Ketamine, catecholamines, and uterine tone in pregnant ewes

Hollingsworth

Volume 146 Number 4

35. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes 28:1039, 1979. 36. White, P.: Diabetes mellitus in pregnancy, Clin Perinatol. 1:331, 1974. 37. Rigg, L., Cousins, L., Hollingsworth, D. R., Brink, G., and Yen, S. S. C.: Effects of exogenous insulin on excursions and diurnal rhythm of plasma glucose in pregnant diabetic patients with and without residual /3-cell function, AM. J. 0BSTET. GYNECOL. 136:537, 1980. 3R. Hollingsworth, D. R., and Ney, D.: Unpublished data. 39. Hollingsworth, D. R., and Grundy, S. M.: Pregnancy aswciated hypertriglyceridemia in normal and diabetic women: Differences in type l, type II and gestational diabetes, Diabetes 31:1092, 1982. 40. Rubenstein, A. H., and Gonen, B.: Clinical significance of C-peptide, in Klachko, D. M., Anderson, R. R., Burns, T. W., and Werner, H. V., editors: The Endocrine Pancreas and Juvenile Diabetes, New York, 1977, Plenum Press, pp. 15-28. 41. Horwitz, D. L., Starr, J. 1., Mako, M. E., Blackard, W. G., and Rubenstein, A. H.: Proinsulin, insulin and C-peptide concentrations in human portal and peripheral blood, J. Clin. Invest. 55:1278, 1975. 42. Kuzuya, H., Blix, P., Horwitz, D., Steiner, D. F., and Rubenstein, A. H.: Determination of free and total insulin and C-peptide in insulin treated diabetics, Diabetes 26:22, 1977. 43. Unger, R. H., and Faloona, G. R.: Radioimmunoassay of glucagon, in Jaffe, B. M., and Behrman, H. R., editors: Methods of Hormone Radioimmunoassay, New York, 1974, Academic Press, Inc., chap. 18.

44. Judd, H. L, Parker, D. C., Rakoff, J. S., Hopper, B. R.. and Yen, S. S. C.: Elucidation of mechanism(s) of the nocturnal rise of testosterone in men, J. Clin. Endocrinol. Metab. 38:134, 1974. 45. Ehara, Y., Siler, T., VandenBerg, G., Sinha, Y. N., and Yen, S. S. C.: Circulating prolactin levels during the menstrual cycle: Episodic release and diurnal variation, AM.j. 0BSTET. GYNECOL. 117:962, 1973. 46. Kalkhoff, R. K., Kissebah, A. H., and Kim, H.-J.: Carbohydrate and lipid metabolism during normal pregnancy: Relationship to gestational hormone a<.tion, in Merkatz, I. R., and Adam, P. A. ]., editors: The Diabetic Pregnancy, A Perinatal Perspective, New York, 1979, Grune & Stratton, Inc., pp. 10-17. 47. Warth, M. R., Arky, R. A., and Knopp, R. H.: Lipoprotein metabolism in pregnancy. III. Altered lipid wmposition in intermediate, very low, low and high density lipoprotein fractions, J. Clin. Endocrinol. Metab. 41:649, 1975. 48. Knopp, R. H., and Warth, M.: Lipoprotein changes in pregnancy. A distinct endogenous hypenriglyceridemia, J. Clin. Invest. 52:48a, 1973. 49. Kennedy, A. L., Lappin, T. R., Lavery. T. D., Hadden, D. R., Weaver,J. A., and Montgomery, D. A. D.: Relation of high-density lipoprotein cholesterol concentration to type of diabetes and its control, Br. Med.J 2:1191, 1978. 50. Knopp, R. H., Chapman, M., Bergellin, R., Wahl, P. W., Warth, M. R., and Irvine, S.: Relationships of lipoprotein lipids to mild fasting hyperglycemia and diabetes in pregnancy, Diabetes Care 3t4l6, 1980.

