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Effect of lidocaine on fetal heart rate and fetal brain metabolism and function
OBSTETRICS
Effect of lidocaine on fetal heart rate and fetal brain metabolism and function LEON
I.
COLIN
MANN, BAILEY,
ANDREW SYBIL New
M.D.*
CARMICHAEL, DUCHIN,
York,
M.D.
New
D.V.M. B.A.,
M.A.
York
The eflect of lidocaine (xylocaine) on fetal heart rate and fetal cerebral metabolism and function was studied in 15 fetal sheep experiments. A significant btadycardia occurred in each experiment. Vagcctomy did not influence the bradycardic effect. The electroencephalogram (EEG) showed either slowing, slowing followed by an isoelectric (flat) record, or the development of low-voltage fast activity. While cerebral blood flow decreased significantly, cerebral metabolism was unaflected, Fetal heart rate, blood flow, and cerebral function in terms of the EEG recovered within 20 minutes of injection.
LOCAL ANESTHETICS areusedcommonly in obstetrics for analgesiaor anesthesia during labor and delivery. Paracervical block (PCB) in particular has become a popular procedure. The experience with PCB has revealed the successfulrelief of pain during
From the Department Gynecology, Cornell College.
labor and delivery with few maternal and fetal complications.lS3 However, several reports have presented evidence from careful fetal monitoring that changes in the fetal heart rate may occur as frequentiy as 30 per cent of the time following PCB.“, 5 Fetal bradycardia has been the most frequent abnormality and has occurred in association with a significant decrease in fetal pH as determined by fetal scalp blood analysis.’ The significance of these observations of heart-rate and acid-base abnormalities has remained unclear. A few reports have associated an increased incidence of neonatal depressionas evaluated by Apgar scoresand neonatal death with PCB, but direct evidence for a cause-and-effect relationship appeared tenuous.7p* This report presents observations from
of Obstetrics and University Medical
This investigation was supported by grants from the National Institutes of Health, No. RO-INS 08800, and The United Cerebral Palsy Research and Educational Foundation, No. R-237-71. Received
for Publication
August
$;;pted
for pubiication
November
2, 1971. IO,
*Recipient of National Institute of Health Research Career Deuelopment Award No. 5KO4HD-30085.
789
790
Mann
et al.
March Am. J. Obstet.
fetal sheep experiments on the effect of lidoCaine injection on fetal heart rate and brain function and metabolism. The analysis suggests that fetal bradycardia and changes in functional activity of the brain in terms of the electroencephalogram (EEG) that were observed following toxic levels of lidocaine were transient phenomena and were the resuit of a direct action on the myocardium and cerebral cell. Materials
and
methods
Fifteen experiments are reported that were conducted on 8 sheep fetuses whose gestational ages were from 120 to 143 days (term gestation is approximately 145 days). In each of these experiments, the injection of lidoCaine,* 1 or 2 per cent was followed by a significant change in fetal heart rate, EEG, and cerebral blood flow. Other experiments where there was no effect of lidocaine on these parameters are not reported. The ewes were prepared for operation by restricting food for 24 to 48 hours and water for 12 hours. Anesthesia was induced with halothane,? 2 to 4 per cent, and maintained at a concentration of 0.6 to 1.4 per cent with 50 per cent oxygen delivered through a cuffed endotracheal tube by means of an anesthetic and negative-positive pressure apparatus respirator (Bird) . Reinforced segmented polyurethane “T” catheters were placed in the carotid and jugular vessels by the technique described in detail elsewhere.g A perivascular ultrasonic blood flow electrode was placed below the carotid “T” catheter, and the output was calibrated intermittently by clamping above the catheter and collecting a timed sample in a graduated cylinder. Extradural solder ball or silver-silver chloride EEG electrodes were placed by the technique described prelo Direct write-out of pressure in the viously. carotid and jugular vessel, blood flow, and bipolar recordings of the fetal EEG was obtained by means of an 8 channel dynograph (Type RM, Beckman Instruments, Inc.,
15, 1972 Gynecol.
