Chemical stability of sublingual nitroglycerin tablets carried on paramedic vehicles

CORRESPONDENCE

computed

tomography

of the head, and carotid or cerebral

angiography . HOWARD RODENBERG,MD MATTHEW GRATTON, MD

Truman Medical Center Kansas City, Missouri

References Wolff L, Parkinson J, White PD: Bundle branch block with short R-P interval in healthy young people prone to paroxysmal tachycardia. Am Heart J 1930;5:665 Levine SB, Snow JB Jr: Pulsatile tinnitus. Laryngoscope 1967;97:401-406 Sila CA, Furlan AJ, Little JR: Pulsatile tinnitus. Stroke 1987;18:252-256

POVIDONE-IODINE SOLUTIONS IN TRAUMATIC WOUND PREPARATION To the Editor:-AJEM published a letter by Michael S. Oberg, MD entitled “Povidone-Iodine Solutions in Traumatic Wound Preparation,“’ which contained opinions based on a very limited number of references. In addition, some of the references quoted have little or no relevance to the practical and proper use of povidone-iodine. Dr Oberg declares the data to be conflicting, yet reaches conclusions and a recommendation. The reason for conflicting data derives from the difficulties encountered in the studies reported rather than the failure of the agent. Numerous studies which are not cited conclusively demonstrate the usefulness of povidone-iodine solution in the management of wounds.‘-” KENNETH G. ROTHWELL, MD

Easton, Connecticut

References 1. Oberg MS: Povidone-iodine solutions in traumatic wound preparation. Am J Emerg Med 1987;5:553-555 (letter) 2. Garnes AL, Davidson E, Taylor LE, et al: Clinical evaluation of povidone-iodine spray in surgical practice. Am J Surg 1959;97:49-53 3. Lee BY, Trainor FS, Thoden WR: Topical application of povidone-iodine in the management of decubitis and stasis ulcers. J Am Geriatr Sot 1979;27:302-306 4. Kwaan JHM, Connolly JE: Successful management of prosthetic graft infection with continuous povidone-iodine irrigation. Arch Surg 1981;116:716-720 5. Morgan WJ: The effect of povidone-iodine aerosol spray on superficial wounds. Br J Clin Pratt 1979;33:109-110 6. Gilgore A: The use of povidone-iodine in the treatment of infected cutaneous ulcers. Curr Ther Res 1978;24:843-848 7. Stefanides MM, Copeland DE, Kominos SD, et al: In vitro penetration of topical antiseptics through eschar of burn patients. Ann Surg 1976;183:358-364 8. Wynn-Williams D, Monballiu G: The effects of povidoneiodine in the treatment of burns and traumatic losses of skin. Br J Plast Surg 1965;18:146-150 9. Connell JF Jr, Rousselet LM: Povidone-iodine: Extensive surgical evaluation of a new antiseptic agent. Am J Surg 1964;108:849-855 10. Linkner LM, Cloud DT, Trump DS, et al: Prevention of bac-

terial growth and local infection in burn wounds. J Ped Surg 1972;7:310-314 11. Georgide NG, Matton GE, Kessel FV: Facial burns. Plast Reconstr Surg 1962;29:648-657

The author replies:-1 have read Dr Rothwell’s letter and it is not clear to me that he read either the title or the body of my correspondence. Nor is it clear to me what his interest in the subject is. My interest is as an emergency physician who had to deal with one of those mundane but important issues that face us all in the emergency department (ED). My letter dealt with the use of povidone-iodine solutions on acute traumatic wounds in the ED, ie, lacerations. I offered it in the hope that other emergency physicians who have to deal with this issue might find it helpful. I fail to see that the references Dr Rothwell offers on the treatment of decubitus ulcers, stasis ulcers, cutaneous ulcers, penetration through bum eschar, and chronic bum care have much relevance to treatment of acute lacerations. Many of the references he cites were unearthed in my search but not used for the reasons noted or because some had been superseded by more recent studies. Elsewhere in the letter, I stated that povidoneiodine is a valuable agent (our own hospital uses it by the gallon); I just question its value in this context. I feel that my letter fairly summarized the recent and still somewhat sparse literature on this subject. The results are indeed conflicting and the conclusions I reached are clearly labeled as my own beliefs. I stand by the letter as written. Thank you for this opportunity to reply. MICHAEL S. OBERG, MD

