Drugs in Pregnancy and Lactation: Tenth Edition

ATRACURIUM

Skeletal Muscle Relaxant

PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible

BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY

No adverse effects in the fetus or newborn attributable to in utero atracurium exposure have been reported. Because of the drug’s high molecular weight and ionization at physiologic pH, only small amounts cross the human placenta, thus limiting the exposure of the embryo or fetus. Moreover, direct administration to the fetus in the latter part of pregnancy has not been associated with fetal harm. Human fetal exposures early in pregnancy, however, have not been reported. Animal reproduction studies have only been conducted in rabbits, and although the drug may be a potential teratogen in this species, further studies are required to determine the magnitude of this potential. Based on the data below, the use of atracurium during the latter portion of human pregnancy appears to represent little, if any, risk.

FETAL RISK SUMMARY

The competitive (nondepolarizing) neuromuscular blocking agent, atracurium besylate, provides muscle relaxation during surgery or mechanical ventilation. The drug undergoes rapid, nonenzymatic, spontaneous degradation in the plasma (Hofmann elimination) that is independent of hepatic or renal mechanisms (1,2).

In reproduction studies in rabbits with SC doses of 0.15 mg/kg once daily or 0.10 mg/kg twice daily (human IV bolus doses vary from 0.08 to 0.5 mg/kg), an increased incidence of spontaneously occurring visceral or skeletal anomalies was observed in both treatment groups when compared with nontreated controls (3). Moreover, in comparison to controls, a lower percentage of male fetuses (41% vs. 51%) and a higher percentage of post-implantation losses (15% vs. 8%) were observed in the 0.15 mg/kg-once-daily group (3).

In a study conducted by the manufacturer published in 1983, SC doses of atracurium, identical to those above, were injected into rabbits on days 6–18 of pregnancy (4). Rabbits, and cats in the perinatal study below, were used because the pharmacokinetics of atracurium in these species are similar to those in humans, whereas the kinetics in rats is markedly different from humans. No teratogenicity or adverse effects were observed in the rabbit fetuses (4).

Theoretically, the relatively high molecular weight (about 1244) of atracurium besylate and its high degree of ionization at physiologic pH should inhibit the placental passage of atracurium. In the perinatal portion of the study cited above, six pregnant cats, 1–3 days before term, were given a single dose of atracurium, 0.6 mg/kg IV (4). No atracurium was detected in fetal blood, leading to the conclusion that the drug did not cross the placenta (4). Moreover, no depression of respiratory activity was observed when a dose of 0.6 mg/kg was injected directly into the fetuses. A brief 1985 report described the failure to detect placental transfer of atracurium during a 60-minute interval after a 0.5-mg/kg IV dose in five pregnant sheep (5). Small amounts of laudanosine, the major metabolite, crossed the placenta and were detected in some of the fetuses. The metabolite, however, is considered to be inactive at the doses of parent drug used clinically (1).

In contrast to the above animal data, human placental transfer of atracurium has been documented (6,7). In five women, from a total group of 26 undergoing cesarean section, average venous concentrations of the drug, following a 0.3-mg/kg IV dose, ranged from 3.34 mcg/mL at 3 minutes to 0.7 mcg/mL at 10 minutes (6). Venous cord blood concentrations of atracurium ranged from undetectable to 0.23 mcg/mL, suggesting that the cord:maternal ratio varied from 5% to 20% (6). In the second report by these authors, 53 women, delivered by cesarean section, received atracurium 0.3 mg/kg IV followed by increments of 0.1–0.2 mg/kg IV as necessary to maintain surgical relaxation (7). Concentrations of the drug in 16 women at delivery ranged from 0.54 to 3.34 mcg/mL. Only one patient received a second IV dose (0.2 mg/kg). Venous cord concentrations in seven newborns were undetectable (<0.1 mcg/mL in two and <0.05 mcg/mL in five), one cord blood sample was contaminated, and in eight newborns, concentrations ranged from 0.05 to 0.23 mcg/mL. The cord:maternal blood ratio varied from 0.03 to 0.33 (mean 0.12). Newborn neuromuscular activity was reported as normal in all newborns. Further, no adverse effects on Apgar scores or on the time to sustained respiration attributable to atracurium were observed in these two studies (6,7) or in an earlier report by the same authors (8).

A number of reports have described the safe use of atracurium during human pregnancy (913). A woman scheduled for a cesarean section had a low plasma concentration of cholinesterase activity. Atracurium, which does not depend on plasma cholinesterase for its metabolism, was successfully used for neuromuscular blockade in a dose of 0.4 mg/kg IV bolus (9). A healthy newborn with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively, was delivered 10 minutes after the IV bolus. In another case, an IV infusion of atracurium was used during a 16-hour interval to maintain maternal muscle paralysis in a patient with pneumococcal pneumonia who required mechanical ventilation (10). In addition to other anesthetic agents, the woman received 520 mg of atracurium over 16 hours or an average of 32.5 mg/hour until vaginal delivery of a 1800-g female infant. No neuromuscular blockade was observed in the newborn that had Apgar scores of 7, 10, and 10 at 1, 5, and 10 minutes, respectively. Neuromuscular blockade with atracurium was used in a pregnant woman at 24 weeks’ gestation that underwent resection of a pheochromocytoma (11). She eventually delivered a healthy, 2977-g male infant at 39 weeks’ gestation. Normal newborns were also described in two other reports following the use of atracurium prior to cesarean section (12,13). Moreover, a 1986 review on obstetrical anesthesia concluded that atracurium was safe to use in obstetric patients (14).