Ketamine, catecholamines, and uterine tone in pregnant ewes John B. Craft.jr., M.D., Lee A. Coaldrake, M.B., B.S., M. Lynn Yonekura, M.D., Son D. Dao, M.D., Evelyn G. Co, M.D., Michael F. Roizen, M.D., Paul Maze!, Ph.D., Robin Gilman, M.S.E.E., Leslie Shokes, M.S.E.E., and Anthony J. Trevor, Ph.D. Washington, D. C., and San Francisco, California

Blood levels of ketamine. measured in both mother (1,230 ng/ml at 1 minute) and fetus (470 ng/ml at 1 minute) illustrate not only rapidly decreasing levels of the drug after its intravenous administration but also its transplacental passage. Concentrations of norepinephrine, epinephrine, and dopamine did not change in the mother or fetus after ketamine, with the exception of maternal levels of epinephrine, which were significantly higher at 45 minutes than control values (p < 0.05). Matemal effects of ketamine consisted of increases in mean arterial pressure (7% p <0.05), cardiac output (16% p <0.01), and respiratory acidosis, all of which were slight and transitory. Although resting uterine tone increased (39% p < 0.01), the uterine blood flow remained constant None of the physiologic alterations could be correlated with changes in catecholamine levels. Therefore, the cardiovascular and uterine stimulating properties of ketamine at a dose of 0.7 mg/kg are small and are not the result of increased catecholamine levels in plasma. Further studies are necessary to elucidate the mechanism. (AM. J. OssTET. GYNECOL. 146:429, 1983.)

From the Departments of Anesthesiology, Obstetrics and Gynecology, and Pha'f11UJ,Cology, George Washington University Medical Cen12r, and the Departments of Anesthesiology, Medicine, and Pharmacology, University of California (San Francisco). Suppurted in part by National Institutes of Health Grant No. 5 SOJ-RR-5359-18. Presented in part at the annual meetings of the Society for Obstetric Anesthesia and Perinarology, May, 1980, and the American Society of Anesthesiologists, October, 1980.

Received for publication August 26, 1982. Revised for publication December 22, 1982. Accepted]anuary 7, 1983. Reprint requests: John B. Craft, Jr., M.D., Department of Anesthesiology, Tlu! George Washington University Medical Center, 901 23rd St., N.W., Washington, D. C. 20037.

429

430 Craft et al.

Ketamine [d,l-2(0-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride] produces dissociative anesthesia characterized by amnesia and analgesia. Therefore, ketamine has, at a dose of 1 mg/kg or less, been recommended for use in obstetric anesthesia as a general anesthetic induction agent in lieu of thiopental sodium. 1 However, ketamine also increases heart rate, blood pressure, and cardiac output. The precise mechanisms of this pressor response have not been fully elucidated. Evidence includes indications that it stimulates the central nervous system to augment sympathetic tone, direct peripheral release or diminished reuptake of catecholamines, partial vagal blockade, and diminished baroreceptor activity. 2- 6 This sympathetic stimulation may increase uterine artery tone and thus decrease fetal oxygenation. In addition, ketamine may increase uterine tone. 7 These effects would limit its usefulness in the obstetric patient. We investigated the possible passage of ketamine and its metabolites across the placenta, the effects of an analgesic dose (0. 7 mg/kg) of ketamine on maternal and fetal cardiovascular variables, uterine blood flow, and uterine tone, and the relationship of these effects to changes in the sympathetic nervous system.