Arlington, Texas

CHEMICAL STABILITY OF SUBLINGUAL NITROGLYCERIN TABLETS CARRIED ON PARAMEDIC VEHICLES To the Editor:-Sublingual nitroglycerin (NTG) has long been used for the treatment of patients with cardiac chest pain. Although its predominant action is as a venodilator effectively reducing cardiac preload, NTG also relaxes peripheral vascular smooth muscle, producing a fall in cardiac afterload as well.’ Both atherosclerotic and normal coronary arteries dilate following NTG administration.’ These vascular effects are the rationale for the administration of sublingual NTG tablets in patients experiencing angina pectoris, myocardial infarction, and acute pulmonary edema during the prehospital phase of illness. Upon exposure to air, NTG tablets begin to degrade, and their pharmacological potency decreases.3 Variability in NTG potency also has been reported with different ambient temperatures.4 Because the chemical efficacy of NTG is often critical in the prehospital management of patients who have chest pain or heart failure, and because temperatures to which NTG tablets are exposed are variable, we evaluated the actual amount of active NTG present in tablets sampled from paramedic vehicles in the Los Angeles area. In Los Angeles County, paramedics normally carry NTG in small brown glass bottles of 25 tablets (400 p,g) per bottle. After 3 months, or when the number of tablets in the bottle falls below five, paramedics are instructed to resupply with a new bottle of 25 tablets. Between October 1986 and March 1987, bottles of NTG tablets were removed from 18 para681

AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 6, Number 6 n November 1988

medic vehicles assigned to various locations in Los Angeles County with varying temperatures and humidity levels. The vehicles involved included helicopters (2), fire engines (2), small rescue trucks (4), and van-type ambulances (10). Three major climatic zones were represented: coastal ocean areas with high humidity, 52” to 67°F mean temperature range; valley areas with dry conditions and mean temperature extremes of 45” to 71°F; and lowland zones, which approximate sea level but with less ocean moisture and 51” to 71°F mean temperature ranges.’ The NTG removed for study was exchanged for fresh bottles of sublingual tablets from the University of California-Los Angeles (UCLA) Medical Center pharmacy. The study bottles were labeled with numerical codes, and sent by mail to the University of Florida at Gainsville, where 50% of the tablets from each bottle containing ten tablets were randomly selected and assayed for their content of active NTG using a high-performance liquid chromatography (HPLC) technique.6 In those bottles containing ~10 tablets, all tablets were assayed. Four freshly prepared and numerically coded bottles, containing between 11 and 15 NTG tablets from the UCLA hospital pharmacy, were also sent for analysis as controls. The results of the NTG tablet analysis are presented in Table 1. The mean, SD, and range (pg) for control NTG were 438, 24.6, and 390 to 478, respectively, and those for paramedic-carried NTG were 443, 24.6, and 404 to 462. Using a one-tailed Students t test, the mean differences in NTG contents for the two groups were not significant (t = .067, P > .05). In addition, every tablet tested from each vehicle sampled was found to contain acceptable amounts of NTG, according to United States Pharmacopeia (USP) standards, regardless of the type of vehicle or climatic zone surveyed. Chest pain suspicious of cardiac origin and shortness of breath consistent with pulmonary edema are both frequent prehospital patient presentations. NTG in therapeutic amounts is an effective first-line drug for both of these conditions. Its role in potential salvage of ischemic myocardium is well documented.7.8 Because of its chemical instability, however, it is important to ensure that the tablets carried on paramedic vehicles contain a therapeutic amount of the drug. Patients who carry their own NTG tablets for selfadministration commonly are advised to keep their personal supply fresh, but in a 1987 survey of presently used formulations of NTG tablets from 153 patients in nine states, 17% of the patients carried tablets containing subtherapeutic amounts of the drug.’ This was especially true when the

