Some effects of meperidine hydrochloride on maternal and fetal sheep

FETUS, PLACENTA, AND NEWBORN

Some effects of meperidine hydrochloride

on

maternal and fetal sheep VAN P.

R. V.

Lexington,

JENKINS

DILTS,

II, JR.,

M.D.

M.D.

Kentucky

Single intravenous injection into the Pregnant ewe of meperidine HC1 in dosages of 0.85 to 2.5 mg. per kilogram of maternal weight and 14.7 to 76.9 mg. per kilogram of fetal weight was not associated with significant effects on maternal and fetal arterial blood pressure and heart rate. Furthermore, no significant changes could be found in maternal arterial, fetal arterial, and umbilical venous blood gas values or acid-base values. The mean dosage of lidocaine HCl in milligrams per minute required for satisfactory continuous spinal anesthesia in the pretest period was 3.66 times that required following the injection of meperidine HCl.

EFFECTIVE

OBSTETRIC

ford and Rudofsky3 showed that meperidine HCl given intravenously reached the fetus within 2 minutes and that the fetal concentration was parallel to the maternal, but always lower. Redden4 demonstrated that maternal and fetal blood levels of meperidine HCl reached equilibrium within 30 minutes after intravenous administration and that blood meperidine HCl levels appeared to be more a function of time elapsed since the last administration rather than of total dosage. This study is intended to provide information concerning the effects of maternal meperidine HCl administration on maternal and fetal blood pressure, heart rate, acid-base balance, and blood gases in the pregnant ewe and fetus.

ZinalgeSia

without harmful effects on the fetus has been sought for many years. Meperidine HCl seems to provide this, but clinical observations are the basis for the majority of information concerning placental transfer of analgesics and their effects on the neonate. Neonates whose mothers have received meperidine HCl within 6 hours of the time of delivery have a greater incidence of respiratory depression. Laboratory evidence concerning the placental transfer of meperidine HCl is found in only a few reports in the English literature. Way and associates1 identified meperidine HCl in the urine of neonates and Apgar and colleagues2 identified meperidine HCl in cord blood. CrawFrom the Department Gynecology, University College of Medicine. Supported of Health

of Obstetrics of Kentucky

and

Materials and methods Nine ewes at 90 or more days’ gestation were utilized for the study of the placental

in part by National Institutes Grant No. HE 12476-02. 1005

1006

Jenkins

and

Table I. Meperidine Experiment No.

Dilts

Amer.

HCl Ewe

:

Fetus

weight (Kg.) 4.8 2.8

80 68 64 65 54 44 71

Table II. Mean

control

Maternal artery FetaI artery Umbilical vein

values He)

*Pontocaine

HCI,

Heart

Pot (mm. Hd 202229 1822 25k3

rate

6853 181-+9

Labs.,

Ewe HCl

meperidine (mg./Kg.)

Fetus HCl

meperidine (mg./Kg.)

0.89 1.67

17.9 20.8

1.87 1.84 2.50 1.54 0.93 1.14 0.85

71.4 32.9 42.1 76.9 25.1 14.7 17.6

* 1 S.E.

8253 6 7+2

Winthrop

HCl

150 125 160 100 50 50 60

transfer of meperidine and its effects on maternal and fetal sheep. Of these, 2 had twins. In e&e No. 11, the first twin died and the second was used for the study. All 9 ewes had either continuous spinal or epidural anesthesia with 4 mg. of tetracaine HCl* initially supplemented with 2% lidoCaine HCl as necessary. The animal was placed in the left lateral recumbent position. Under 2% lidocaine HCl local infiltration, catheters were placed in the right common carotid artery and right external jugular vein, to be used for sample collection, arterial pressure and heart rate measurement, and injection of meperidine HCI. A cuffed endotracheal tube was placed in the trachea through a tracheotomy. Each animal was ventilated upon demand with 9570 0, and 5% CO, mixed with room air via a Bird Respirator. The lungs were periodically overinflated to decrease the occurrence of atelectasis which is frequent in the lateral position. The abdomen was entered through a right paramedian infra-umbilical incision with marsupialization of the pregnant uterine horn to the abdominal wall. The fetus was delivered

York.

Meperidine (w.) 100 50

2.1 3.8 3.8 1.3 2.0 3.4 3.4

BP fmm.

1, 1971 Gym.

dosages

Weight (Kg.) 60 56

3 4 5 6 8 10 11

April J. Obstet.