Material and methods For this investigation, we used the chronic maternalfetal sheep preparation. Eight pregnant ewes (124 to 138 days' gestation; term, 145 to 150 days) were studied with the use of the humane standards of the American Physiological Society. The sheep were anesthetized with halothane/nitrous oxide/oxygen for placement of cannulas into a maternal femoral artery and vein (polyvinyl Fr. 8) and into the pulmonary artery via the right internal jugular vein. A hysterotomy was performed via a midline abdominal incision for insertion of catheters into a fetal femoral artery (Fr. 4) and vein (catheter size dependent on vein size) and into the uterine cavity (Fr. 8) for measurement of amniotic fluid pressure. A precalibrated electromagnetic flow probe (Carolina Medical Co.) was secured around a main branch of a uterine artery. The sheep recovered from operation for at least 24 hours before investigations were begun. During subsequent experiments, we monitored and continuously recorded the following variables on an R411 Beckman dynograph eight-channel recorder: maternal arterial pressure, heart rate, pulmonary artery pressure and central venous pressure, fetal arterial pressure and heart rate, and uterine blood flow and amniotic fluid pressure. With the use of a thermal dilution technique, we calculated maternal cardiac output with a cardiac output computer (Elecath). Maternal temperature was measured by means of a Yellow Springs rectal probe. Arterial pressures, central venous pressure, pulmonary

.June 15, I 9H'l Am . .J. Obstet. Gynecol.

Table I. Maternal and fetal cardiovascular and acid-base values during control period (mean ± SE) Parameter

Maternal

Cardiovascular data Heart rate (bpm) 120 ± 9 Mean arterial pressure 93 ±3 (torr) Cardiac output (L/min) 8.7 ±0.6 833 ± 66 Systemic vascular resistance (dynes/sec/cm- 5 ) Uterine blood flow (mllmin) 340 ± 86 Uterine tone (torr) 9±1 Acid-base data 7.39 ± 0.02 pH 27 ± 1 Paco, (torr) 72 :t 3 Pa0 , (torr) Base excess (mEq/L) -8 :t 2

Fetal 192 ± II 56± 4

7.34 44 13 -2

± 0.01 ±I ± l ± l

artery pressure, and intra-amniotic pressure were measured with Statham pressure transducers. Maternal stroke volume and total peripheral resistance were calculated by means of the following formulas: Stroke volume (mllbeat) cardiac output (L/min x 1,000). heart rate (beats/min) Total peripheral vascular resistance (dynes/sec/em) = mean arterial pressure (torr) mean central venous pressure (torr) X 80 cardiac output (Limin) Arterial blood gases were measured immediately after sampling with the use of a Radiometer BMS 3 blood gas analyzer. All results were corrected for temperature. The ewe was positioned and restrained on the left side, and after 60 minutes the control period was begun. After 30 minutes of stable observations, the ewe was given ketamine, 0. 7 mg/kg intravenously within a 30-second period. An excitement period was not seen. At 1, 3, 5, 10, 15, 30, 45, and 60 minutes after injection, maternal and fetal arterial blood samples were obtained for determinations of acid-base status and concentrations of ketamine and catecholamines. Blood samples obtained for determination of ketamine and catecholamine levels were separated into plasma, frozen, and later analyzed. Levels of ketamine and its metabolites were assayed with the use of the modification by Cohen and associates 8 of the gas chromatographic procedure of Chang and Glazko. 9 Catecholamine levels were assayed according to a modification of the method described by Roizen and coworkers.10 Control values for cardiovascular and acid-base variables consisted of averages of three determinations made at 15-minute intervals-0, 15, 30 minutes (Table

Ketamine, catecholamines, and uterine tone

Volume 146 :-lumber 4

...J

MEAN ARTERIAL PRESSURE

0

a:

~

431

10

(.)

~

1000 500 0

g IXl

E

0. c:

"":/ ----t----

~t--....,

100

~ 0

•KETAMINE + NORKETAMINE • METABOLITE 2

a:

LL

w

~ -10

5

~ ~ !:!_---~

(1l~t--~--,

50

1

10

i~

!

MEAN·SE

CARDIAC OUTPUT

20

I-----.

ffiQ.

0

5

15

30

l
I

.............................................................................. ..

0 0

~---==!'''"' !