Fullerton, California). After a stable control period of 15 to 30 minutes, 2 to 5 ml. of a 1 or 2 per cent solution of lidocaine was injected into the jugular vein over a 20 to 30 second interval. The total dose of lidocaine that was injected was between 14.3 and 36.8 mg. per kilogram of fetal weight. Blood samples were drawn from the carotid and jugular vessels prior to the injection of lidocaine, following the injection of lidocaine when frequency and amplitude changes appeared in the EEG, and, on occasion, several minutes after lidocaine injection when the physiologic parameters had returned to control level. The blood samples were immediately deproteinated and determined within 48 hours for glucose, lactate, and pyruvate contents by enzymatic methods. pH and blood gas analyses were performed within 15 minutes by previously described methods.ll Blood flow was calculated from a calibration factor determined in vivo and expressed as milliliters per 100 Gm. of wet weight of the brain per minute. Cerebral metabolic rate was calculated from the product of blood flow and arteriovenous difference of substrate. Perfusion pressure was calculated from mean carotid (diastolic plus f/3 pulse pressure) minus jugular pressure, and resistance was calculated from the quotient of pressure/flow x 1,000 (millimeters per liter per minute) . Heart rate was obtained from the carotid pulse tracing. Statistical evaluation was performed by comparing grouped means by the Student t test and expressed in terms of probability (p) values. Results
Base-line period prior to iidocaine injection. Blood gas, pH, cardiovascular, and cerebral metabolic observations prior to the injection of lidocaine are shown in Table I. These values are consistent with those reported previously from this laboratory for the range of gestational ages of these fetuses.g
Observations following lidoeaine injection. ‘Xylocaine, rkGlsa&usetts. tlluothane,
Astra
Pharm.
Ayerst
Labs.,
Products, New
York,
Inc., New
Warchester, York.
Fetal electroencephalogram. The changes that were observed in the fetal EEG con-
Volume Numbrr
Lidocaine
112 6
on fetal heart rate and brain
791
Baseline
3 min. following
xylocaine
18 min.
H.R. 146
Fig. 1. Fetal of lidocaine
EEG and heart rate (14 mg. per kilogram).
(H.R.) prior Gestational
to and 3 and 18 minutes age, 123 days.
following
the injection
Table I. Physiologic and metabolic observations following xylocaine injection in 15 sheepexperiments Bate Oxygen PH
tension
(mm.
Hg)
line
21.4 k 7.293 +
Xylocains 1.0 0.020
20.2 t 7.264 i
B 0.9 0.020
N.S. N.S.
Cardiovascular pressure
Perfusion
(mm.
Hg)
41.8 441.9 151.5 166.1
Resistance(mm./L./min.) Blood Heart
flow rate
(ml./100 (beats/min.)
Gm./min.)
+ 2.5 2 48.9 2 16.5 t 9.2
33.7 561.4 108.4 120.2
+ 2.3 + 47.4 t 11.1 f 5.6
2 t ++
3.1 7.5 -11.8 0.3
-* 0.4 ” 2.5 2 10.7 t 0.4
< < < <
0.025 0.05 0.025 0.0005
Metabolic Oxygen Glucose Lactate Pyruvate N.S.
consumption consumption metabolism metabolism
(ml./100 (mg./lOO (mg./lOO (mg./lOO
GmJmin.) Gm./min.) Gm./min.) Gm./min.)
3.7 6.9 7.9 -0.6
0.3 2.4 8.8 0.5
N.S. N.S. N.S. N.S.
= not significant.
s&ted primarily of a dropping out of the faster frequencies and slowing of the over-all record (Fig. 1) which on occasion preceded a decreasein amplitude and the onset of an isoelectric (flat) EEG (Fig. 2). The frequency and amplitude changes that were noted occurred within 3 minutes following the injection of lidocaine. The isoelectric EEG appeared more commonly in the young-
er fetuses and at a lower concentration (milligrams per kilogram of fetus) of lidoCaine when compared to the somewhat older fetuses. Blood levels of lidocaine were not obtained, so this dose-effect relationship could not be quantitated. The return of the EEG to base-line frequency and amplitude generally followed the recovery of the fetal bradycardia (seebelow)
792 Mann et al.
March Am. J. Obstet.