TABLE1. Analysis of Sublingual Nitroglycerin Tablets Based on Climatic Zone and Type of Rescue Vehicle Mean NTG Level (pg) Climatic zone Coastal (4) Lowland (7) Valley (7) Type of vehicle Fire engine (2) Helicopter (2) Small rescue truck (4) Van-type ambulance (10) 682

428.70 449.00 433.0 462.45 411.75 448.15 434.65

NTG tablets were kept in plastic containers and/or in direct contact with other medications. In sampling NTG tablets carried by 18 different paramedic units in the Los Angeles area both with varying climatic conditions and on different types of vehicles, we found that all tablets contained USP-approved therapeutic levels (80% to 120% of labeled amount).” To control for the possible change in the potency of NTG tablets caused by shipping them from Los Angeles to Florida for chemical assay, we also shipped fresh samples from our hospital pharmacy for analysis. There were no differences in the amount of available NTG present in either group of tablets. While our sample sizes were admittedly small for both controls and paramedic-carried NTG tablets, the actual value of measured NTG for each sample revealed little variance between them. The SDS for control and paramedic-carried NTG tablets were only 5% and 6%, respectively, of the 400 pg presumed to be contained in each tablet. With so little sample variance, the size of our sample should not be construed as detracting from the uniformity of the NTG in each bottle we evaluated. An additional consideration might be raised in that the NTG we analyzed was removed from paramedic vehicles during the six cooler months of the Los Angeles seasonal calendar. Clearly, however, some tablets sampled in October and November would have been placed on the paramedic vehicles during July, August, and September (traditionally our warmest months, when daytime temperatures may approach 90” to 100°F). Nonetheless, a specific look at NTG carried on vehicles only during those hotter periods, with measures of vehicular temperatures as well, might further clarify the effect of thermal changes on fieldadministered NTG. We did not attempt to assess the time elapsed from the date these NTG tablets were placed on paramedic vehicles until they were removed for content analysis. Indeed, we wished to sample the existing tablets from a variety of paramedic services, under varying conditions, to learn whether or not the content of NTG used in the field setting is therapeutic. Given that every tablet analyzed was within therapeutic guidelines, and that the number of tablets used and thus their replacement schedules will vary from one paramedic station to another, we feel confident that at any given time, using the 3-month replacement guideline, the NTG tablets administered by paramedics in our system will be within USP requirements. We also did not attempt to assess the ultimate duration of viability of these tablets in the field setting. In fact, the required 3-month turnover of any unused NTG tablets in our system might result in the discarding of some acceptable pharmacoactive medication. However, the cost of 25 tablets of NTG to our hospital pharmacy is 84 cents, or roughly three cents per tablet. Even if a full bottle of NTG went unused and was discarded after the prescribed 3-month period, the 84 cents wasted seems like “cheap insurance” compared with the need for prompt, effective cardiac unloading in the acutely ill patient experiencing myocardial ischemia or pulmonary edema in the unstable field setting. Paramedics in Los Angeles County are instructed to resupply their sublingual NTG tablets after the tablets have been carried on their vehicles for 3 months, or when the number of remaining tablets in a given bottle dwindles to

CORRESPONDENCE

five. Given these guidelines, this mechanism for resupplying NTG tablets results in the ability of paramedics in our emergency medical services (EMS) system to administer this medication in therapeutic amounts in the prehospital setting. STEVENJ. ROTTMAN,MD BAXTERLARMON,MICP TOM MANNIX, MICP UCLA Hospital Los Angeles, California STEVENH. CURRY, MD University of Florida Gainesville, Florida