5

15

45

30

45

60

MINUTES AFTER INJECTION

MINUTES AFTER INJECTION

Fig. 1. Maternal pharmacokinetics of ketamine and its two major metabolites, norketamine and metabolite 2, following the intravenous injection of 0. 7 mg/kg. ...J

:::::::~:.:~"" '/]~ CONTROLS

0

a: 75 .....

z

0

(.)

~

0

a:

LL

w

C!l

~

25

J:

(.)

w < ..... C!l

0

z

";r~==:J

w


z

"'

r-(

w -25

UTERINE ARTERY BLOOD FLOW 10

CONTROL •340 t86 ml/min

I

(,)

w

~ .... z

LI.J

()

a: w a.

Wt-Y;r-f.······. · · · · · · · · · · · · · . . . . . . . . . . . . . . . . . . r

(.)

ffi

Fig. 3. Percentage change from control (±SE) of maternal mean arterial pressure and cardiac output following intravenous ketamine, 0. 7 mg/kg. Ketamine caused a significant increase in mean arterial pressure (p < 0.05) .

INTRA-UTERINE PRESSURE

15 torr

10

Q.

0

5

15

30

45

60

MINUTES AFTER INJECTION

Fig. 2. Percentage change from control (±SE) of maternal plasma catecholamines (epinephrine, norepinephrine, and dopamine) following intravenous ketamine, 0.7 mg/kg. The increase in epinephrine concentration was significant at 45 minutes (p < 0.05).

1). Data were analyzed with analysis of variance with repeated measures. P < 0.05 was considered to be statistically significant. The data are presented as the percentage of change from control because there is variation in the control values and this is a normalizing technique. Results Maternal effects. A peak maternal ketamine blood level of 1,230 ng/ml was determined from the first blood sample, which was obtained l minute after intravenous injection (Fig. 1). Levels fell very rapidly over

5 0

5

15

30

45

60

MINUTES AFTER INJECTION

Fig. 4. Percentage change from control (±SE:) of uterine artery blood flow and absolute values of intrauterine pressure following intravenous ketamine, 0.7 mg/kg. Intrauterine pressure increased significantly (p < 0.01).

the first 5 minutes but then declined more slowly, with small amounts of ketamine still detectable at 60 minutes. The main metabolite ofketamine, norketamine, is formed by N-demethylation of the parent compound by the hepatic P-450 microsomal system. Subsequent processes of hydroxylation and dehydration yield further metabolites. Metabolite 2, as measured by the assay techniques described above, represents end products of perhaps as many as six hydroxylated intermediates. Maternal levels of norketamine were detectable early, with a peak value of 380 ng/ml being obtained at 1 minute. Measurable levels of nor-

432 Craft et al.

June 15, 198:3 Am. J. Obstet. Gynecol.

