Dextromethorphan in Pregnancy

caution during pregnancy for safety reasons. Further studies are needed to clarify this issue. Otfried Debus, MD Gerd Kurlemann, MD Josef Gehrmann, MD Thomas Krasemann, MD University Children’s Hospital Muenster, Germany Correspondence to: Otfried Debus, MD, University Children’s Hospital Muenster, Department of Pediatrics, Albert-SchweitzerStr.33, D-48129 Muenster, Germany; e-mail: [email protected]

References 1 Einarson A, Lyszkiewicz D, Koren G. The safety of dextromethorphan in pregnancy: results of a controlled study. Chest 2001; 119:466 – 469 2 Lipton SA, Kater SB. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci 1989; 12:265–270 3 Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283:70 –74 4 Ikonomidou C, Bittigau P, Ishimaru M, et al. Ethanolinduced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287:1056 –1060 5 Rogawski MA. The NMDA receptor, NMDA antagonists and epilepsy therapy: a status report. Drugs 1992; 44:279 –292 6 Schmitt B, Steinmann B, Gitzelmann R, et al. Nonketotic hyperglycinemia: clinical and electrophysiologic effects of dextromethorphan, an antagonist of the NMDA receptor. Neurology 1993; 43:421– 424 7 Kurlemann G, Debus O, Schuierer G. Dextrometorphan in molybdenum cofactor deficiency. Eur J Pediatr 1996; 155: 422– 423 8 Debus O, Schellscheidt J, Stra¨ ter R, et al. Erfolgreicher Einsatz von Dextrometorphan beim Ohtahara-Syndrom [abstract]. Monatsschrift Kinderheilkd 1999; 147:898A 9 Schmitt B, Bauersfeld U, Fanconi S, et al. The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study. Neuropediatrics 1997; 28:191–197 10 Schmitt B, Wohlrab G, Steinlin M, et al. Treatment with the N-methyl-D-aspartate receptor antagonist dextromethorphan in severe bacterial meningitis: preliminary results. Eur J Pediatr 1998; 157:863– 868 To the Editor: We wish to thank Dr. Debus and colleagues for their letter asking us to consider the role of dextromethorphan as an N-methyl-D-aspartate (NMDA)-receptor antagonist in the developing fetal brain. We agree that the NMDA receptor plays an important role in the developing mammalian brain, and that NMDA-receptor antagonists can potentially disrupt these processes. However, these adverse effects on the brain are probably dose related. Over-the-counter antitussives generally contain either 15 mg or 30 mg of dextromethorphan per dose, and in any 24-h period, the dose is not to exceed 60 mg. As pointed out, several studies have established dextromethorphan as an anticonvulsant due to its ability to block NMDA receptors. However, these anticonvulsant effects are only achieved if high doses are administered, generally 160 to 200 mg/d in both adults and children.1– 4 Although these doses were shown to exhibit anticonvulsant properties, one of the potential problems of using dextromethorphan as an anticonvulsive agent is the occurrence of adverse neurobehavioral effects

that have been attributed to extensive NMDA-receptor blockade in the brain.5 Dextromethorphan is a weak blocker of NMDA receptors. In animal models6 showing apoptotic neurodegeneration, much more potent NMDA-receptor antagonists were used, such as dizocilpine ([⫹] MK-801). Such potent agents cause behaviors and discriminative stimulus effects that are nearly indistinguishable from those produced by the psychotomimetic phencyclidine and ketamine. In humans, clinical trials with MK-801 were withdrawn due to the high incidence of adverse effects such as somnolence, ataxia, and mood changes.5 In our study, patients were never exposed to ⬎ 60 mg/d of dextromethorphan. Furthermore, when administered orally, dextromethorphan has low bioavailability due to its extensive firstpass elimination by the cytochrome P450 2D6 enzyme, further reducing dextromethorphan plasma concentrations.7 Generally, patients who ingest dextromethorphan as a cough suppressant do not experience adverse effects due to the low dose used; therefore, such low doses are not sufficient to significantly block NMDA receptors. Regarding the fetus, fetal expression of NMDA receptors peaks during weeks 20 to 22 of gestation, a period that marks the beginning of the brain growth spurt.6,8 As the outcome of this study was not postnatal neurodevelopment, merely the occurrence of birth defects, assessing long-term neurodevelopment would be important in children exposed in the second and third trimester, particularly among women who are taking more than the recommended dosage of cough suppressants, or are using cough syrups recreationally (not for the prescribed indication). While we agree that more studies are needed, it is important not to extrapolate animal data or studies with doses that are several orders of magnitude higher than the standard human dose to the human experience. The predictive value of in vivo fetal animal data is poor at best. Dorothy A. Lyszkiewicz, BSc Adrienne Einarson, RN Gideon Koren, MD Hospital for Sick Children Toronto, Ontario, Canada Correspondence to: Adrienne Einarson, RN, Hospital For Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; e-mail: [email protected]