30 sec. following
15, 1972 Gynccol.
xylocaine
2 min.
H.R. 105
H.R. 100
13 min.
H.R. 185
18 min.
H.R. 185
Fig. 2. Fetal EEG mg. per kilogram),
and heart Gestational
rate age;
(H.R.)
prior 131 dais.
and consisted first of periodic slow waves which became continuous, increased in amplitude, and were superimposed with faster rhythms (Fig. 2). On two occasions, the injection of a large concentration of lidocaine (120 mg.) to fetuses that were 143 days’ gestational age resulted in the onset of low-voltage fast activity (LVFA-beta) in the EEG (Fig, 3). The EEG failed to recover in these experiments, and a progressively severe fetal bradycardia preceded fetal death. Similar concentrations injected into younger fetuses resulted in slowing and the appearance of isoelectric EEG’s that failed to recover but did not reveal LVFA in the EEG. The development of the reticular activating system in the older fetus might explain the difference in response.lO
to and
following
the injection
of lidocaine
(20
Cardiova.wular parameters. The injections of lidocaine in each of the 1.5 experiments resulted in a significant decrease in fetal heart rate from a mean of 166 + 9 to 120 rt 6 beats per minute (p < 0.0005, Table I) . The fetal bradycardia occurred within 60 seconds of injection and generally returned to base-line values in 7 to 10 minutes following the lidoCaine injection. The heart rate had returned to normal prior to the reappearance of a preinjection EEG record (Figs. 2 and 3). A bilateral vagectomy was performed prior to lidocaine injection in two experiments. The fetal heart rate increased following vagectomy. The infusion of lidocaine resulted in a significant fetal bradycardia. EEG changes were also similar to the experiments where the vagi were intact. Blood flow decreased significantly follow-
Volume Number
112 6
Lidocaine
on
fetal
heart
rate
and
brain
793
Baseline
15 min.
xylocaioe
Fia. 3. Fetal EEG urior to and 15 minutes following k&gram). GestatioGal age, 143 days. ing the injection of lidocaine from 152 to 108 ml. per 100 Gm. of brain per minute (Table I, p < 0.025). The decrease in blood flow occurred as the result of both a significant fall in perfusion pressure (p < 0.025) and a significant increase in vascular resistance (p < 0.05). The time sequence of these cerebral vascular alterations closely paralleled the changesin heart rate. Cerebral metabolic observations. Oxygen tension in the carotid artery did not change significantly following the lidocaine injections (Table I) . The significant decreasein blood flow was associated with an increase in the arteriovenous difference in oxygen content so that cerebral oxygen consumption did not change significantly after the injection of lidocaine. Cerebral glucose consumption was unchanged by the injection of lidocaine. Lactate and pyruvate metabolism of the fetal brain was similarly unaffected and remained insignificant from zero. The slight decrease in pH in the carotid artery that occurred following lidocaine injection was insignificant in relation to the base-line value (Table I). Comment
There was no attempt in this study to quantitate blood levels of lidocaine. Concentrations of lidocaine were injected into the fetal circulation that resulted in significant alterations in fetal heart rate so that simultaneous observations of fetal cerebral function and metabolism could be obtained. Therefore, no statement can be made of a critical level of lidocaine beyond which physiologic alterations would be expected. Such
the injection
of lidocaine
(30 mg. per
determinations have been made by Asling and associates,5Gordon,12 and Teramo and Widholm6 in the human being. These invesfigators found that fetal bradycardia occurred when umbilical cord blood levels of lidocaine were greater than 2 pg per milliliter. Shnider and co-workers4 reported that the median time of onset of fetal bradycardia was 4.6 minutes following completion of drug administration by PCB and that the fetal bradycardiac lasted a median time of 3.3 minutes. These time sequencesare quite similar to those reported here when one considers that the lidocaine was injected directly into the fetal circulation. Following the injection of 50 + 5 mg. per kilogram of fetal body weight of mepivacaine directly into the brains of fetal guinea pigs, Morishima and Adamsons13 found the concentration in fetal blood within 7 minutes to average 23.0 +_1.4 ~pgper milliliter and beyond 45 minutes to average 6.9 i: 0.4 ,ug per milliliter. It might be assumed, therefore, that fairly similar toxic levels of lidocaine occurred in the present experiment at least in terms of physiologic response. The return of physiologic parameters to base-line values in most experiments excluded concern for the inadvertent injection of lethal concentrations of lidocaine. The effect of local anesthetics on the cardiovascular systemhas been studied in several species including the human being. Both bradycardia and tachycardia have been noted, bradycardia being the more common finding. Shnider and associates4 reported fetal heart rate changesin 30 per cent of casesfollowing PCB, 24 per cent of which were bradycardia. Anderson and coIleagues14 studied the effect of local anesthetics (mepi-
794
Mann
et al.