Table II. Maternal acid-base values during study (mean ± SE) Parameter

pH

Paco, Base excess Pa 0 ,

I

Control 7.39 ± 0.02 27 ± 1

-8 ± 2 72 ± 3

I

Minutes l----1----,r----3---.----5---,.----1-0---.---1-5----7.39 ± 0.03 29 ± 2

-7 ± 2 70 ± 4

7.36 29 -8 68

± ± ± ±

0.02* 2* 2 4

7.37 28 -9 71

± ± ± ±

0.03* 3 2 5

7.37 :!: 29 ± -8:!: 77 ±

0.03 2 2 10

7.38 ± 27:!: -8 ± 73 ±

0.02 2 2 5

*P < 0.05 (compared to control value). ketamine were still present at 60 minutes. Although metabolite 2 was detectable in some of the !-minute samples, peak levels of90 ng/ml were obtained at about 10 minutes after injection. The levels obtained for metabolite 2 were values much lower than those obtained for the primary metabolite. Although maternal levels of norepinephrine and dopamine appeared to increase following ketamine, none of the changes reached statistical significance, due in part to the wide variability in levels obtained in different sheep (Fig. 2). Maternal epinephrine values increased after the first I 0 minutes of the experiment, reaching a peak value 40% above control at 45 minutes (p < 0.05). The difference between values obtained at 3 and 5 minutes were also statistically different from those obtained at 45 minutes (p < 0.05). Ketamine in a dose of 0. 7 mg/kg caused an early rise in matetmal blood pressure, the peak value being 7% above control and occurring at 3 minutes (p < 0.05). Blood pressure had returned to control levels by 15 minutes (Fig. 3). Although maternal heart rate did not alter significantly (p > 0.05), maternal cardiac output increased 16% at 5 minutes (p < 0.01; Fig. 3). No significant alterations occurred in central venous pressure, pulmonary artery pressure, stroke volume, or systemic or pulmonary vascular resistances. The change in uterine blood flow (±5% of baseline value) was not significant (p > 0.05; Fig. 4). Intravenous ketamine significantly increased intrauterine pressure in the near-term pregnant sheep (Fig. 4). The maximum increase in uterine pressure occurred at 3 minutes after injection, at which time the pressure had increased from a control value of 9 to 13 torr (p < 0.01). Uterine pressure subsequently decreased toward control levels. Analysis of linear regression of data failed to show a direct correlation between changes in any individual catecholamine and the increases in maternal blood pressure or intrauterine pressure. Maternal Pa0 , and base excess after ketamine did not change significantly from control levels. However, at 3 minutes, pH dropped from 7.39 (control) to 7.36 (p < 0.05) and Paco, increased from 27 ± l to 29 ± 2 torr (p < 0.05). Both values returned to control levels by 10 minutes (Table II).

Fetal effects. Fetal levels of ketamine peaked within minute at 470 ng/ml and then fell rapidly over the next 30 minutes, with detectable levels in only three of the eight fetuses at 60 minutes (Fig. 5). Norketamine was also detectable as early as I minute, with levels peaking at 3 minutes (125 ng/ml). Norketamine was still detectable at 60 minutes. Very low levels of metabolite 2 were detectable over the duration of the experiment, the highest levels being obtained at 60 minutes (26 ng/ml). As in the mother, fetal levels of norepinephrine and epinephrine appeared to increase after ketamine; however, these changes were not statistically significant (p > 0.05, Fig. 6). Fetal dopamine concentration appeared to decrease but not significantly (p > 0.05). Neither fetal heart rate nor blood pressure changed significantly after administration of ketamine to the ewe (p > 0.05, Fig. 7). No significant changes in fetal pH, Pac 0., Pa 0 , or base-excess values occurred following the administration of ketamine (p > 0.05).

Comment Several of the pharmacologic properties of ketamine, including its ability to cause amnesia and analgesia of rapid onset and short duration, make it a drug with much potential for use in obstetric anesthesia. However, its acceptance has been hampered by the possibility of adverse effects on the fetus, for example, the potential decrease in uterine blood flow and increase in uterine tone .11 Greiss and co-workers 12 and Shnider and associates 13 demonstrated that drugs that increase maternal blood pressure by producing generalized vasoconstriction usually constrict uterine vessels as well, with resulting fetal hypoxemia and acidosis. The exact mechanism of ketamine's pressor response is still unclear. However, Zsigmond and Kelsch 3 • 4 demonstrated increased levels of free norepinephrine in man in association with the cardiovascular stimulation following ketamine, 2 mg/ kg. Increased levels of circulating free norepinephrine would be expected to increase uterine vascular resistance and hence decrease uterine blood flow. Traber and associates5 • 6 demonstrated in dogs that epidural