References 1. Williams DO, Amsterdam EA, Mason DT: Hemodynamic effects of nitroglycerin in acute myocardial infarction: Decrease in ventricular preload at the expense of cardiac output. Circulation 1975;51:421-427 2. Abrams J: Nitroglycerin and long-acting nitrates. N Engl J Med 1980;302:1234-1237 3. Cummings AJ, Martin BK: Deterioration of nitroglycerin tablets. J Pharm Sci 1988;57:893 4. Fusari SA: Nitroglycerin sublingual tablets. I: Stability of conventional tablets. J Pharm Sci 1973;82:122-129 5. California Temperature Normals. US Department of Commerce, National Oceanic and Atmospheric Administration, Los Angeles 8. Olsen CS, Scroggins HS: High-performance liquid chromatographic determination of nitroglycerin in sublingual sustained-release, and ointment dosage forms. J Pharm Sci 1983;72:983-985 7. Epstein SE, Kent KM, Goldstein RE, et al: Reduction of ischemit injury by nitroglycerin during acute myocardial infarction. N Engl J Med 1975;292:29-34 8. Awan NA, Amsterdam EA, Vera 2, et al: Reduction of ischemit injury by sublingual nitroglycerin in patients with acute myocardial infarction. Circulation 1978;54:781-773 9. Curry SH, Mehta M, Pharm M, et al: Survey of sublingual nitroglycerin-tablet potency under conditions of patient use. Int Med 1987;8:83-71 10. The United States Pharmacopeia, 21st revision. Rockville, MD, US Pharmacopeial Convention, Inc, 1985

POSSIBLE INTERFERENCE OF FLUMAZENIL ON BENZOOIAZEPINE MEASUREMENT IN BLOOD AND URINE To the Editor:-Benzodiazepines are widely prescribed throughout the world. They are also largely abused and are frequently implicated in drug overdose situations and fatalities also involving other drugs. Both quantitative and qualitative methods for measuring benzodiazepines are available. Actually, three qualitative methods are largely used in laboratories and emergency department: the Emit-dau benzodiazepine assay, designed to detect benzodiazepines and their metabolites in human urine; the Emit-tox and Emit-St (Syva Company, Palo Alto, CA), designed for serum or plasma; and the benzodiazepine TDX (Abbott Laboratories, Irving, TX) method for detection of benzodiazepines and their metabolites in urine. These

TABLE 1.

Benzodiazepine Measurement

Time Before injection 30 sect 15 min 30 min 80 min 90 min 12 h 24 h

Blood Samples’

Urine Samples”

0 0 0

0 -

0 0

0 -

0 -

0 0 0

* Syva Emit-St, serum < 0,3 mg/L (diazepam); Syva Emit-St, urine < 0,3 mg/L (oxazepam); Abbott TDX, urine < 0,3 mg/L (nordiazepam). T Withdrawn through the injection syringe.

methods permit the quick qualitative analysis of the main benzodiazepines, although some (eg, flunitrazepam) react poorly. l-3 Recently, a new and specific antagonist of the benzodiazepines is in investigation and on the market in some countries (Denmark, France, New Zealand, Switzerland): the flumazenil, an imidazobenzodiazepine marketed by HoffmannLa Roche under the name of Anexate. It is eliminated in about 48 to 72 hours. The half-life of elimination is about 60 minutes. Two hours after intravenous injection, 60% to 70% is found in the urine.4 We were anxious about the possible crossreactivity of the flumazenil with the previously mentioned tests, as in some cases the patient may receive the antagonist before the blood or urine is drawn for drug measurement. For that, a healthy volunteer received, by intravenous injection, 1.0 mg Anexate (10 mL). Blood and urine samples were drawn and analyzed before and after injection of flumazenil. The results are shown in Table 1. In conclusion. although flumazenil had a close relationship with other benzodiazepine (flumazenil is the 8fluoro-5,6-dihydro-5-methyl-6-0x0-4 H-imidazo( 1,5-a) (1,4) benzodiazepine-3-ethyl-carboxylate), we observe no crossreaction using the previously mentioned test. This is of importance for any patients who are treated first with flumazenil and then postponed benzodiazepine analysis. ANDRE DOEM, PHD PIERRE-FRANCOIS UNGER Universiry Cantonal Hospital Geneva, Switzerland

References 1. Syva: Serum Benzodiazepine assay for in vitro diagnostic use. Palo Alto, CA, Syva, 1984 2. Syva: Urine Benzodiazepine assay for in vitro diagnostic use. Palo Alto, CA, Syva, 1984 3. Kiang W, Backes D: Clinical evaluation of a TDX fluorescence polarization immunoassay for the detection of benzodiazepine in urine. AACC Meeting, San Francisco, 1987 4. Roche: Anexate leaflet. F. Hoffmann-La Roche and Cie, Pharma Suisse, Basel, 1988

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