March Am. J. Obstet.
vacaine and lidocaine; concentrations 2.5 to 20 pg per milliliter) on isolated human fetal hearts from mid-gestation. A moderate slowing of the pacemaker activity of the sinus node, changes in the electrocardiogram that indicated a reduced conduction velocity, and a reduction in the contractility of the hearts were observed. The mechanisms behind these actions were not obvious. However, it was clear that the action of the local anesthetics was at the cellular level with either the transport system within the membrane or the excitation-contraction coupling in the myocardial cell. The direct cellular action of the effect of local anesthetics on the heart would explain the bradycardic response to lidocaine that was observed following vagectomy in the present experiment. In addition, the reduction in active systolic pressure noted by Anderson and colleagues is consistent with the significant fall in cerebral perfusion pressure that was observed. The increase in resistance reflected active vasoconstriction that occurred following the injection of lidocaine. Blood flow decreased, therefore, as a result of both these vascular changes. Cerebral oxygen consumption decreased insignificantly because of the increase in the arteriovenous difference in oxygen content. The reciprocal relationship between blood flow and arteriovenous substrate difference serves to maintain a constant metabolic rate. This relationship has been shown previously for the fetal cerebral circulationll and for the umbilical circulation as we11.15 The insignificant change in cerebral metabolism occurred while cerebral function in terms of the EEG was significantly altered. The slowing of the EEG that occurred following lidocaine injection in these fetal sheep experiments is similar to the EEG observations that were made by Foldes and associ-
REFERENCES
1.
Page, C.
2. 3.
C.:
E. AM.
ates16 in human volunteers and consistent with the use of lidocaine as an antiepileptic drug. I7 In the present experiments, large concentrations of lidocaine, particularly in the younger fetuses, resulted in an isoelectric EEG. Within 12 to 20 minutes, the EEG returned to base-line (Fig. 2) appearance unless heart failure ensued and the fetus died. The transient nature of the changes in fetal heart rate and EEG would seem to indicate that immediate delivery of the fetus under these circumstances would be contraindicated. This suggestion was first proposed by Morishima and Adamsons13 who showed that the local anesthetic was cleared by the guinea pig placenta and that the degree of newborn depression decreased as the time of delivery was prolonged from the injection of mepivacaine. Immediate delivery would necessitate neonatal resuscitation during potentially severe central nervous system depression. Further, the placenta may act more efficiently in eliminating the lidocaine than the neonatal kidney. Fetal bradycardia following PCB would present a major indication for fetal acid-base evaluation if delivery was delayed. The development or progression of acidosis would reflect fetal asphyxia as a result of severe depression of the myocardium by toxic levels of lidocaine, cardiac failure, and poor placental perfusion. Immediate delivery would be indicated under these conditions. Teramo and Widholm6 and Asling and associates5 have reported a significant acidosis in depressed neonates following PCB. It is not possible at this time to evaluate properly the significance of a transient period of slowing or isoelectricity in the EEG in terms of eventual brain function. Hopefully, such information will be available in the near future.
4.
Kamm,
P., J.
OBSTET.
M.
L.,
and
GYNECOL.
1961. Pitkin, R. M., and Goddard, Gynecol. 21: 737, 1963. Seeds, A. E., Stein-Messinger, J. H.: Obstet. Gynecol. 20:
Chappell, 81:
1094,
5. W.
B.:
Obstet.
P., and Dorsey, 462, 1962.