Ketamine. catecholamines, and uterine tone

Volume 146 Number4

500

7.40 ± 0.02 26 ± 2 -8:!:: 2

69:!:: 4

7.40 28 -7 76

± ± ± ±

0.03 3 2 8

7.39 ± 26 ± -9 ± 76 ±

+ NORKETAMINE

~

60

45

30

• KETAMINE

'\

Minutes 100

0.02 2

2 8

anesthesia, ganglionic blockade with hexamethonium, and a-adrenergic blockade with phentolamine all abolished the typical pressor response of ketamine. These studies also suggested that ketamine might constrict uterine arteries and thereby induce fetal deterioration. However, Levinson and colleagues14 were unable to confirm this hypothesis in their studies of the effect of ketamine in a dose of 5 mg/kg on pregnant ewes. In fact, they demonstrated that uterine blood How increased after intravenous administration of ketamine and postulated that this occurred because of increased cardiac output. Furthermore, they hypothesized that the uterine arteries were spared any vasoconstrictive effect that ketamine might have induced in other vascular beds. Our study demonstrates that uterine blood How remained fairly constant after ketamine (0.7 mg/kg), varying within only 5% of control levels. Reports about the effect ofketamine on uterine tone have varied largely because different stages of gestation were used. A recent study by Marx and coworkers,15 using immediate postpartum measurements of uterine pressure in women, demonstrated that 50 to l 00 mg of intravenous ketamine increased the intensity of several subsequent contractions and that higher doses also increased the frequency of these contractions. These investigators did not demonstrate any change in the resting uterine tone between contractions. However, Galloon 7 showed a dose-related increase in basal uterine tone after administration of ketamine to women undergoing abdominal hysterotomy for second-trimester abortion. We demonstrated a slight but significant increase in uterine tone in the 15 minutes following ketamine. However, by 30 minutes, uterine pressure did not differ significantly from control values. None of our sheep were in labor, and the effects observed were in the near-term pregnant ewe. Therefore, an important question raised by this study is whether ketamine raises intrauterine pressure during labor. i'io adverse effects occurred in either the mother or the fetus after administration of this dose of ketamine. The only changes that occurred in the mother were a mild transient elevation in both mean arterial pressure and cardiac output and a slight, transitory respiratory acidosis. No significant alterations occurred in any fetal

0

0

• METABOLIT< 2

/r4 -~i I\ ~ T~t----

50

g

IIl

E ac:

433

l

10

5

0

5

! .,,,.

i5

30

I

60

MINUTES AFTER INJECTION

Fig. 5. Fetal pharmacokinetic!\ of ketamine and its two major metabolites, norketamine and metabolite 2, following the maternal intravenous injection of 0. 7 mg/kg. ..J

0

....0::: z

50

0 0

:::e

0 0::: u..

w

(!)

z<( 0

:X: 0

w

CJ

....z<(

w

4:::Jd~t

f'-.,I--i

•

t

,

CONTROLS

Norepinephnne •559t2225 (pg/ml)

+ Epinephrine •65~35

0

ffi -50 c..

0

5

15

30

60

MINUTES AFTER INJECTION

Fig. 6. Percentage change from control (±SE} of fetal plasma catecholamines (epinephrine, norepinephrine, and dopamine) following the maternal intravenous injection of ketamine, 0.7 mg/kg. None of the changes were statistically significant (p > 0.05).

cardiovascular or respiratory parameters, but our mothers and fetuses were healthy. It might be important to verify the same absence of effects in sick mothers or fetuses were one to desire to use k(•tamine on less than healthy parturients. Ellingson and co-workers 16 demonstrated earlier in human subjects that ketamine crosses the placenta following its intravenous administration. Our study confirms that ketamine is rapidly transferred across the placenta, with maximal fetal levels occurring at 1 minute. Following an intravenous injection. blood levels of ketamine fall very rapidly, mainly because of its rapid

Craft et al.

434

June 15, 1983 Am. J. Obstet. Gynecol.

MEAN FETAL ARTERIAL PRESSURE

B 101

CONTROL•56±4mmHg

~jL~~=-~!

1

UJ


z

~ 2o

FETAL HEART RATE

()

UJ

~ z

10

UJ

()

ffia..

