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Case Reports  |   October 1998
Secretion of Dantrolene into Breast Milk after Acute Therapy of a Suspected Malignant Hyperthermia Crisis during Cesarean Section 
Author Notes
  • (Ficker, Hoerauf, Kress) Staff Anesthesiologist, Department of Anesthesiology and Intensive Care Medicine (B), General Hospital, University of Vienna, A-1090 Vienna, Austria.
  • (Drewe) Associate Professor, Department of Internal Medicine, Kantonsspital, University of Basel, CH-4031 Basel, Switzerland.
  • (Kress) Professor and Head of the Department, Ludwig Boltzmann Institute for Experimental Anesthesiology and Research in Intensive Care Medicine, A-1090 Vienna, Austria.
Article Information
Case Reports
Case Reports   |   October 1998
Secretion of Dantrolene into Breast Milk after Acute Therapy of a Suspected Malignant Hyperthermia Crisis during Cesarean Section 
Anesthesiology 10 1998, Vol.89, 1023-1025. doi:
Anesthesiology 10 1998, Vol.89, 1023-1025. doi:
IMMEDIATE intravenous administration of dantrolene is the pharmacologic first line treatment of malignant hyperthermia (MH) crisis. [1] There exist extensive data about its pharmacology and its placental transfer when administered during pregnancy and delivery. [2,3,4] However, it was unclear whether and for what duration dantrolene is detectable in human breast milk after intravenous administration of therapeutic doses. [5] 
Case Report
Tachycardia, respiratory acidosis, and hyperthermia (39.8 [degree sign]C) developed in a 37-yr-old pregnant woman (62 kg body weight) shortly after the induction of general anesthesia for urgent cesarean section because of oblique fetal position. Succinylcholine and thiopental were used for the induction of anesthesia, which was maintained with oxygen/nitric oxide and isoflurane, 0.4%. Despite immediate discontinuation of isoflurane administration and hyperventilation with oxygen, 100%, the symptoms did not vanish, and an MH crisis was suspected.
Intravenous dantrolene (160 mg) was administered after the umbilical cord was clamped and after the delivery of a healthy and obviously unaffected newborn (birth weight, 3.1 kg; gestational age, 36 weeks; Apgar score, 8 at 1 min of age, 10 at 5 min of age) was accomplished. Postoperatively, the patient was transferred to the intensive care unit, where intravenous dantrolene was continued in decreasing doses for 3 days until full recovery (560 mg on day 1, 320 mg on day 2, and 80 mg on day 3). Because of potential exposure of the newborn to dantrolene, on day 1 after delivery the question arose of whether breast feeding could be allowed. Because reliable data were not found in the literature, written informed consent was obtained from the mother to determine dantrolene concentrations in her breast milk. Dantrolene concentrations were measured using an HPLC-technique according to Katogi et al. [6] in a registered laboratory of clinical chemistry with special expertise in dantrolene determinations (Dr. H. Sirowej, Dortmund, Germany).
As expected, dantrolene was found in the breast milk and concentrations were measured, ranging from 1.2 [micro sign]g/ml on day 2 to 0.05 [micro sign]g/ml on day 4. Based on the concentrations observed after the last bolus administration of dantrolene, the half-life of dantrolene in breast milk was calculated to be 9.02 h using a log-linear fitting of the terminal elimination phase (Figure 1).
Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
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Six months after the event, in vitro contracture testing using halothane and caffeine according to the protocol of the European MH Group [7,8] did not confirm the suspected MH of the mother, who was clearly classified as MH nonsusceptible.
Discussion
Until now, no data were available about the secretion of dantrolene into human breast milk after intravenous administration of therapeutic doses to women during labor. Therefore, a potential influence of dantrolene on breast-fed neonates in such a case was unclear. Nausea, vomiting, fatigue, and muscle weakness are known side effects of therapeutic doses in adults and might also potentially occur in breast-fed newborns.
In our patient, the highest concentration of dantrolene in breast milk (1.2 [micro sign]g/ml) was detected 36 h after the first intravenous bolus of 160 mg dantrolene (day 2 after delivery, when breast-feeding normally would have been started). At that time, the total dose administered was 720 mg. Even if 70% of orally administered dantrolene is expected to enter the circulating blood (80 ml/kg) by gastrointestinal absorption, [11] the resulting dantrolene peak levels (<0.5 [micro sign]g/ml) after breast-feeding are assessed to be far less than those described as uneventful after the transfer of dantrolene across the placental barrier. [5,9,10] Morison [9] found dantrolene in venous cord blood (1.39 [micro sign]g/ml) without obvious side effects in neonates, and also Shime et al. [5] described neonatal dantrolene serum concentrations of 0.72 +/− 0.36 [micro sign]g/ml (half-life, 20 h) without adverse effects in newborns. In a maternal-fetal sheep model, no relevant adverse effects of intravenously administered dantrolene (1.2 mg/kg and 2.4 mg/kg respectively) could be shown. [10] Moreover, based on the determined half-life of 9.02 h for dantrolene in breast milk, breast-feeding can be expected to be safe for the newborn 2 days after discontinuation of intravenous dantrolene administration in the mother.
The authors thank Drs. F. Zdrahal and Stefanie Sulzgruber (Krankenanstalt des Gottlichen Heiland, Vienna, Austria), for presenting the patient to our MH investigation unit, and Dr. H. Sirowej (Praxis fur Laboratoriumsmedizin, Dortmund, Germany) for the determination of dantrolene levels by HPLC.
REFERENCES
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Longmire S, Lee W, Pivarnik J: Malignant hyperthermia, Anesthetic and Obstetric Management of High-Risk Pregnancy. Edited by Datta S. St. Louis, Mosby Year Book, 1991, pp 330-44
Pacifici G, Nottoli R: Placental transfer of drugs administered to the mother. Clin Pharmacokinet 1995; 28:235-69
Shin YK, Kim YD, Collea J, Belcher M: Effect of dantrolene sodium on contractility of isolated human uterine muscle. Int J Obstet Anesth 1995; 4:197-200
Shime J, Gare D, Andrews J, Britt BA: Dantrolene in pregnancy: Lack of adverse effects on the fetus and newborn infant. Am J Obstet Gynecol 1988; 159:831-4
Katogi Y, Tamaki N, Adache M: Simultaneous determination of dantrolene and its metabolite, 5-hydroxy dantrolene in human plasma by high performance liquid chromatography. J Chromatogr 1982; 228:404-8
The European Malignant Hyperpyrexia Group: A protocol for the investigation of malignant hyperpyrexia. Br J Anaesth 1984; 56:1267-9
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Morison DH: Placental Transfer of Dantrolene (letter). Anesthesiology 1983; 59:265
Craft J, Goldberg N, Lim M, Landsberger E, Mazel P, Abramson F, Stolte A, Braswell M, Farina J: Cardiovascular effects and placental passage of dantrolene in the maternal sheep-model. Anesthesiology 1988; 68:68-72
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Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
Figure 1. Estimation of half-life of dantrolene in breast milk by log-linear fitting of the terminal elimination phase (dantrolene measured in breast milk by HPLC, reverse-phase high-pressure liquid chromatographic column, by in-line ultraviolet absorption spectrometer; detection limit, 0.02 [micro sign]g/ml).
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