15, 1972 Gynecol.
6.
Shnider, S. M., Asling, J. H., Hall, and Margolis, A. J,: Ax J. OBSTET. COL. 107: 619, 1970. Asling, J. H., Shnider, S. M., Margolis, Wilkinson, G. L., and Way, E. L.: OBSTET. GYNECOL. 107: 626, 1970. Teramo, K., and Widhohn, 0.: Acta Gynecol. Stand. 46: Suppl. 2, 1967.
J.
W.,
GYNE-
A. J., AM. J. Obstet.
Volume 112 Number 6
7. Nyirjesy, 8. 9. 10. 11. 12.
I., Hawks, B. L., Herbert, B. E., Hopwood, H. G., and Falls, H. C.: AM. J. OBSTET. GYNECOL. 87: 231, 1963. Sinclair, J. C., Fox, H. A., Lentz, J. F., Fuld, G. L., and Murphy, J.: N. Engl. J. Med. 273: 1173, 1965. Mann, L. I.: Exp. Neurol. 26: 136, 1970. Mann, L. I., Prichard, J., and Symmes, D.: AM. J. OBSTET. GYNECOL. 106: 39, 1970. Mann, L. I.: Exp. Neurol. 29: 336, 1970. Gordon, H. R.: N. Engl. J. Med. 279: 910, 1968.
Lidocaine
13. 14. 15. 16. 17.
on fetal heart rate and brain
795
Morishima, H. O., and Adamsons, K.: Anesthesiology 28: 343, 1967. Anderson, K.-E., Gennser, G., and Nilsson, E.: Acta Physiol. Stand. 80: 34, 1970. Mann, L. I.: Am. J. Physiol. 218: 1453, 1970. Foldes, F. F., Molloy, R., McNall, P. G., and Koukal, L. R.: J. A. M. A. 90: 1493, 1960. Bernhard, C. G., Bohm, E., and Hojeberg, S.: A. M. A. Arch. Neurol. Psychiat. 74: 208, 1955.
Effect of lidocaine on fetal heart rate and fetal brain metabolism and function LEON
I.
COLIN
MANN, BAILEY,
ANDREW SYBIL New
M.D.*
CARMICHAEL, DUCHIN,
York,
M.D.
New
D.V.M. B.A.,
M.A.
York
The eflect of lidocaine (xylocaine) on fetal heart rate and fetal cerebral metabolism and function was studied in 15 fetal sheep experiments. A significant btadycardia occurred in each experiment. Vagcctomy did not influence the bradycardic effect. The electroencephalogram (EEG) showed either slowing, slowing followed by an isoelectric (flat) record, or the development of low-voltage fast activity. While cerebral blood flow decreased significantly, cerebral metabolism was unaflected, Fetal heart rate, blood flow, and cerebral function in terms of the EEG recovered within 20 minutes of injection.
LOCAL ANESTHETICS areusedcommonly in obstetrics for analgesiaor anesthesia during labor and delivery. Paracervical block (PCB) in particular has become a popular procedure. The experience with PCB has revealed the successfulrelief of pain during
From the Department Gynecology, Cornell College.
labor and delivery with few maternal and fetal complications.lS3 However, several reports have presented evidence from careful fetal monitoring that changes in the fetal heart rate may occur as frequentiy as 30 per cent of the time following PCB.“, 5 Fetal bradycardia has been the most frequent abnormality and has occurred in association with a significant decrease in fetal pH as determined by fetal scalp blood analysis.’ The significance of these observations of heart-rate and acid-base abnormalities has remained unclear. A few reports have associated an increased incidence of neonatal depressionas evaluated by Apgar scoresand neonatal death with PCB, but direct evidence for a cause-and-effect relationship appeared tenuous.7p* This report presents observations from
of Obstetrics and University Medical
This investigation was supported by grants from the National Institutes of Health, No. RO-INS 08800, and The United Cerebral Palsy Research and Educational Foundation, No. R-237-71. Received
for Publication
August
$;;pted
for pubiication
November
2, 1971. IO,
*Recipient of National Institute of Health Research Career Deuelopment Award No. 5KO4HD-30085.
789
790
Mann
et al.
March Am. J. Obstet.
fetal sheep experiments on the effect of lidoCaine injection on fetal heart rate and brain function and metabolism. The analysis suggests that fetal bradycardia and changes in functional activity of the brain in terms of the electroencephalogram (EEG) that were observed following toxic levels of lidocaine were transient phenomena and were the resuit of a direct action on the myocardium and cerebral cell. Materials
and
methods
Fifteen experiments are reported that were conducted on 8 sheep fetuses whose gestational ages were from 120 to 143 days (term gestation is approximately 145 days). In each of these experiments, the injection of lidoCaine,* 1 or 2 per cent was followed by a significant change in fetal heart rate, EEG, and cerebral blood flow. Other experiments where there was no effect of lidocaine on these parameters are not reported. The ewes were prepared for operation by restricting food for 24 to 48 hours and water for 12 hours. Anesthesia was induced with halothane,? 2 to 4 per cent, and maintained at a concentration of 0.6 to 1.4 per cent with 50 per cent oxygen delivered through a cuffed endotracheal tube by means of an anesthetic and negative-positive pressure apparatus respirator (Bird) . Reinforced segmented polyurethane “T” catheters were placed in the carotid and jugular vessels by the technique described in detail elsewhere.g A perivascular ultrasonic blood flow electrode was placed below the carotid “T” catheter, and the output was calibrated intermittently by clamping above the catheter and collecting a timed sample in a graduated cylinder. Extradural solder ball or silver-silver chloride EEG electrodes were placed by the technique described prelo Direct write-out of pressure in the viously. carotid and jugular vessel, blood flow, and bipolar recordings of the fetal EEG was obtained by means of an 8 channel dynograph (Type RM, Beckman Instruments, Inc.,
15, 1972 Gynecol.
Fullerton, California). After a stable control period of 15 to 30 minutes, 2 to 5 ml. of a 1 or 2 per cent solution of lidocaine was injected into the jugular vein over a 20 to 30 second interval. The total dose of lidocaine that was injected was between 14.3 and 36.8 mg. per kilogram of fetal weight. Blood samples were drawn from the carotid and jugular vessels prior to the injection of lidocaine, following the injection of lidocaine when frequency and amplitude changes appeared in the EEG, and, on occasion, several minutes after lidocaine injection when the physiologic parameters had returned to control level. The blood samples were immediately deproteinated and determined within 48 hours for glucose, lactate, and pyruvate contents by enzymatic methods. pH and blood gas analyses were performed within 15 minutes by previously described methods.ll Blood flow was calculated from a calibration factor determined in vivo and expressed as milliliters per 100 Gm. of wet weight of the brain per minute. Cerebral metabolic rate was calculated from the product of blood flow and arteriovenous difference of substrate. Perfusion pressure was calculated from mean carotid (diastolic plus f/3 pulse pressure) minus jugular pressure, and resistance was calculated from the quotient of pressure/flow x 1,000 (millimeters per liter per minute) . Heart rate was obtained from the carotid pulse tracing. Statistical evaluation was performed by comparing grouped means by the Student t test and expressed in terms of probability (p) values. Results
Base-line period prior to iidocaine injection. Blood gas, pH, cardiovascular, and cerebral metabolic observations prior to the injection of lidocaine are shown in Table I. These values are consistent with those reported previously from this laboratory for the range of gestational ages of these fetuses.g
Observations following lidoeaine injection. ‘Xylocaine, rkGlsa&usetts. tlluothane,
Astra
Pharm.
Ayerst
Labs.,
Products, New
York,
Inc., New
Warchester, York.
Fetal electroencephalogram. The changes that were observed in the fetal EEG con-
Volume Numbrr
Lidocaine
112 6
on fetal heart rate and brain
791
Baseline
3 min. following
xylocaine
18 min.
H.R. 146
Fig. 1. Fetal of lidocaine
EEG and heart rate (14 mg. per kilogram).
(H.R.) prior Gestational
to and 3 and 18 minutes age, 123 days.
following
the injection
Table I. Physiologic and metabolic observations following xylocaine injection in 15 sheepexperiments Bate Oxygen PH
tension
(mm.
Hg)
line
21.4 k 7.293 +
Xylocains 1.0 0.020
20.2 t 7.264 i
B 0.9 0.020
N.S. N.S.
Cardiovascular pressure
Perfusion
(mm.
Hg)
41.8 441.9 151.5 166.1
Resistance(mm./L./min.) Blood Heart
flow rate
(ml./100 (beats/min.)
Gm./min.)
+ 2.5 2 48.9 2 16.5 t 9.2
33.7 561.4 108.4 120.2
+ 2.3 + 47.4 t 11.1 f 5.6
2 t ++
3.1 7.5 -11.8 0.3
-* 0.4 ” 2.5 2 10.7 t 0.4
< < < <
0.025 0.05 0.025 0.0005
Metabolic Oxygen Glucose Lactate Pyruvate N.S.
consumption consumption metabolism metabolism
(ml./100 (mg./lOO (mg./lOO (mg./lOO
GmJmin.) Gm./min.) Gm./min.) Gm./min.)
3.7 6.9 7.9 -0.6
0.3 2.4 8.8 0.5
N.S. N.S. N.S. N.S.
= not significant.
s&ted primarily of a dropping out of the faster frequencies and slowing of the over-all record (Fig. 1) which on occasion preceded a decreasein amplitude and the onset of an isoelectric (flat) EEG (Fig. 2). The frequency and amplitude changes that were noted occurred within 3 minutes following the injection of lidocaine. The isoelectric EEG appeared more commonly in the young-
er fetuses and at a lower concentration (milligrams per kilogram of fetus) of lidoCaine when compared to the somewhat older fetuses. Blood levels of lidocaine were not obtained, so this dose-effect relationship could not be quantitated. The return of the EEG to base-line frequency and amplitude generally followed the recovery of the fetal bradycardia (seebelow)
792 Mann et al.
March Am. J. Obstet.
30 sec. following
15, 1972 Gynccol.
xylocaine
2 min.
H.R. 105
H.R. 100
13 min.
H.R. 185
18 min.
H.R. 185
Fig. 2. Fetal EEG mg. per kilogram),
and heart Gestational
rate age;
(H.R.)
prior 131 dais.
and consisted first of periodic slow waves which became continuous, increased in amplitude, and were superimposed with faster rhythms (Fig. 2). On two occasions, the injection of a large concentration of lidocaine (120 mg.) to fetuses that were 143 days’ gestational age resulted in the onset of low-voltage fast activity (LVFA-beta) in the EEG (Fig, 3). The EEG failed to recover in these experiments, and a progressively severe fetal bradycardia preceded fetal death. Similar concentrations injected into younger fetuses resulted in slowing and the appearance of isoelectric EEG’s that failed to recover but did not reveal LVFA in the EEG. The development of the reticular activating system in the older fetus might explain the difference in response.lO
to and
following
the injection
of lidocaine
(20
Cardiova.wular parameters. The injections of lidocaine in each of the 1.5 experiments resulted in a significant decrease in fetal heart rate from a mean of 166 + 9 to 120 rt 6 beats per minute (p < 0.0005, Table I) . The fetal bradycardia occurred within 60 seconds of injection and generally returned to base-line values in 7 to 10 minutes following the lidoCaine injection. The heart rate had returned to normal prior to the reappearance of a preinjection EEG record (Figs. 2 and 3). A bilateral vagectomy was performed prior to lidocaine injection in two experiments. The fetal heart rate increased following vagectomy. The infusion of lidocaine resulted in a significant fetal bradycardia. EEG changes were also similar to the experiments where the vagi were intact. Blood flow decreased significantly follow-
Volume Number
112 6
Lidocaine
on
fetal
heart
rate
and
brain
793
Baseline
15 min.
