Risk Factor: B
Class: Central nervous system drugs / General anesthetic

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Fetal Risk Summary

Ketamine is a rapid-acting IV general anesthetic agent related in structure and action to phencyclidine. No teratogenic or other adverse fetal effects have been observed in reproduction studies during organogenesis and near delivery with rats, mice, rabbits, and dogs (1,2,3,4 and 5). In one study with pregnant rats, a dose of 120 mg/kg/day for 5 days during organogenesis resulted in no malformations or effect on fetal weight (4).

Ketamine rapidly crosses the placenta to the fetus in animals and humans (6,7). Pregnant ewes were given 0.7 mg/kg IV, and 1 minute later the maternal and fetal concentrations of ketamine were 1230 ng/mL and 470 ng/mL (ratio 0.38), respectively (6). Maternal effects were slight, transitory increases in maternal mean arterial pressure and cardiac output, respiratory acidosis, and an increase in uterine tone without changes in uterine blood flow. In humans, the placental transfer of ketamine was documented in a study in which a dose of 250 mg IM was administered when the fetal head reached the perineum (7). The ketamine concentration in cord venous plasma at the 0- to 10-minute dose-to-delivery interval was 0.61 g/mL, compared with 1.03 g/mL at the 10- to 30-minute interval, reflecting absorption following the IM route.

Pregnant monkeys (Macaca nemistrina) were administered ketamine in a dose of 2 mg/kg IV (N=3) or 1 mg/kg IV (N=2) in an investigation of the anesthetic's effects on the fetus and newborn (8). No fetal effects were observed from either dose. The newborns from the mothers given 2 mg/kg, but not those exposed to lower doses, however, had profound respiratory depression.

The use of ketamine (CI-581) for obstetric anesthesia was first described in 1966 (9). Since then, a large number of References have documented its use for this purpose (10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29, 30,31,32,33,34,35,36,37 and 38). Among the maternal and newborn complications reported with ketamine are oxytocic properties, an increase in maternal blood pressure, newborn depression, and an increased tone of newborn skeletal musculature. These adverse effects were usually related to higher doses (1.52.2 mg/kg IV) administered during early studies rather than to the lower doses (0.20.5 mg/kg IV) now commonly used.

Ketamine usually demonstrates a dose-related oxytocic effect with an increase in uterine tone, and in frequency and intensity of uterine contractions (9,10,11 and 12,22,37), but one investigator reported weakened uterine contractions following a 250-mg dose administered IM when the fetal head reached the perineum (7). Uterine tetany was observed in one case (12). Low doses (0.2751.1 mg/kg IV) of ketamine increased only uterine contractions, whereas a higher dose (2.2 mg/kg IV) resulted in a marked increase in uterine tone (22). Maximum effects were observed within 24 minutes of the dose. In one study, however, the effect on uterine contractions from an IV dose of 1 mg/kg, followed by succinylcholine 1 mg/kg, was no different from thiopental (14). No effect on intra-uterine pressure was measured in 12 term patients treated with ketamine 2 mg/kg IV, in contrast to a marked uterine pressure increase in patients in early pregnancy undergoing termination (39). Similarly, in 12 women given ketamine 2.2 mg/kg IV for termination of pregnancy at 819 weeks, uterine pressure and the intensity and frequency of contractions were increased (40).

Several investigators have noted a marked increase in maternal blood pressure, up to 30%40% in systolic and diastolic in some series, during ketamine induction (7,10,12,13,15,23,24). An increased maternal heart rate is usually observed. These effects are dose-related with the greatest increases occurring when 22.2 mg/kg IV was administered, but smaller elevations of pressure and pulse have been noted with lower IV doses.

Maternal ketamine anesthesia may cause depression of the newborn (7,12, 15,16,17 and 18,21,23,26,32). As with the other complications, the use of higher doses (1.52.2 mg/kg IV) resulted in the highest incidence of low neonatal Apgar scores and requirements for newborn resuscitation. The induction-to-delivery (ID) interval is an important determinant for neonatal depression (7,21,32,34). In two studies, neonatal depression was markedly lower or absent if the ID interval was less than 10 minutes (7,32). In a third report, significant depression occurred with an ID interval of 9.2 minutes, but a dose of 2.1 mg/kg IV had been used (21).

The use of ketamine in low doses apparently has little effect on fetal cardiovascular status or acid-base balance as evidenced by neonatal blood gases (7,24,26, 29, 31,32 and 33). In one study, a ketamine dose of 25 mg IV administered with nitrous oxide and oxygen within 4 minutes of delivery did not adversely affect neonatal blood pressure (38).

Ketamine doses of 2 mg/kg IV have been associated with excessive neonatal muscle tone, sometimes with apnea (10,11,17). In some cases, the increased muscle tone made endotracheal intubation difficult. In contrast, lower doses (e.g., 0.251 mg/kg) have not been associated with this complication (24).

Neonatal neurobehavior, as measured by the Scanlon Group of Early Neonatal Neurobehavioral Tests during the first 2 days, is depressed following maternal ketamine (1 mg/kg IV) anesthesia but less than the effect measured after thiopental anesthesia (4 mg/kg IV) (41,42). In these studies, spinal anesthesia with 68 mg of tetracaine was associated with the best performance, general anesthesia with ketamine was intermediate, and that with thiopental was the poorest in performance.

In summary, although ketamine anesthesia close to delivery may induce dose-related, transient toxicity in the newborn, these effects are usually avoided with the use of lower maternal doses. No reports of malformations in humans (43) or in animals attributable to ketamine have been located, although experience with the anesthetic agent during human organogenesis apparently has not been published.

Breast Feeding Summary

Because ketamine is a general anesthetic agent, breast feeding would not be possible during use of the drug, and no reports have been located that measured the amount of the agent in milk. The elimination half-life of ketamine has been reported to be 2.17 hours in unpremedicated patients (31). Thus, the drug should be undetectable in the mother's plasma approximately 11 hours after a dose. Nursing after this time should not expose the infant to pharmacologically significant amounts of ketamine.


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