Inpatient Theophylline Toxicity: Preventable Factors Gordon D. Schiff, MD; Hemant K. Hegde, MD; Lisa LaCloche, RN; and Daniel O. Hryhorczuk, MD, MPH

Objective: To identify preventable factors contributing to inpatheophylline toxicity so that strategies could be developed to decrease its incidence and complications. tient theophylline toxicity. Design: Case series. Setting: Tertiary care public hospital. Patients and Methods Patients: Forty consecutive adult inpatients (mean age, 56.5 The study site was a public teaching hospital where 3 million years) with theophylline levels > 140 /Ltmol/L (25.0 mg/L). theophylline tablets and 25 000 parenteral aminophylline vials Measurements and Main Results: A retrospective chart audit was are dispensed annually. During the 6-month study period, 10 359 theophylline levels were measured. All patients with a done. Toxicity was produced in 27 of 40 patients by inpatient or level over 140 /xmol/L (25.0 mg/L) were identified by reviewing emergency department theophylline administration. Management daily toxicology logs: One hundred thirty-eight patients were errors found included delay (> 10 hours) in taking action from time identified, of whom 44 were adult inpatients. Outpatients as well as emergency department and pediatric patients were extoxic blood levels were drawn (20 patients), inappropriately high cluded. dosing of patients with congestive heart failure (17 patients), failure After discharge, complete inpatient charts of 40 of the 44 to recognize obvious symptoms (16 patients), recurrent toxicity (11 patients were retrievable. Each was reviewed with abstraction of patient demographics, weight, clinical presentation, indicapatients), additional emergency department treatment of already tion for methylxanthine therapy, details of theophylline dosing toxic patients (7 patients), overlap of intravenous and oral therapy and toxicity, symptoms and signs associated with toxic levels, (6 patients), patient discharged with no physician awareness of and physician response to toxicity. Flow diagrams showing temporal relations among dosing, toxic levels, and symptoms toxicity or dosage change (5 patients). were made for each patient. Conclusions: A set of recurring management errors was identiIn our study, as was the convention in several previous fied as contributing to inpatient theophylline toxicity. Effective studies (10, 17), theophylline toxicity was defined in terms of elevated serum levels rather than as clinical manifestations. preventive mechanisms could have prevented most toxicity and The retrospective collection of data precluded reliance on associated morbidity. Theophylline's overallrisk-benefitratio in the charted signs and symptoms for the case definition. Classificainpatient setting may be less than that measured in well-controlled tion of the likelihood that an elevated level was responsible for observed morbidity or mortality was done using the Food and studies of the drug's efficacy because of these management errors. Drug Administration Division of Drug Experience scheme (19). Morbidity was rated as substantial if it caused admission, prolonged the hospital stay, or caused the physician to order a Annals of Internal Medicine. 1991;114:748-753. medication to counteract toxicity-associated symptoms. