Threefold increase in theophylline serum concentration after addition of mexiletine

Correspondence INTUBATION OF PATIENTS WITH CERVICAL SPINE INJURIES To the Editor-1 read with interest the article by Wright et al.’ It is reassuring to have additional data that support the low incidence of serious cervical spine injury in blunt trauma patients and the rare incidence of neurologic deterioration following intubation techniques. This article supports the fact that the most important component of intubation technique in the potentially cervical spine injured patient is physician skill and training, ie, using whatever technique the practitioner feels most “comfortable” with. In Table 3 the authors show that 62.6% of their patient population was intubated orally. However, only 30% of patients with unstable fractures without neurologic deficit were intubated orally. In this same group of patients, 58% had an associated head injury. Recent data suggest that the use of neuromuscular blockade for intubation of head injured patients is safe regardless of the status of the cervical spine.2 I am curious as to the philosophy regarding neuromuscular blockade at the authors’ institution and whether neuromuscular blockade was used has an adjunct to oral intubation in these patients. The authors state that patients in traumatic arrest were excluded from their study. However, of the 20 patients with “neurologic impairment” at the time of intubation, nine were apneic with cardiopulmonary resuscitation in progress. Only two of these patients were discharged from the hospital, both to rehabilitation facilities. It seems difficult to retrospectively determine whether these patients had true spinal cord injury from fracture or whether their lack of movement after resuscitation was secondary to severe head injury coupled with cerebral anoxia. If these patients were truly in traumatic arrest at the time of intubation they should have been excluded from the study. The controversy regarding airway management in the cervical spine-injured trauma patient will continue. The authors are to be commended for their excellent addition to the literature on this important topic in trauma management. DANIEL J. DEBEHNKE, MD Medical College of Wisconsin Milwaukee, WI

References 1. Wright SW, Robinson GG, Wright MB: Cervical spine injuries in blunt trauma patients requiring emergent endotracheal intubation. Am J Emera Med 1992:10:104-109 2. Redan JA, Livingston DH, Tortella BJ, et al: The value of intubating and paralyzing patients with suspected head injury in the emergency department. J Trauma 1991;31:371:375

The authors rep/y:-1 thank Dr DeBehnke for his comments regarding our manuscript. I would like to answer the questions that he raised. First, the issue of the use of neuromuscular blockade as an adjunct to oral intubation was raised. Neuromuscular blockade with succinylcholine and/or vecuronium is commonly used in our emergency department (ED). I do not have data available to determine the percentage of patients in this study who received these agents. Second, the issue of excluding patients in cardiac arrest was raised. Patients who presented in traumatic arrest to our ED, all of whom were pronounced dead in our ED, were excluded. The patients who received cardiopulmonary resuscitation in the field or at an outside ED, but had vital signs on arrival to our hospital, were included. I suspect that many of these patients were not truly in cardiac arrest, but were either apneic and bradycardic, or were severely hypotensive. It is obviously difficult to retrospectively (or prospectively) determine whether a head injury or cervical injury was the cause of the arrest. In reviewing the charts and x-rays, I am 506

convinced that the severe high-level cervical injuries in these patients were sufficient to have caused the apnea. As Dr DeBehnke points out, the controversy regarding the appropriate method of airway control will continue. This paper helps to demonstrate that unstable cervical injuries are less common than reported in some of the literature and that commonly used methods of intubation are not likely to cause a neurologic problem. SETH

