0
I
[
I
I
60
120
180
240
TIME (minutes)
Fig. 8. Arterial blood pH before, during, and after infusion of lidocaine in eight fetal lambs (10 infusions) with phasic increases in blood pressure during the infusion. The dotted line indicates the occurrence of the first phasic increase in blood pressure in each study.
polyspikes of high amplitude, less than 80 msec. in duration, with a mean frequency of 3 to 4 cycles per second (Fig. 5). These epileptiform bursts preceded the increases in blood pressure and heart rate by approximately 2 seconds (Fig. 6). The cortical epileptiform activity and the phasic cardiovascular changes were closely correlated (Figs. 2 to 4). When the epileptiform bursts were rapidly repeated, a second increase occurred in fetal blood pressure and heart rate. The epileptiform bursts and the corresponding cardiovascular changes usually occurred at a rate of one to four per minute. After each epileptiform activity the fetal electrocortical tracing became isoelectric (Figs. 3 to 5). The epileptiform activity and the phasic cardiovascular changes were not altered when the fetus was paralyzed with succinylcholine (Fig. 4) or gallamine. Fetal respiratory movements stopped promptly when the fetus was paralyzed. Intravenous injection of sodium pentobarbital, 10 mg., into one fetus during the infusion of lidocaine stopped the epileptiform bursts and corresponding phasic
cardiovascular changes for approximately 10 minutes. In all fetuses epileptiform activity stopped rapidly after the infusion of lidocaine was discontinued and cortical activity slowly returned to preinfusion levels (Fig. 5). In six fetuses in which no cardiovascular changes occurred during the infusion of lidocaine, arterial pH was stable (Fig. 7). In the eight fetuses with phasic increases in blood pressure during the infusion, pH remained unchanged until the phasic changes occurred, after which it began to fall rapidly except in one fetus (Fig. 8). This fetus (No. 5) was the youngest in this group (gestation 125 days). Table II shows the mean values for fetal pH, Po2, Pco.2, and base excess (BE) during infusion of lidocaine in the eight fetuses (10 experiments) with phasic cardiovascular changes. In this group the mean decreases in the pH and BE of fetal arterial blood were statistically significant after the phasic increases in blood pressure had commenced. During the infusion of lidocaine, but before the first phasic increase in blood pressure, the decrease in fetal pH was of
Effects of lidocaine
Volume I18 Number 7
943
pH (units ~, LIDOCAINE 2.0 mg.min 1.kg-I
750 SUCCINYLCHOLINE
I I
~ I-~-FIRST PHASIC
7.5 mg
//BLOOD ~',Jr
PRESSURE I
INCREASE
I
Pco2 Po2 (mmHg) (mmHg) Z~ O
7.40
r
50
30
40
2O
20
10
t
I 730
0---
72C
I l 0 100 200 300 TIME (minutes) Fig. 9. pH, Po=, and Pco.. of fetal arterial blood before, during, and after infusion of lidocaine into the fetal femoral vein (fetus No. 10, 135 days' gestational age). Fetal acidosis developed after phasic increases in fetal blood pressure although the fetus was paralyzed with succinylcholine eight minutes before the first phasic increase in blood pressure. I
-200
-100
0
30
DECREASE IN SYSTOLIC PRESSURE (mm Hg)
3C
20
DECREASE iN DIASTOLIC PRESSURE (mm Hg)
./: ../ I
8
I
16
I
2G
10
0
0 DOSE OF LIDOCAiNE(mg/kg) 24
I
8
I
16
J
24
Fig. 10. Dose-response curves of decreases in systolic and diastolic pressures after bolus injections of lidocaine into the femoral vein in six fetal lambs. The highest dose of lidocaine produced epileptiform activity in each fetus.
borderline significance (p < 0.05). T h e mean increase in Pco2 was also statistically significant. The Po2 decreased significantly (p < 0.05) two to eight minutes after the first phasic increase in blood pressure. The maximal changes in the mean Po2 and Pco2 were observed two to eight minutes after the first phasic increase in blood pressure,
whereas the mean values for p H and BE fell continuously after the phasic changes had begun. T h e mean levels of fetal arterial pH, Po2, Pco2, and BE returned partially or completely to the preinfusion levels after the infusion was discontinued (Table I I ) . Fetal acidemia was not prevented by muscle paralysis in the three fetuses given succinyl-
944
T e r a m o et al.