References 1 Kimiskidis VK, Mirtsou-Fidani V, Papaioannidou PG, et al. A phase I clinical trial of dextromethorphan in intractable partial epilepsy. Methods Find Exp Clin Pharmacol 1999; 10:673– 678 2 Kazis A, Kimiskidis V, Niopas I. Pharmacokinetics of dextromethorphan and dextrorphan in epileptic patients. Acta Neurol Scand 1996; 93:94 –98 3 Hamosh A, Maher JF, Bellus GA, et al. Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 1998; 132:709 –713 4 Schmitt B, Netzer R, Fanconi S, et al. Drug refractory epilepsy in brain damage: effect of dextromethorphan on EEG in four patients. J Neurol Neurosurg Psychiatr 1994; 57:333–339 5 Rogawski MA, Porter RJ. Antiepileptic drugs: pharmaoclogical mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42:223–285 6 Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283:70 –73 7 Zhang Y, Britto MR, Valderhaug KL, et al. Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6. Clin Pharmacol Ther 1992; 51:647– 655 CHEST / 120 / 3 / SEPTEMBER, 2001

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8 Lee H, Choi BH. Density and distribution of excitatory amino acid receptors in the developing human fetal brain: a quantitative autoradiographic study. Exp Neurol 1992; 118:284 – 290

Medical Problems in Scuba Diving To the Editor: We read with great interest the Roentgenogram of the Month by Hamad et al1 in a recent issue of CHEST (January 2001). Concerning the anamnesis and the chest radiograph, we agree with the diagnosis but not with some of the explanations regarding medical problems encountered during scuba diving or any other hyperbaric exposure (hyperbaric chambers, etc). There are a number of inaccuracies in the text. The authors mention barotrauma, decompression sickness, and nitrogen narcosis as common complications of scuba diving, going on to state that “the mechanism in all these complications is the same.” Indeed, all of these phenomena may result from breathing compressed gas under water, but the mechanisms are different.2 Barotrauma is due to a failure to equalize pressures between different compartments, or doing so at an insufficient rate, with the result that during descent there is a relative underpressure in these compartments. In this case, there is no relation to Henry’s law but rather to Boyle’s law. It is therefore erroneous to state that “compressed gases cause a negative pressure on the walls of the body cavities.” Common complications are middle ear and sinus barotrauma. Stomach rupture due to barotrauma is a rare event, in contrast to what may be understood from the text.3,4 At every depth, the pressure of the air (which is the breathing mixture in most sport diving) in the lung must be equivalent to the ambient pressure. If the diver holds his breath during ascent, when the ambient pressure drops by one atmosphere for every 10 m, according to Boyle’s law the lung will expand to a point of rupture, resulting in subcutaneous emphysema, pneumothorax, cerebral gas embolism, and pneumocardia, as in the presented case. Again, there is no relation to Henry’s law. The gas involved is whatever gas is breathed during the dive, and not “expanding nitrogen” as mentioned by the authors. It is our impression that the authors have confused barotrauma with decompression sickness. In the latter, nitrogen bubbles form in the tissues and blood after a certain nitrogen load is formed in the lipid-rich tissues during the dive, and supersaturation occurs during an uncontrolled ascent due to the rapid decrease in ambient pressure. This is not the mechanism in the case described. Finally, the US Navy protocols were not developed to prevent subcutaneous emphysema, pneumothorax, or pneumocardia, as may be understood from the text. They are designed to prevent decompression sickness, by restricting the rate of ascent and by instructing the diver to interrupt his/her ascent at certain depths for certain lengths of time. This allows a more gradual release of nitrogen into the blood and avoids supersaturation of nitrogen in the tissues, so that there is less possibility of nitrogen bubbles forming in the tissues and the blood. Amir Abramovich, MD Yoav Yanir, MD Avi Shupak, MD Israel Naval Medical Institute Haifa, Israel Correspondence to: Amir Abramovich, MD, Israel Naval Medical Institute, PO Box 8040, 31 080 Haifa, Israel 1040