xylocaioe
Fia. 3. Fetal EEG urior to and 15 minutes following k&gram). GestatioGal age, 143 days. ing the injection of lidocaine from 152 to 108 ml. per 100 Gm. of brain per minute (Table I, p < 0.025). The decrease in blood flow occurred as the result of both a significant fall in perfusion pressure (p < 0.025) and a significant increase in vascular resistance (p < 0.05). The time sequence of these cerebral vascular alterations closely paralleled the changesin heart rate. Cerebral metabolic observations. Oxygen tension in the carotid artery did not change significantly following the lidocaine injections (Table I) . The significant decreasein blood flow was associated with an increase in the arteriovenous difference in oxygen content so that cerebral oxygen consumption did not change significantly after the injection of lidocaine. Cerebral glucose consumption was unchanged by the injection of lidocaine. Lactate and pyruvate metabolism of the fetal brain was similarly unaffected and remained insignificant from zero. The slight decrease in pH in the carotid artery that occurred following lidocaine injection was insignificant in relation to the base-line value (Table I). Comment
There was no attempt in this study to quantitate blood levels of lidocaine. Concentrations of lidocaine were injected into the fetal circulation that resulted in significant alterations in fetal heart rate so that simultaneous observations of fetal cerebral function and metabolism could be obtained. Therefore, no statement can be made of a critical level of lidocaine beyond which physiologic alterations would be expected. Such
the injection
of lidocaine
(30 mg. per
determinations have been made by Asling and associates,5Gordon,12 and Teramo and Widholm6 in the human being. These invesfigators found that fetal bradycardia occurred when umbilical cord blood levels of lidocaine were greater than 2 pg per milliliter. Shnider and co-workers4 reported that the median time of onset of fetal bradycardia was 4.6 minutes following completion of drug administration by PCB and that the fetal bradycardiac lasted a median time of 3.3 minutes. These time sequencesare quite similar to those reported here when one considers that the lidocaine was injected directly into the fetal circulation. Following the injection of 50 + 5 mg. per kilogram of fetal body weight of mepivacaine directly into the brains of fetal guinea pigs, Morishima and Adamsons13 found the concentration in fetal blood within 7 minutes to average 23.0 +_1.4 ~pgper milliliter and beyond 45 minutes to average 6.9 i: 0.4 ,ug per milliliter. It might be assumed, therefore, that fairly similar toxic levels of lidocaine occurred in the present experiment at least in terms of physiologic response. The return of physiologic parameters to base-line values in most experiments excluded concern for the inadvertent injection of lethal concentrations of lidocaine. The effect of local anesthetics on the cardiovascular systemhas been studied in several species including the human being. Both bradycardia and tachycardia have been noted, bradycardia being the more common finding. Shnider and associates4 reported fetal heart rate changesin 30 per cent of casesfollowing PCB, 24 per cent of which were bradycardia. Anderson and coIleagues14 studied the effect of local anesthetics (mepi-
794
Mann
et al.
March Am. J. Obstet.
vacaine and lidocaine; concentrations 2.5 to 20 pg per milliliter) on isolated human fetal hearts from mid-gestation. A moderate slowing of the pacemaker activity of the sinus node, changes in the electrocardiogram that indicated a reduced conduction velocity, and a reduction in the contractility of the hearts were observed. The mechanisms behind these actions were not obvious. However, it was clear that the action of the local anesthetics was at the cellular level with either the transport system within the membrane or the excitation-contraction coupling in the myocardial cell. The direct cellular action of the effect of local anesthetics on the heart would explain the bradycardic response to lidocaine that was observed following vagectomy in the present experiment. In addition, the reduction in active systolic pressure noted by Anderson and colleagues is consistent with the significant fall in cerebral perfusion pressure that was observed. The increase in resistance reflected active vasoconstriction that occurred following the injection of lidocaine. Blood flow decreased, therefore, as a result of both these vascular changes. Cerebral oxygen consumption decreased insignificantly because of the increase in the arteriovenous difference in oxygen content. The reciprocal relationship between blood flow and arteriovenous substrate difference serves to maintain a constant metabolic rate. This relationship has been shown previously for the fetal cerebral circulationll and for the umbilical circulation as we11.15 The insignificant change in cerebral metabolism occurred while cerebral function in terms of the EEG was significantly altered. The slowing of the EEG that occurred following lidocaine injection in these fetal sheep experiments is similar to the EEG observations that were made by Foldes and associ-
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