April 1, 1974 Am. J. Obstet. Gynecol,
100 -80DECREASE IN HEART RATE (beats/mln)
60 40
20 0
I 8
I 16
I 24
DOSE OF LIDOCAINE(mg/kg)
Fig. 11. Dose-response curves of decreases in heart rate after bolus injections of lidocaine into the femoral vein in six fetal lambs. The highest close of lidocaine produced epileptiform activity in each fetus.
choline or gallamine. Fig. 9 shows the results of one such experiment. Paralyzing the fetus with 10 mg. of succinylcholine had no effect on fetal acid-base balance. Maternal p H and blood gas values remained stable during fetal infusion of lidocaine in every experiment. Continuous infusion of lidocaine into newborn lambs. In all four newborn lambs, phasic blood pressure increases occurred when lidocaine was infused at a rate of 0.5 to 0.76 rag. • rain. 1 • Kg. -1. In association with each phasic increase in blood pressure, convulsive motor activity was also observed. The first convulsion was associated with the first phasic increase in blood pressure. The recording of electrocortical activity showed high-voltage epileptiform waves similar to those observed during the phasic increases in blood pressure in the fetuses. Although the infusion of lidocaine was discontinued immediately after the first convulsion in three of the four newborn lambs, the phasic convulsions and cardiovascular changes persisted. Diazepam in a dose of I mg. intravenously promptly stopped the convulsions and the phasic cardiovascular changes in three of the four newborn lambs. The remaining newborn lamb, in which the lidocaine infusion was not discontinued, died 10 minutes after the first seizure. The newborn lambs became acidemic after they started to convulse. The mean (_+S.D.) concentration
of lidocaine in arterial whole blood in the four newborn lambs was 15.0 (_+3.1) ~g per milliliter at the time of the first convulsion. Bolus injection of lidocaine into fetal lambs. A bolus injection of lidocaine, 10 to 60 rag. (3.0 to 22.2 rag. per kilogram of body weight), into the femoral vein consistently caused a transient fall in fetal systolic and diastolic pressures and heart rate in all six fetuses. These changes lasted less than 30 seconds with low doses of lidocaine but with high doses the decrease in blood pressure lasted up to 2 minutes t5 seconds and the decrease in heart rate up to 10 minutes. The magnitude of decrease in blood pressure was directly related to the dose of lidocaine in all six fetuses (Fig. 10). The decrease in fetal heart rate after a bolus injection of lidocaine was also directly related to the dose of the drug in five of the ~ix fetuses (Fig. 11). Atropine did not block the fetal hypotension or bradycardia after a bolus injection of lidocaine. With doses of lidocaine below 8 rag. per kilogram of fetal weight, no epileptiform activity was noted on the fetal corticogram. The convulsive dose of lidocaine injected as a bolus ranged from 8.0 to 22.2 rag. per kilogram of fetal weight. A close correlation existed between fetal epileptiform activity and increase in blood pressure; however, the blood pressure rise was small during the first seizure (Fig. 12). In three fetuses it was necessary to increase the dose of lidocaine above 18 mg. per kilogram to produce fetal epileptiform activity. However, above 18 mg. per kilogram of lidocaine no further decrease in the systolic pressure was observed (Fig. 10). Comment
Although it is well known that local anesthetic agents rapidly cross the placenta and can produce fetal asphyxia, the precise mechanisms responsible for the fetal depression have not been delineated. Although some studies about effects of local anesthetic agents on the fetal sheep have recently been published,13, 15 these were performed under
Effects of lidocaine
Volume 118
945
Number 7
LIDOCAINE 50 mg I
FEMORAL ARTERY PRESSURE (mmHg)
I
l~f OL
HEARTRATE (beats/min) 120u" ~ - - ~ - ~ ' ~
......