References 1 Hamad A, Alghadban A, Ward L. Seizure in a scuba diver. Chest 2001; 119:285–286 2 Melamed Y, Shupak A, Bitterman H. Medical problems associated with underwater diving. N Engl J Med 1992; 326:30 –35 3 Halpern P, Sorkine P, Leykin Y, et al. Rupture of the stomach in a diving accident with attempted resuscitation: a case report. Br J Anaesth 1986; 58:1059 –1061 4 Cramer FS, Heimbach RD. Stomach rupture as a result of gastrointestinal barotrauma in a scuba diver. J Trauma 1982; 22:238 –240 To the Editor: We read the interesting comments by Abramovich et al on our article in CHEST (January 2001),1 which raise some issues that need to be clarified. While the main mechanism in all the complications of scuba diving is the same (compression of gases underwater on descending and expansion under decreasing pressure on ascending), it depends on two laws to explain its pathophysiology: Henry’s law, which states that the amount of a given gas that is dissolved in a liquid is proportional to the partial pressure of that gas, which explains decompression sickness and nitrogen necrosis, and Boyle’s law, which explains barotrauma. Cerebral gas embolism and pneumocardia are complications of Henry’s law, as they result from insufficient time for nitrogen to re-equilibrate between the tissues and the blood. This causes the formation of nitrogen bubbles in the blood, which can be very extensive and result in fatal gas embolism.2 Although all gases expand under decreasing pressure, nitrogen is the main component (80%) of air, so it is the main gas to expand and cause barotrauma. Stomach rupture was mentioned with the rest of the complications in the first paragraph, but was stated and referenced as an infrequent complication in the third paragraph.3 In our case, we think that the mechanism of pneumocardia was secondary to both Henry’s and Boyle’s laws. First, there was insufficient time for nitrogen gas to re-equilibrate, which caused accumulation of gas in the heart chambers and massive embolism (Henry’s law).2 Second, there was barotrauma with expanding air entering the left chambers of the heart through traumatic pulmonary veins (Boyle’s law).4 Although the US Navy and the Royal Navy protocols were designed originally and mainly to prevent decompression sickness, it does also prevent barotrauma by allowing more time for entrapped expanding gases to be exhaled from the lung during these stops upon ascending. Abdullah Hamad, MD Adnan Alghadban, MD Laurie Ward, MD Nassau University Medical Center East Meadow, NY Correspondence to: Abdullah Hamad, MD, Apt #24F 200 Carman Ave, East Meadow, NY 11554; e-mail: abdhamad@ hotmail.com

References 1 Hamad A, Alghadban A, Ward L. Seizure in a scuba diver. Chest 2001; 119:285–286 2 Tibbles PM, Edelsburg JS. Hyperbaric-oxygen therapy. N Engl J Med 1996; 334:1642–1648 3 Barotrauma. In: Edmonds C, Lowry C, Pennefather J. Diving and subaquatic medicine. 2nd ed. Mosman, N.S.W., Australia: Diving Medical Center, 1983; 93–127 4 Dutka AJ. A review of the pathophysiology and the potential application of experimental therapies for cereberal ischemia to the treatment of cerebral arterial gas embolism. Undersea Biomed Res 1985; 12:403– 421 Communications to the Editor