Risk Factor: CM
Class: Autonomics/ Skeletal muscle relaxants
Fetal Risk Summary
Pancuronium (pancuronium bromide) is a competitive (nondepolarizing) neuromuscular blocking agent. Structurally, it is a bisquaternary ammonium compound (i.e., contains two quaternary ammonium groups) and is commercially available as the dibromide. Pancuronium is used to induce skeletal muscle relaxation during anesthesia and other procedures, and has been used to produce fetal muscle paralysis during intrauterine procedures.
Unpublished reproduction studies in rats and rabbits with pancuronium did not reveal any effect on the number of resorptions, litter size, birth weight and vitality, or the frequency of malformations (gross, skeletal, and internal organs) (1). Pregnant rats (average gestational length 2122 days ) received intraperitoneal doses of 0.16 mg/kg/day either from the 7th to the 14th day or from the 1st to the 20th day of gestation, whereas pregnant rabbits (average gestational length 3134 days ) were given IV doses of 0.02 mg/kg/day from day 8 to day 16 of gestation.
Theoretically, the combination of relatively high molecular weight (about 733 for the dibromide) and the presence of two quaternary ammonium groups that are ionized at physiologic pH should limit the placental transfer of pancuronium. An animal study, published in 1973, appeared to confirm the lack of significant transfer when cumulative IV doses up to 16.3 mg/kg administered to pregnant ferrets (neuromuscular block in the mother complete at 0.015 mg/kg) did not cause neuromuscular blockade in the fetus during a 1-hour observation period (3). The fetus was responsive to pancuronium-induced blockade by direct administration. Further, the lack of adverse effects in newborns after mean doses of 0.0875 mg/kg at cesarean section led some authors to conclude that the drug did not cross the placenta (4). However, several human studies have demonstrated placental transfer, at least near term, when pancuronium was used during cesarean section (5,6,7,8,9,10 and 11).
Maternal IV bolus doses between 0.04 mg/kg and 0.12 mg/kg (approximately 2.88.6 times the maternal ED50, the dose producing a 50% depression of evoked twitch tension ), resulted in mean umbilical vein:maternal vein ratios ranging from 0.19 to 0.26. These ratios were higher than those measured with atracurium, fazadinium, pipecuronium, rocuronium, d-tubocurarine, and vecuronium (13). No clinical evidence of neuromuscular blockade was observed in five studies in which the neonatal condition was noted (5,6,7,8 and 9), but in one of the studies (9) the Neurologic and Adaptive Capacity Scores (NACS) system indicated that neonatal depression was present. The NACS evaluates adaptive capacity, passive and active muscular tone, primary reflexes, and general assessment (13). The maximum score possible is 40, with a score of 3540 denoting a normal, vigorous baby.
The NACS was measured at 15 minutes, 2 hours, and 24 hours in seven newborns whose mothers had been given IV doses of d-tubocurarine (3 mg), thiopental (4 mg/kg), succinylcholine (1.5 mg/kg), and pancuronium (0.04 mg/kg) immediately prior to cesarean section (9). Five newborns (71%) had a NACS value
The direct administration of pancuronium has been reported in animals and humans (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) . A 1989 report compared the effects of pancuronium (0.5 mg/kg IV over 5 minutes) and d-tubocurarine (3.0 mg/kg IV over 5 minutes) on the heart rate and mean arterial pressure of fetal lambs (14). Whereas pancuronium significantly increased both rate and pressure, both measures were significantly decreased by d-tubocurarine. Only pancuronium effected fetal pH and Pco2, increasing the former and decreasing the latter. The human studies, discussed below, all involve pancuronium administration during the second half of gestation.