u
aEaRo- , 100 :::=:===~:- !r~l,
IIII IIII III IIIIIIII IIIIIIIIIll IIIlll I Ill lUlIIIII I l l l III IIII J l l l l lII II IIIIIIIIIIIIII I III II l l l l lI l l l l u l l l l l l H I I I I
I
I
I
[
I
I
I
TIME(seconds] Fig. 12. Effect of 50 mg. (22.2 mg. per kilogram) of lidocaine injected as a bolus into the femoral vein in fetal lamb No. 3 (123 days' gestational age).
T a b l e II. Means of arterial p H , Po2, Pco2, and base excess (BE) before, during, and after infusion of lidocaine in fetuses with phasic increases in blood pressure during the infusion
Be~ore lidocaine pH: X 7.363 S.D. 0.032 N 10 p~* Po2 (mm. Hg) : X 20.5 S.D. 3.5 N 10 p* Pco.. (ram. Hg) : X 41.3 S.D. 4.5 N 10 p* BE (mEq./L.) : X -1.72 S.D. 2.46 N 10 p~
Be/ore first increase in blood pressure
Time (min.) alter first increase in blood pressure
2-8
I
9-25
I 26-6o
Time (rain.) after ending inlusion o/ lidocaine
o-15
I 16-3o
I 46-9o
7.345 0.041 10 < 0.05
7.269 0.081 7 < 0.01
7.261 0.084 9 <( 0.005
7.248 0.097 8 < 0.005
7.171 0.113 6 < 0.01
7.226 0.117 8 < 0.01
7.255 0.113 8 < 0.05
19.3 3.0 10 n.s.
15.4 3.6 7 < 0.05
17.1 4.0 9 n.s.
18.6 4.5 8 n.s.
20.2 1.6 6 n.s.
20.6 4.6 8 n.s.
21.4 3.9 8 n.s.
45.7 7.0 9 ~ 0.05
53.3 11.5 6 ~ 0.05
48.9 8.2 8 ~ 0.005
48.1 7.3 8 ~ 0.005
49.7 5.9 6 < 0.05
45.1 6.8 8 n.s.
45.1 4.0 8 < 0.05
-1.03 2.17 9 n.s.
-3.98 3.78 6 n.s.
-5.64 3.91 8 < 0.05
-6.86 3.34 8 < 0.01
-10.15 5.34 6 < 0.01
-8.41 5.67 8 < 0.01
-6.71 5.68 8 n.s.
*The statistical evaluation (paired t t e s t ) w a s done comparing the change of parameters with values obtained immediately before the infusion lidocaine.
circumstances in which fetal physiological functions m ay be compromised. We therefore studied the effects of lidocaine on chronically catheterized sheep fetuses in utero. A direct relationship between the rate of
infusion of lidocaine for more than 50 minutes into the fetus and the concentration of the d r u g in the fetal arterial blood was d e m o n s t r a t e d in the present study. A f t er 50 minutes of infusion there was only a very slow f u r t h er increase in the co n cen t r at i o n of
946
T e r o m o et al.
lidocaine in fetal arterial blood suggesting that a steady state had almost been reached. This also suggests that the total clearance of lidocaine in relation to fetal weight is nearly constant at least over the gestational period and at all rates of lidocaine infusion studied. When lidocaine concentrations were below 7 /ag per milliliter in fetal arterial blood, no fetal cardiovascular changes were observed with one exception. Above 7/~g per milliliter a pattern of phasic changes in blood pressure and heart rate were observed in the majority of the fetuses. The range of fetal arterial concentration of lidocaine (6.8 to 17.5 t~g per milliliter) at the time of the first phasic increase in blood pressure is rather large. The reason for this is not clear. Electrocortical recordings showed that the phasic increases in the blood pressure of the fetuses were due to epileptiform activity during infusion of lidocaine. The reason fetal epileptiform activity was not seen with the first phasic increases in blood pressure during continuous infusion of lidocaine in two of our fetuses may be technical. Our electrodes record electrical activity only in the fetal cortex. It is possible that low concentrations of lidocaine caused seizure activity in deeper parts of the brain resulting in cardiovascular changes, but did not affect the cortex. Cortical epileptiform activity was recorded three and 10 minutes, respectively, after the first increase in blood pressure in the two fetuses. The mean threshold concentration of lidocaine for epiteptiform activity was 11.6 + 3.8 ~g per milliliter during continuous infusion of the drug. Munson and Wagman, 1'~ in studies on adult monkeys, reported 24.5 ~g per milliliter as the mean arterial plasma concentration of lidocaine when the first convulsion occurred during rapid infusion of lidocaine. However, the possibility of species differences in sensitivity to local anesthetics does not allow us to draw conclusions about differences in the toxicity of local anesthetics in fetal and adult animals. Phasic increases in blood pressure observed in our studies were similar to those described
April 1, 1974 Am. J. Obstet, Gynecol.
in both adult man ~, 14 and experimental animals 1",17 during epileptic seizures. Fetal seizures after administration of a local anesthetic, however, have not been previously described. Our results differ from those of Mann and associates, 13 in which the electrocorticogram did not show epileptiform activity in fetal lambs receiving lidocaine intravenously in doses as high as 36.8 mg. per kilogram of fetal weight. The most likely explanation for the lack of epileptiform activity in their study is that these studies were performed in acute sheep preparation under halothane anesthesia. It has been shown that volatile anesthetics, e.g., nitrous oxide," methoxyfluorane, fluoroxene, and halothane, '-'~ increase the seizure threshold to local anesthetics, de Jong and colleagues ~ have also shown that acute operative stress per se probably increases the seizure threshold. Our findings emphasize the importance of studying fetal sheep as nearly as possible under undisturbed conditions. Although we did not actually observe fetal convulsions, since the fetuses were within the uterus, we assume that motor convulsive activity did occur. This is based on the recordings of tracheal pressure, which showed strong respiratory movements in association with electrical epileptiform activity. Also, in similar experiments in newborn lambs, electrocortical epileptiform activity of similar type observed in the fetuses was associated with tonic-clonic movements of the limbs and the body. It is possible, although unlikely, that our fetuses did not have motor activity during epileptiform bursts, because Bernhard and colleagues 4 observed fetal epileptiform activity after electrical and pentylenetetrazole stimulation but no tonic or clonic movements in exteriorized sheep fetuses. They did, however, observe motor reactions in newborn lambs after electrically induced seizures. Why these investigators did not observe fetal motor reactions with seizure activity remains unclear. One possibility is that their fetuses were asphyxiated, since exteriorization considerably decreases placental blood flow in the sheep. 11 Bernhard
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Effects of lidocaine 947
Number 7
and colleagues 4 did not include data on fetal cardiovascular functions or blood gases in their report. In most fetuses with an intact placenta acute increases in blood pressure are buffered by a low resistance in the placenta. The magnitude of the increase in fetal blood pressure in association with epileptiform activity in our fetuses was therefore surprisingly large. We think that the acute pressure increases during lidocaine infusion were due to central stimulation of the autonomic nervous system, resulting in transient peripheral vasoconstriction. The concomitant increase in the fetal heart rate was probably also attributable to central stimulation. The deceleration following the acceleration may be a baroreflex response resulting from the acute pressure increase, but this response was not studied in more detail. Another possible explanation for the deceleration of fetal heart rate would be that fetal arterial Po2 decreases acutely during an epileptiform burst. However, the rapidity of the changes both in blood pressure and heart rate suggests that these changes reflect phasic stimulations of the vasomotor centers of the brain. The gradual increases in blood pressure and heart rate between the phasic increases could be due to catecholamine release from adrenals following central nervous stimulation during the seizures. Fetal pH was stable during the infusion of lidocaine until the phasic increases in fetal blood pressure had occurred. In all but one fetus the pH then fell rapidly; it is of interest that this fetus was the youngest (124 days of gestation) in the group. The fetal acidemia was mixed respiratory and metabolic. Metabolic acidemia both in arterial blood and in brain tissue has been shown to develop during induced seizures in experimental animals.9, 1~ This metabolic acidosis appeared to be due mainly to respiratory failure, since it could be prevented by adequate ventilation of the animal. 3, 16 The mechanisms of the fetal acidosis during the electroencephalographic and phasic cardiovascular changes remains unclear.