0 0

5

15

30

45

60

MINUTES AFTER INJECTION

Fig. 7. Percentage change from control (±SE) of mean fetal arterial pressure and heart rate following maternal intravenous injection of ketamine, 0.7 mg/kg. No changes were statistically significant (p > 0.05).

uptake and redistribution. The metabolism of ketamine appears to be an efficient process, norketamine and metabolite 2 appearing early in both maternal and fetal plasma. Zsigmond and Kelsch 4 demonstrated earlier that ketamine increases free norepinephrine but not free epinephrine concentrations in healthy human volunteers. We were unable to corroborate this in the pregnant ewe. Only epinephrine levels in the mother increased significantly from control values, and then only the level at 45 minutes was shown to be signifi.cantly different from the baseline levels. We are unable to explain the wide variability in the levels of norepinephrine and dopamine following the injection of ketamine. We conclude that ketamine, when given to ewes in a dose of 0. 7 mg/kg, has slight uterine and maternal cardiovascular stimulating effects which appear unrelated to increases in plasma catecholamines. Further studies are necessary to elucidate the mechanism of its stimulating properties.

REFERENCES 1. Pelz, B., and Sinclair, D. M.: Induction agents for caesarean section: A comparison of thiopentone and ketamine, Anaesthesia 28:37,-1973. 2. Zsigmond, E. K., and Domino, E. F.: Ketamine-clinical pharmacology, pharmacokinetics and current clinical uses, Anesthesia!. Rev. 7:13, 1980. 3. Zsigmond, E. K.: Comment on Corssen, C. G.: Ketamine in the anesthetic management of asthmatic patients, Anesth. Analg. 51:595, 1972. 4. Zsigmond, E. K., and Kelsch, R. C.: Elevated plasma norepinephrine concentration during ketamine anesthesia, Clin. Pharmacol. Ther. 14:149, 1973. 5. Traber, D. L., Wilson, R. D., and Priano, L. L.: The effect of alpha-adrenergic blockade on the cardiopulmonary response to ketamine, Anesth. Analg. 50:737, 1971. 6. Traber, D. L., Wilson, R. D., and Priano, L. L.: Blockade of the hypertensive response to ketamine, Anesth. Analg. 49: 420, I 970. 7. Galloon, S.: Ketamine for obstetric delivery, Anesthesiology 44:520, 1976. 8. Cohen, M. L., Chan, S. L., Way, W. L., et al.: Distribution in the brain and metabolism of ketamine in the rat after intravenous administration, Anesthesiology 39:370, 1973. 9. Chang, T., and Glazko, A. J.: A gas chromatographic assay for ketamine in human plasma, Anesthesiology 36: 401, 1972. 10. Roizen, M. F., Moss, J., Henry, D. P., et a!.: Effect of halothane on plasma catecholatnines, .LA:..nesthesiology 41: 432, 1974. 11. Hodgkinson, R., Marx, G. F., Kim, S. S., et al.: Neonatal neurobehavioral tests following vaginal delivery under ketamine, thiopental, and extradural anesthesia, Anesth. Analg. 56:548, 1977. 12. Greiss, F. C., and Van Wilkes, D.: Effects of sympathomimetic drugs and angiotensin on the uterine vascular bed, Obstet. Gynecol. 23:925, 1964. 13. Shnider, S. M., deLorimier, A. A., and Steffensen, J. L.: Vasopressors in obstetrics. IlL Fetal effects of metaraminol infusion during spinal hypotension, AM. J. OBSTET. GYNECOL.l08:1017, 1970. 14. Levinson, G., Shnider, S.M., Gildea,J. E., et al.: Maternal and foetal cardiovascular and acid-base changes during ketamine anaesthesia in pregnant ewes, Br. J. Anaesth. 45:llll' 1973. 15. Marx, G. F., Hwang, H. S., and Chandra, P.: Postpartum uterine pressures with different doses of ketamine, Anesthesiology 50:163, 1979. 16. Ellingson, A., Haram, K., Sagen, N.,etal.: Transplacental passage of ketamine after intravenous administration, Acta Anaesthesiol. Scand. 21:41, 1977.