In a study published in 1988, the baseline fetal heart rate (FHR), number of accelerations, and beat-to-beat variability were assessed before and after an IV bolus dose of pancuronium (0.050.10 mg/kg) was given to 17 fetuses before transfusion (15). Twenty minutes after transfusion, no changes were noted in the baseline FHR, although some heart rate patterns appeared sinusoidal-like, but significant decreases in accelerations (p=0.003) and variability (p=0.0003) were observed (15). The transient FHR changes were not indicative of fetal compromise and returned to normal when the fetus awakened (15). A 1991 abstract reported significantly less bradycardia with the use of pancuronium (0.3 mg/kg) compared with no muscle relaxant after cordocentesis (3.6% [8/224] vs. 8.2% [27/329], p=0.04) and a near significant difference after intravascular transfusion (7.9% [9/114] vs. 40% [2/5], p=0.06) (16).
Pancuronium (0.1 mg/kg IV) was administered to 20 fetuses immediately before blood transfusion at 28 to 34 weeks’ gestation (17). A control group of 20 fetuses matched for gestational age and hematocrit who did not receive pancuronium was used for comparison. After transfusion, compared with controls, fetuses that received pancuronium had significantly fewer FHR accelerations (mean 0 vs. 3.0, p
Fetal death at 25.5 weeks’ gestation, that was apparently the result of a cord hematoma, occurred 2 hours after an intravascular intrauterine transfusion (19). The authors thought that the accident was related to the injection of pancuronium before confirmation of needle placement by aspiration of fetal blood. The results of an autopsy confirmed that the cause of death was compression of the umbilical vein by the hematoma with subsequent umbilical venous thrombosis.
Fetal administration of pancuronium immediately preceding magnetic resonance imaging (MRI) has been described in a number of publications (20,21,22,23,24,25,26,27 and 28). Most used doses varying from 0.08 to 0.3 mg/kg (IV into the umbilical vein or IM) (20,21,22,23,24 and 25), two used 0.5 mg IM (26,27), and one reported 100 mg (sic) into the intrahepatic vein of each twin (28).
Direct fetal administration of pancuronium for intrauterine procedures, such as cordocentesis and intravascular transfusion, has been reported (29,30,31,32,33,34,35,36,37 and 38). The fetal dose ranged from 0.1 to 0.3 mg/kg IV or IM, but in one report a single 0.5-mg IM dose was administered (29). In another study, pancuronium (0.15 mg/kg of the estimated total fetal body weights of twins) was administered in two cases to the smaller of a set of twins (38). The procedure was undertaken in an attempt to diagnose twin-twin transfusion syndrome. In the first case, the FHR patterns of both twins showed lack of accelerations and decreased variability and, in addition, the larger twin had a sinusoidal-like pattern. In the second case, absent accelerations and decreased variability occurred only in the smaller twin (38).
A continuous infusion of morphine, midazolam, and pancuronium was administered for 10 hours to allow mechanical ventilation in a seriously ill, pregnant (about 35 weeks’) woman with pneumonia due to Legionella pneumophila (39). No evidence of fetal harm was observed during the infusion, but the fetus was noted to have a consistent pattern of sleeping. Approximately 3 to 4 weeks later, at 40 weeks’ gestation, the mother gave birth to a healthy female infant.
In summary, pancuronium has been administered directly to the fetus during the last half of pregnancy and to the mother at cesarean section without causing fetal harm. Although no teratogenicity was observed in two animal species, the use of pancuronium in early human pregnancy has not been reported. The drug is known to cross the human placenta to the fetus, at least near term. Placental transfer early in pregnancy has not been reported. Large or repetitive doses and/or prolonged dose-to-delivery intervals may potentially result in newborn depression, but the clinical significance of this appears to be low. Moreover, other anesthetic agents may contribute to the condition. In addition, transient FHR changes, such as decreased accelerations and beat-to-beat variability, and an occasional sinusoidal-like pattern, have been observed after direct fetal administration, but apparently this does not indicate fetal compromise.
Breast Feeding Summary
No reports describing the use of pancuronium in a lactating woman have been located. Because of the nature of the drug and its indications, such reports are unlikely to occur. Moreover, because pancuronium is a bisquaternary ammonium compound, it is ionized at physiologic pH. Only the nonionized form would be available for excretion into milk, and this would probably be only trace amounts (40). In addition, compounds of this type are poorly absorbed from the gastrointestinal tract (40).
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