NW

York,

New

PC02 (mm. fW 3ot3 4326 38k4

PH 7.43kO.06 7.13+0.04 7.1420.05

Base deficit (mEq./L.) 843 1722 14&3

and its head was placed in a warm salinefilled glove to prevent spontaneous respiration. The edges of the uterine incision were clamped to the fetal abdomen around the umbilical cord to maintain the umbilical circulation. A catheter was placed in the fetal left femoral artery for monitoring arterial pressure and heart rate and securing samples. Another catheter was placed into a tributary of the umbilical vein and advanced under direct vision into a main umbilical vein for collection of samples. Umbilical blood flow and oxygen transfer were determined in 2 of the fetuses by entering the fetal abdomen through a midline supraumbilical incision and placing a cuff electromagnetic flow transducer around the intra-abdominal umbilical vein. The arterial pressure, heart rate, and flowmeter signals were recorded on a Hewlett-Packard heated stylus rectilinear recorder. Both pulsatile and electronically averaged signals were recorded every 5 minutes throughout the experiment. Blood samples were collected via anaerobic techniques for Po2, Pco,, and pH analysis at least 3 times during the control period and at intervals of 5 to 10 minutes throughout the test period from 10 to 65 minutes. Blood samples were collected once during

Volume Number

109 7

Effects

MATERNAL

ARTERIAL

BLOOD

of

meperidine

MATERNAL

hydrochloride

HEART

1007

RATE

~;*+q:*$gq#

70-

130

I

I

FETAL

I

I

ARTERIAL PRESSURE

I

I

I

BLOOD

I

FETAL

I

I

I

I

HEART RATE

120 I IO t w

2 IOO> -J 90is 5 BOz 8

7060 50 40 1 0

I

IO

I

210 30 4b 5b MINUTES POST INJECTION

Fig. 1. Mean maternal as per cent of control

and period

L

6’0

0

fetal arterial pressures and mean * 1 S.E. The changes

the control period and at varying intervals throughout the test period from 10 to 65 minutes for analysis for meperidine. The serum was separated and refrigerated for later analysis. Meperidine analysis required 6.5 ml. of whole blood in each sample. PoZ, PcoZ, and pH determinations were done on an IL Ultra Micro Model 113 gas and pH analyzer immediately after being drawn. Base excess was calculated with a Radiometer Blood ,Gas Calculator, type

lb

I I 2’0 30 4b 50 MINUTES POST INJECTION

heart rates during are not significant.

test period

6b

expressed

BGCl. Meperidine analyses were done by gas-liquid chromatography.5 Following the operative procedures and stabilization of the preparation, a control period averaging 68 minutes with a range of 44 to 90 minutes was observed. Meperidine HCl was injected intravenously into the pregnant ewe slowly over a 3 minute period via the external jugular vein catheter. Meperidine HCl dosages(Table I) varied from 0.85 to 2.5 ,mg. per kilogram of maternal

11338

Jenkins

and

Dilts

MATERNAL

April J. Obstet.

Amer.

ARTERIAL

MATERNAL

p02

1, 1971 Gyne~.

ARTERIAL

0,

ARTERIAL

pC0,

140 120 100 80

w 2 140

FETAL

ARTERIAL

80 -

p0,

s FETAL k- 100 z ii! * 120 80 1 E UMBILJCAL

VENOUS

w 2120 a ’ II0 2 : 100 2

pop

Loap

I

80 -

$JOL 0

1

1

1

t

1

1

IO

20

30

40

50

80

fetal during mean

UMBILICAL

I

I

I

I

VENOUS pCO2

120 -

MINUTES POST IN JECTfON Fig. 2. Mean maternal and umbilical venous PO, values expressed as per cent of control changes are not significant.

I

arterial and test period + 1 S.E. The

weight. Meperidine HCI dosages compared to fetal weight varied from 14.7 to 76.9 mg. per kilogram. The dosage and interval sample time were varied somewhat to investigate Redden’s report that meperidine HCl levels in the fetus are more a function of time since last administration rather than of dosage. Blood samples were drawn at 10 minutes after injection of meperidine HCl and varying times at from 5 to 10 minute intervals through 50 to 65 minutes post injection. The

II0

-

100 90 80 70 0

I

I

Y

I

I

I

IO

20

30

40

50

60

MINUTES POST INJECTION Fig. 3. Mean

maternal and fetal arterial and umbilical venous Pcoz values during test period expressed as per cent of control mean + 1 S.E. The changes are not significant.

Volume Number

109 7

Effects of meperidine

MATERNAL

ARTERIAL

pH 350 -

IO1 r

hydrochloride

1009

MATERNAL ARTERIAL BASE DEFICIT

.

300 250 200 -

CJTL

I

I

I

I

I

I

I50 100 -

FETAL

ARTERIAL

pH 50-

I

I

I

I

I

I

w 3 3 J zz

s UMBILICAL

VENOUS

50 [

I50 too

0

I

IO

20

30

I 40

I

I

I

I

I

I

100

200

I

I

FETAL ARTERIAL BASE DEFICIT

8 a9

I

I

I

I

I

I

pH

IO1 r

97L

d .M’

I 50

I 60

MINUTES POST INJECTION

50 I 0

UMBILICAL VENOUS BASE DEFICIT

l-&$$ . I

I

I

I

I

I

IO

20

30

40

50

60

MINUTES POST INJECTION

Fig. 4. Mean maternal and fetal arterial and umbilical venous pH values during test period expressed as per cent of control mean t 1 S.E. The changes are not significant.