Three studies have described the direct human fetal administration of atracurium to achieve neuromuscular blockade (1517). In one study, atracurium (0.4 mg/kg) was used in 11 fetuses during 18 intrauterine transfusions and compared with pancuronium (0.1 mg/kg, 12 fetuses, 19 transfusions) (gestational ages not specified in either group) (15). The two agents were similar in onset of neuromuscular blockade. Atracurium, however, was statistically superior to pancuronium in terms of return of fetal movements (22 vs. 67 minutes), more fetal movements, fetal movements/minute, and more heart accelerations than pancuronium after transfusion (15). The authors concluded that atracurium was the preferred drug if fetal paralysis was required. A 1988 reference also used a 0.4-mg/kg IV fetal dose after determining that a 0.2-mg/kg dose was inadequate to arrest fetal activity during intrauterine transfusions (16). Atracurium was used in 6 women undergoing 12 transfusion procedures for fetal Rh isoimmunization. Onset of paralysis occurred within 1–5 minutes and fetal activity returned between 20 and 130 minutes. One fetus developed bradycardia and died 1 hour after transfusion of severe erythroblastosis fetalis and rupture of the spleen.

Atracurium, 1.0 mg/kg IM (fetal gluteal muscle), was used in five fetuses for various intrauterine procedures conducted between 32 and 38 weeks’ gestation (17). In comparison to five fetuses treated with pancuronium, 0.15 mg/kg IM, neuromuscular blockade was achieved slightly faster (mean 4.7 vs. 5.8 minutes) and fetal movements returned sooner (mean 36 vs. 92 minutes) with atracurium. One fetus with peritonitis given pancuronium was stillborn, one fetus with peritonitis given atracurium was born alive with a gastrointestinal perforation, and one fetus given atracurium for ascites drainage and albumin transfusion died after birth. Although the authors did not discuss these outcomes, they do not appear to be related to the neuromuscular blocking agents. No evidence of soft tissue, nerve, or muscle damage at the sites of injection was observed in the newborns.

BREASTFEEDING SUMMARY

No reports describing the use of atracurium during human lactation have been located. Atracurium undergoes rapid, spontaneous degradation in plasma (Hofmann elimination) with an elimination half-life of approximately 20 minutes. The metabolites are not biologically active. In addition, the drug has a relatively high molecular weight (about 1244) and is highly ionized at physiologic pH, both of which are factors that would markedly reduce transfer into milk. Although usage in a lactating woman is possible, at least several hours (and most likely much more time) would pass after use of atracurium before lactation was resumed. The rapid breakdown of atracurium that occurs in plasma would also be expected in milk, even though the latter medium is slightly more acidic than plasma. Thus, any amounts that were transferred into milk would most likely be rapidly degraded. Based on these data, nursing can probably be safely resumed, especially after single-dose use, following recovery from atracurium-induced neuromuscular blockade. A 1994 review of anesthetic agents also concluded that nursing could be allowed as soon as feasible after surgery (18).

References

1.Drenck NE, Viby-Mogensen J, Ostergaard D, Seraj M. Atracurium (tracrium). Middle East J Anesthesiol 1988;9:457–65.

2.Anonymous. Atracurium. Lancet 1983;1:394–5.

3.Product information. Tracrium. Glaxo Wellcome, 1998.

4.Skarpa M, Dayan AD, Follenfant M, James DA, Moore WB, Thomson PM, Lucke JN, Morgan M, Lovell R, Medd R. Toxicity testing of atracurium. Br J Anaesth 1983;55:27S–9S.

5.Mandel MB, Stiller RL, Kennedy RL, Tyler IL, Edelmann CA, Cook DR. Placental transfer of atracurium and laudanosine in the pregnant ewe (abstract). Anesthesiology 1985;63:A429.

6.Frank M, Flynn PJ, Hughes R. Atracurium in obstetric anaesthesia. A preliminary report. Br J Anaesth 1983;55:113S–4S.

7.Flynn PJ, Frank M, Hughes R. Use of atracurium in caesarean section. Br J Anaesth 1984;56:599–604.

8.Flynn PJ, Frank M, Hughes R. Evaluation of atracurium in caesarian section using train-of-four responses (abstract). Anesthesiology 1982;57:A286.

9.Baraka A, Jaude CA. Atracurium in a parturient with atypical cholinesterase. Br J Anaesth 1984;56:930–1.

10.Thomas D, Windsor JPW. Prolonged sedation and paralysis in a pregnant patient. Delivery of an infant with a normal Apgar score. Anaesthesia 1985;40:465–7.

11.Mitchell SZ, Freilich JD, Brant D, Flynn M. Anesthetic management of pheochromocytoma resection during pregnancy. Anesth Analg 1987;66:478–80.

12.Hardy PAJ. Atracurium and bradycardia. Anaesthesia 1985;40:504–5.

13.Stuart JC, Kan AF, Rowbottom SJ, Yau G, Gin T. Acid aspiration prophylaxis for emergency caesarean section. Anaesthesia 1996;51:415–21.

14.Biehl D, Palahniuk RJ. Update on obstetrical anaesthesia. Can Anaesth Soc J 1986;33:238–45.

15.Mouw RJC, Hermans J, Brandenburg HCR, Kanhai HHH. Effects of pancuronium or atracurium on the anemic fetus during and directly after intrauterine transfusion (IUT): a double blind randomized study (abstract). Am J Obstet Gynecol 1997;176:S18.

16.Bernstein HH, Chitkara U, Plosker H, Gettes M, Berkowitz RL. Use of atracurium besylate to arrest fetal activity during intrauterine intravascular transfusions. Obstet Gynecol 1988;72:813–6.

17.Fan SZ, Huang FY, Lin SY, Wang YP, Hsieh FJ. Intrauterine neuromuscular blockade in fetus. Acta Anaesth Sin 1990;28:31–4.

18.Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994;38:94–103.