Paralyzing the fetus with neuromuscular blocking agents did not prevent acidosis, which excludes excessive muscle movements as the main causative factor. The number of fetuses in our study is too small to allow any comparison of acid-base balance between groups paralyzed and not paralyzed during lidocaine-induced seizures. It is possible that fetal cardiac output fell during the phasic cardiovascular changes, resulting in hypoperfusion of fetal tissues and decreased umbilical flow. Also, marked fetal peripheral vasoconstriction during epileptiform activity could have been a contributory factor by interfering with local flow and thus resulting in tissue hypoxia and increased anaerobic metabolism. It has been shown that local anesthetic agents depress oxidative metabolism in cell culture. 7 It is possible that enzyme systems can be affected by local anesthetics in vivo, but no information on this is available. The results of bolus injections of lidocaine into the femoral vein of our fetuses showed that lidocaine has, at least in fetal sheep, two different toxic effects. With all doses studied, an immediate transient bradycardia and hypotension was observed after a bolus injection. Both changes correlated directly with the dose of lidocaine. With larger doses of lidocaine, epileptiform cortical activity was also seen. If the epileptic burst occurred during maximal hypotension and bradycardia, minimal or no increases in blood pressure and heart rate were observed, but if the epileptiform activity occurred during the recovery phase, moderate increases occurred in both arterial pressure and heart rate. Since the hypotension and bradycardia were not blocked by atropine, these changes were not due to an increase in vagal tone. We conclude from the bolus injection studies that lidocaine probably has a direct depressant effect on the fetal heart. This is in accordance with studies which showed similar myocardial depression after intravenous bolus injections of lidocaine to adult dogs. ~s In our studies, during continuous infusion of lidocaine, cardiovascular changes were observed
948
Teramo et al.
only secondary to epileptiform activity. It is possible that lidocaine diffuses more slowly into the fetal brain than into the fetal heart, which would explain why only high doses of lidocaine caused epileptiform activity in the fetal sheep. We have previously described the effect of a bolus injection of 6.7 mg. per kilogram of mepivacaine directly into the umbilical vein of a h u m a n fetus of 20 weeks' gestational age? ° The injection caused immediate bradycardia and arterial hypotension in the fetus. I n the present study bolus injections of lidocaine into the femoral veins resulted in an identical response in fetal lambs. The effects of obstetrical paracervical blockade on the fetal heart rate and fetal intravenous injection of lidocaine are similar. Both produce fetal bradycardia related to the dose of the local anesthetic agent. Direct measurements of the concentrations of the local anesthetic agent in fetal scalp blood after paracervical blocks have shown a relationship between the concentration of the drug and the incidence of fetal bradycardia and acidosis?, ~2 T h e effect of a bolus injection of lidocaine into a fetal femoral vein on the arterial blood pressure and heart rate was rather brief. This can probably be explained by the short half-life of lidocaine in the fetal sheep due to the rapid placental transfer of the drug.