W. WRIGHT, MD Vanderbilt University Nashville, TN

THREEFOLD INCREASE IN THEOPHYLLINE SERUM CONCENTRATlON AFTER ADDlTlON OF MEXlLETlNE To the Editor:-Many drugs are known to interact with theophylline. Certain drugs are known to routinely produce clinically important increases in theophylline serum concentrations (TSC). These include erythromycin, troleandomycin, enoxacin, ciprofloxacin, propranolol, thiabendazole, and influenza vaccine.‘,2 Mexiletine, an antiarrhythmic agent, should be added to this list. In the following case, we report a greater than threefold increase in TSCs associated with hospitalization for gastrointestinal toxicity symptoms due to the concomitant use of mexiletine. The peak TSC was 41.8 pg/mL, the highest concentration reported to date due to this interaction. A 57-year-old man was discharged from the hospital after management of acute exacerbation of chronic bronchitis and congestive heart failure. For 1 month prior to admission, he had been noncompliant with all medications except theophylline extended release (theophylline-ER) tablets (Theodur, Key Pharmaceuticals, Kenilworth, NJ) 300 mg three times a day. Theophylline serum concentration on admission was 13.7 pg/mL. The patient was 67 inches tall and weighed 126 pounds. His medical history was significant for multiple chronic medical problems: coronary artery disease, congestive heart failure, hypertension, chronic obstructive pulmonary disease, ventricular ectopy, peptic ulcer disease, and osteoarthritis. At the time of discharge the patient was on prednisone (1Cday tapering dose regimen), amoxicillin plus clavulanate potassium (7-day course), and chronic treatment with ranitidine, albuterol metered dose inhaler, isosorbide dinitrate, enalapril. furosemide, potassium supplement, and theophylline-ER 300 mg three times a day. Over the subsequent months, all his chronic medical problems remained stable. The TSC on discharge was 8.5 ug/mL. Follow-up TSC 7 days later was 6.7 pg/mL. All theophylline concentrations were measured by florescence polarization immunoassay (TDx. Abbott Laboratories, Diagnostics Division, Irving, TX; therapeutic range IO-20 ug/mL). One month later, the patient’s medical condition was further complicated by an episode of acute renal failure suspected to be secondary to enalapril. His serum creatinine level rose from I .2 to 9.0 mg/dL. At that time, the TSC was 8.7 ug/mL. Routine follow-up 6 weeks later revealed a TSC of 13.5 pg/mL. During this time and subsequently, there were no changes in the drug regimen, including theophylline-ER 300 mg three times a day (except for the enalapril, which was discontinued). One month later, the patient began taking procainamide sustained release (Procan SR, Parke Davis, Morris Plains, NJ) 750 mg every 6 hours and mexiletine (Mexetil, Boehringer-Ingelheim. Ridgefield, CT) 150 mg twice a day for inducible, monomorphic, sustained ventricular tachycardia, which had previously been documented by electrophysiologic studies. One day after starting the antiarrhythmics, the patient complained of nausea and vomiting, and the antiarrhythmics were discontinued. The next day, procainamide alone was restarted and taken for 10 days without gastrointestinal com-

507

CORRESPONDENCE

plaint. Mexiletine was then again started at the same dosage. Within 2 days, the patient complained again of nausea and vomiting. Four days later the nausea and vomiting was unchanged, and the patient complained of two to three loose stools per day for the last l-2 days. The next day, the patient was admitted to the hospital with a TSC of 41.8 pg/mL. Electrocardiogram showed a sinus rhythm of 76 beats per minute with some premature atria1 contractions. Potassium concentration was 3.0 mEq/L (normal range 3.5-5.0 mEq/L), and the serum creatinine concentration was 1.6 mg/dL. There were no signs or symptoms of worsening congestive heart failure, chronic obstructive pulmonary disease, or other conditions known to affect theophylline clearance. While the patient was in the hospital, all routine medications were continued, including mexiletine; however, theophylline was initially withheld. Ceftriaxone was begun to treat a right lower lobe infiltrate and productive cough, which was felt to be an acute exacerbation of chronic bronchitis. The TSC dropped to 27.3 Fg!mL and subsequently to 17.0 &mL, 14.5 hours and 27.5 hours, respectively, after the initial TSC determination. Sixteen hours after the TSC of 17.0 &mL, the patient began to complain of shortness of breath; wheezes and rales could be heard on auscultation. An aminophylline infusion of 30 mglh (0.42 mg/kg/h) without a loading dose was administered using an infusion pump. Forty-five minutes after the infusion began, the TSC was 7.2 &mL; 8.5 and 10 hours after the initiation of the infusion, TSCs were 9.4 and 10.8 &mL, respectively. Five hours later, the theophylline infusion was discontinued, and the patient was discharged to home. The patient was discharged on theophylline-ER 300 mg twice a day, mexiletine 150 mg three times a day, and all routine medications plus cefaclor and ipatropium bromide metered dose inhaler. Follow-up three days later revealed a TSC of 22.1 &mL. The theophylline-ER was reduced further to 300 mg daily. Repeat measurement 3 weeks later revealed a TSC of 10.0 pg/mL. Three and four months later on the same regimen, the TSCs were 13.0 pg/mL and 11.8 &mL, respectively. An interaction between theophylline and mexiletine was first reported in 1987. A 74-year-old man with chronic obstructive pulmonary disease was receiving theophylline-ER 300 mg twice a day when mexiletine 200 mg three times a day was added. The TSC increased from 15.3 kg/mL to 25 Fg/mL over a 2-week period. The patient was hospitalized with anorexia, nausea, and vomiting. When the theophylline dose was reduced to 100 mg twice a day, the TSC dropped at steady state to 14.2 pg/mL and the symptoms subsided.3 Ueno et al reported a series of three cases in which TSCs increased after adding mexiletine. In two cases, TSC doubled; in one, it tripled a few days after adding mexiletine. In the case in which the TSC exceeded the therapeutic range, gastrointestinal symptoms of theophylline toxicity were seen.4 A similar case has been reported,