Fig. 5. Mean maternal and fetal arterial umbilical venous base-deficit values during period expressed as per cent of control _+ 1 S.E. The changes are not significant.

test period averaged of 45 to 95 minutes.

Test period values at intervals after the intravenous injection into the pregnant ewe of meperidine HCl are compared with mean control values for each experiment and expressed as the per cent of control values 5 1 S.E. Results for maternal arterial blood pressure and heart rate, and fetal arterial blood pressure and heart rate are shown. in Fig. 1. The maternal arterial blood pressure and heart rate values do not change significantly from control values. Fetal arterial blood pres-

75 minutes

with

a range

Results The operative procedures necessary for this type of study were well tolerated by both the ewe and fetus as demonstrated by normal mean control period values (Table II) for arterial blood pressure, heart rate, and blood gas and pH levels for preparations of this type.6-0

and test mean

1010

Jenkins

and

April 1, 1971 Amer. J. Obstet. Gynec.

Dilts

sure and heart rate are not changed significantly but do show a drop after 40 minutes. Figs. 2 and 3 present data for maternal arterial, fetal arterial, and umbilical venous PO, and Pcoz values, respectively, which do not change significantly from control levels. Figs. 4 and 5 present maternal arterial, fetal arterial, and umbilical venous pH and basedeficit values which are also not changed significantly from control values. A t test was applied to all data, and no changes were found to be significant. Comment This type of preparation and method of study has been well documented.6-g Both pregnant ewe and fetus demonstrated normal control period values. No significant effects of varying dosages (Table I) of intravenous meperidine HCl given to the pregnant ewe could be demonstrated on maternal and fetal arterial blood pressure and heart rate or on maternal arterial and fetal arterial and umbilical venous blood-gas values or acid-base values (Figs. 1 to 5). A decrease in the dosage of Iidocaine HCI for continuous spinal anesthesia was noted to occur after meperidine HCl was injected intravenously. The mean dosage of lidocaine HCl in milligrams per minute required for satisfactory anesthesia (as judged by peaceful ewes) in 6 animals during the pretest period was 1.65 2 0.23 mg. per minute while after meperidine HCI injection the mean amount

required was 0.45 + 0.2 mg. per minute. A t test was applied to this data, and P = >0.05 < 0.1. Similar data for continuous epidural anesthesia in 3 animals showed the pretest mean dosage of lidocaine HCI to be 3.07 + 0.06 mg. per minute and the test period requirement to be 1.79 + 0.26 mg. per minute. The initial mean arterial hematocrit of the fetuses taken during the control period was 41 (36 to 47) and at the termination of the experiment was 37.5 (31 to 43). The mean change in hematocrit for the experiment was 3.8 with a range of 0 to 9. These changes as well as the length of the experiments may explain the changes found in fetal heart rate, arterial pressure, and blood-gas values observed after 40 minutes in the test period. During the experiment only 1.5 ml. of blood was drawn from the fetus for each analysis of blood gas values and 6.5 ml. for each analysis of meperidine HCl in an attempt to prevent significantly decreasing the blood volume of the animal. Umbilical blood flow and oxygen transfer were determined in 2 experiments. No change was found in either umbilical vein Row or oxygen transfer following the intravenous injection of meperidine HCI into the pregnant ewe. Within the confines of the experimental preparation, no significant changes in maternal or fetal blood gas or acid base are associated with intravenous meperidine HCl injection into the ewe.

REFERENCES

1.

Way, E. L., Gimble, A. T., McKelway, W. P., Ross, H., Sung, C. Y., and Ellsworth, H.: J. Pharmacol. Exp. Ther. 96: 477, 1949. 2. Apgar, V., Burns, J. J., Brodie, B. B., and Papper, E. M.: AMER. J. OBSTET. GYNEC. 64: 1368, 1952. 3. Crawford, J. W., and Rudofsky, S.: Brit. J. Anaesth. 37: 929. 1965. 4. Redden, P. C.: ‘J. Arkansas Med. Sot. 63: 187, 1966. 5. Jenkins, V. R., II, Talbert, W. M., and Dilts, P. V., Jr.: To be published.

6.

7.

8. 9.

Dilts, P. V., Jr., Brinkman, C. R., III, Kirschbaum, T. J., and Assali, N. S.: AMER. J. OBSTET. GYNEC. 103: 138, 1969. Vaughn, D., Kirschbaum, T. H., Bersentes, T., Dilts, P. V., Jr., and Assali, N. S.: J. Appl. Physiol. 24: 135, 1968. Dilts, P. V., Jr.: AMER. J. OBSTET. GYNEC. 107: 1018, 1970. Dilts, P. V., Jr.: AMER. J. OBSTET. GYNEC. 108: 221, 1970.