REFERENCES
1. Asling, J. H., Shnider, S. M., Margolis, A. J., Wilkinson, G. L., and Way, E. L.: AM. J. OBSTET. GYNECOL. 107: 626, 1970. 2. Benowitz, N., and Rowland, M.: Anesthesiology. In press. 3. Beresford, H. K., Posner, J. B., and Plum, F.: Arch. Neurol. 20: 243, 1969. 4. Bernhard, C. G., Kaiser, I. H., and Kolmodin, G. M.: Acta Physiol. Scan& 47: 333, 1959. 5. Brown, M. L., Huston, P. E., Hines, H. M., and Brown, G. W.: Arch. Neurol. Psychol. 69: 601, 1953. 6. de Jong, R. H., Heavner, P. E., and de Oliveira, L. F.: Exp. Neurol. 35: 558, 1972. 7. Fink, B. R., Kenny, G. E., and Simpson, W. E.: Anesthesiology 30: 150, 1967.
April 1, 1974
Am. J. Obstet. Gynecol,
We do not know whether local anesthetics cause convulsions in the h u m a n fetus after paracervical blockades. O u r results with sheep fetuses do not support this possibility, since the mean concentration of lidocaine at the time of the first convulsions was 11.6 txg per milliliter. Fetal concentrations after administration of mepivacaine, 300 to 400 rag., for paracervical block ranged from 1.l to 8.3 ~tg per milliliter in the plasma (scalp capillary blood) of h u m a n terra fetuses. 2~ It is possible that the h u m a n fetal brain is more sensitive to local anesthetic agents than that of the lamb. Also, differences in the prenatal development of the brain m these two species and within the same species may alter the toxic effect of local anesthetics on the central nervous system. It is evident from our results that fetal seizures induced by lidocaine are harmful to the fetus. Electroencephalographic studies of the h u m a n fetus during obstetrical paracervical block are needed if we are to continue using this form of obstetrical anesthesia. We are grateful to Dr. J. E. Hoffman for his recommendations concerning the statistical analyses, to Dr. J. P. Spier for his interpretation of electrocorticograms, and to Dr. M. Rowland for his technical guidance concerning the lidocaine assay.
8. Finster, M., Poppers, P. J., Sinclair, J. C., Morishima, H. O., and Daniel, S. S.: AM. J. OBSTET. GYNECOL.92: 922, 1965. 9. Hamilton, R. W., and Schoolman, A.: Neurology 15: 444, 1965. 10. Heymann, M. A.: Fed. Proc. 31: 44, 1972. 11. Heymann, M. A., and Rudolph, A. M.: Circ. Res. 21: 741, 1967. 12. King, L. J., Lowry, O. H., Passonneau, J. V., and Venson, V.: J. Neurochem. 14: 599, 1967. 13. Mann, L. I., Bailey, C., Carmichael, A,, and Duchin, S.: AM. J. OBSTET. GYNECOL. 112: 789, 1972. 14. Meyer, J. S., Gotoh, F., and Favaie, E.: Electroencephalogr. Clin. NeurophysioI. 2I: 10, 1966. 15. Morishima, H. O., Heymann, M. A., Ru-
11~ Number 7
Voh, m,"
16. 17. 18. 19.
dolph, A. M., and Barrett, C. T.: AM. J. OBSTET. GYNECOL. 112: 72, 1972. Munson, E. S., and Wagman, I. H.: Arch. Neurol. 20: 406, 1969. Plum, F., Posner, J. B., and Troy, B.: Arch. Neurol. 18: 1, 1968. Robinson, S. L., Schroll, M., and Harrison, D. C.: Am. J. Med. Sci. 258: 260, 1969. Siggaard-Andersen, O.: Scand. J. Clin. Lab. Invest. 15: 211, 1963.
Effects of lidocaine
949
20. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, ed. 6, Ames, Iowa, 1971, The Iowa State University Press, p. 157. 21. Staniweski, J. A., and Aldrete, J. A.: Can. Anaesth. Soc. J. 17: 602, 1970. 22. Teramo, K., and Rajam~iki, A.: Br. J. Anaesth. 43: 300, 1971. 23. Teramo, K., and Widholm, O.: Acta Obstet. Gynecol. Scand. 46: Suppl. 2, 1967.