was reduced initially by one third and subsequently to two thirds of the original dose. After these adjustments, the theophylline serum concentration returned to its original level, and was maintained for the 4 months of follow-up. Although we cannot prove that the increased TSCs in our patient were due to the addition to mexiletine, the data are strongly suggestive. Two controlled studies have been conducted in healthy volunteers to assess the effect of mexiletine on steady-state TSCs and on theophylline pharmacokinetic disposition factors. In a preliminary report, eight men took theophylline-ER 300 mg every 12 hours for 7 days. On days 6 and 7, mexiletine 200 mg every 8 hours was added. The TSCs increased an average of 70%.’ In another study, 15 men took theophylline-ER 200 mg every 12 hours alone for 5 days, and together with mexiletine 150 mg every 8 hours for 5 days. A mean 58% increase in TSCs was seen at the end of the combination phase. The mean increase was associated with significant increases in mean peak TSCs, area under the serum concentration-versus-time curve, elimination half-life, and total body clearance without changes in the time to peak concentration or volume of distribution.* It is noteworthy that the mean increase in TSC is considerably less in these two controlled studies (60% to 70%) than the increases seen in anecdotal case reports (100% to 200%). Perhaps patients respond differently than healthy volunteers, or perhaps case reports represent the worst cases. Ueno et al9 present data from patients who took the combination of theophylline and mexiletine, and from a number of control patients who took theophylline alone. Decreased urinary concentrations of demethylation metabolites and increased urinary concentrations of both oxidation metabolites and unchanged theophylline suggest a specific inhibition of demethylation pathways from mexiletine. Notable with these reports is the rapidity of the interaction. Symptoms of theophylline toxicity and elevated TSCs occur within 2-3 days of administering this drug combination. The magnitude of the effect on TSCs, along with the risk of gastrointestinal and cardiac toxicity, clearly indicates the need for close patient monitoring when this combination is used. The risk is present even when initial TSCs are low in the therapeutic range, as seen with our patient. Also, the interaction may not be recognized immediately if the symptoms are assumed to be mexiletine-induced gastrointestinal or proarrhythmic effect. Therefore, it seems reasonable and prudent to recommend a 50% reduction in theophylline dose when mexiletine is added, and to monitor patients closely for symptoms of theophylline toxicity. The TSCs should be monitored accordingly. We gratefully Jerri Harris.

the expert editorial

assistance

of

MARK J. ELLISON,PHARMD DAVIDJ.LYMAN,MD EDUARDOSAN MIGUEL,PA East Carolina University Greenville, NC

in which TSCs doubled and the patient also experienced nausea and gastric upset when mexiletine was added.5

Additionally, new recurrent episodes of spontaneous nonsustained ventricular tachycardia were seen in a 55-year-old patient when mexiletine 200 mg three times a day was added to theophylline 400 mg three times a day. The TSC increased from a baseline of 12.5-15.3 )Ig/mL to a peak of 31 wg/mL over 3 days. After allowing the TSC to drop to 7.9 +g/mL, a lower dose of theophylline (200 mg three times a day) and a higher dose of mexiletine (300 mg three times a day) were started. Short runs of ventricular tachycardia (4-8 beats) were seen after 2 days. The theophylline was discontinued and mexiletine continued; the ventricular arrhythmias subsided within a few hours.6 In our patient, when mexiletine was added, the TSC approximately tripled from about 13.5 to 41.8 +g/mL, and he was hospitalized with nausea, vomiting, and loose stools. No cardiac abnormalities other than some premature atrial contractions were noted. While maintaining the same mexiletine dose, the theophylline dose

acknowledge

References 1. Upton RA: Pharmacokinetic interactions between theophylline and other medication (Part I). Clin Pharmacokinet 1991; 20:66-60 2. Upton RA: Pharmacokinetic interactions between theophylline and other medication (Part II). Clin Pharmacokinet 1991; 20:135-150 3. Katz A: Oral mexiletine-theophylline interaction. Int J Cardiol 1987;17:227-228 4. Ueno K, Miyai K, Seki T, et al: Interaction between theophylline and mexiletine. DICP Ann Pharmacother 1990;24:471-472 5. Stanley R, Comer T, Taylor JL, et al: Mexiletinetheophylline interaction. Am J Med 1969;66:733-734 6. Kessler KM, lnterian A, Cox M, et al: Proarrhythmia related

508

AMERICAN

JOURNAL

OF EMERGENCY

to a kinetic and dynamic interaction of mexiletine and theophylline. Am Heart J 1989;117:964-966 7. Vacek JL, Sztern MI, Botteron GW, et al: Mexiletinetheophylline interaction. J Am Coil Cardiol 1990;15:39A 8. Stoysich AM, Mohiuddin SM, Destache CJ, et al: Influence of mexiletine on the pharmacokinetics of theophylline in healthy volunteers. J Clin Pharmacol 1991;31:354-357 9. Ueno K, Miyai K, Kato M, et al: Mechanism of interaction between theophylline and mexiletine. DICP Ann Pharmacother 1991;25:727-730

ULTRAVIOLET LIGHT-INDUCED KERATlnS SECONDARY TO GERMICIDAL LAMP EXPDSURE RESULTING IN CORNEAL EPITHELIAL SLOUGHING To the E&or:-Patients frequently present to emergency departments due to UV-induced keratitis with the well-known complaints of eye pain and photophobia. Generally UV keratitis heals with time and the appropriate expectant management. We present a case of a patient with an occupational exposure to UV light who subsequently developed comeal sloughing, along with a discussion of the use of germicidal lamps and the pathophysiology of UV light damage. A 48-year-old male presented at four AM with the complaint of bilateral severe eye pain, itching, and photophobia. He stated that he felt as if he had “sand in his eyes.” He had no significant past medical history and was taking no medication. His occupational history was only significant for a brief (seconds) exposure to a welders’ flash at a distance of approximately 20 feet in the periphery of his vision the previous morning. He did not remember getting any foreign body or chemical in his eyes. He later revealed that he has an evening job painting in the dispensary at his place of employment around a blue light located in direct vision where he was working for 4 hours. The physical examination revealed vision to be 20/25 each eye, extraocular movements intact, pupils equal, round, reactive to light and accommodation with 2 + generalized conjunctival injection. Slit lamp examination revealed no evidence of foreign bodies, flare, or anterior chamber cells, and lid eversion was without foreign bodies as well. The cornea was hazy diffusely without evidence of abrasion or erosion. Flourescein staining revealed a diffuse stippling of both corneas with pinpoint uptake. The patient was diagnosed as having UV keratitis. He was treated with 2% Homatropine (Alcon), Bleph 10 (Allergan Inc, Irvine, CA), patching of the most involved eye, and oral analgesia, with instructions to return in 12 hours. The patient returned at 1 PM to the emergency department with complaint of blurred vision and continued eye pain. Examination revealed his vision to be 20/30 left eye, 20/40 right eye with a pinhole. Pupils were dilated and bilateral conjunctival injection was still noted. After Ophthetic 2% (Americana Brand, Erie, PA) was instilled a search was made for foreign bodies. The cornea was now clearing without haziness or abrasion. Stippling was still present and lid eversion revealed no foreign bodies. Both eyes were patched for patient comfort and the patient was given a prescription for analgesics and told to follow up with occupational medicine the following morning. When seen the following day both corneas were clear except for an area of flourescein uptake on the right cornea. The patient was referred to the ophthalmalogy specialist who diagnosed comeal erosion secondary to UV exposure. The erosion resolved in 24 hours with only observation. Phone contact with his employer revealed the blue lights were Americana brand 40 watt germicidal UV lights. Ultraviolet light is found in many places including the workplace in the form of welder arcs, germicidal lights, lasers, high-pressure lamps, graphic arts, electronics, production of printed circuits, surveying equipment, and sophisticated research equipment: at home it

MEDICINE

n Volume 10, Number 5 n September

1992

is found in the form of sunlamps; it is also found in commercial tanning booths, and in the form of naturally occurring sunlight.‘.’ Ultraviolet light can be useful as a sterilizing agent via inactivation of microorganisms by induction of thymine dimers that subsequently lead to destruction of nucleic acids.3 Germicidal lights (such as the one in this patient’s workplace) were installed for upper air disinfection to prevent the spread of influenza in the 1970~.~In 1976 an incident of UV keratitis was reported involving operating room UV lights and affecting several hospital personnel.’ In clinical practice the phenomenon of UV keratitis is well known. “The latent period can vary with the intensity of exposure and is typically four to five hours but can be as long as six to ten hours. Symptoms consist of foreign-body sensation in the eye, pain, lacrimation. and photophobia. Examination reveals chemosis, periorbital and/or lid edema, dilation and engorgement of the conjunctival capillaries, and a tine punctate staining pattern with application of fluorescein. Visual acuity is usually preserved but may be difficult to access because of photophobia.“’ In this patient the cornea1 defect was disconcerting, but on a review of the literature sloughing of the epithelium has been reported.(’ “Cellular tissue is much more sensitive to the UV than to longer wavelengths because at shorter UV wavelengths each photon has sufficient energy to excite electrons and possibly induce photochemical reactions involving the protein and nucleic acid constituents of the cell. It may require only a small number of photon hits (i.e., production of only a small quantity of a given photoproduct) at critical sites to disrupt the normal functioning of the cell and lead eventually to cell lethality. However, the macroscopic observation of any abnormality in the exposed tissue may be delayed. typically by periods of hours. from the actual UV exposure. The epithelium consists of six or seven layers of cells which normally have a life of about 1 wk from the time they complete migration towards the surface and are dispersed by the tear layer. UVinduced cell damage may result in an acceleration of this process of disintegration and sloughing into the tear layer, yielding a partially denuded epithelial layer.“’ In rabbits exposed to germicidal UV lamps it was demonstrated that the destructive effects may be attributed to damage to nucleic acids and protein in the epithelium. alterations of the energy transformation pathway, and changes in comeal hydrati0n.s Repair of the cornea1 epithelium is exponential, the rate can be calculated, and due to a slow repair rate (46 hours) there can be cumulative effects if personnel were exposed to UV lights on a daily basis.’ The cornea is most sensitive via photochemical damage mechanism in the 260-280 nm range and is able to absorb UV light in wavelengths less than 300 nm. At wavelengths greater than 300 nm the UV light may induce damage to the lens leading to cataracts as well as inducing retinal lesions.’ There are numerous sources of UV light that can potentially induce keratitis. The emergency department physician is frequently the first physician to evaluate these patients. provide expectant management, analgesia, and often provides follow-up. This case demonstrates an uncommon but potential problem for these patients. In cases of sloughing of the cornea due to UV-induced epithelial damage. patients should be referred to an ophthalmologist for care due to the potential for repeated sloughing. In addition the emergency physician is often in an ideal position to provide counseling for prevention of UV-induced damage to the eye. THOMAS RUSSELL JONES, MD JAMES PATRICK GILLEN, MD, FACEP Geisinger Medical Center Danville, PA

References 1. Pitts DG: Threat of ultraviolet radiation to the eye-How protect against it. J Am Optom Assoc 1981;52(12):949-957

to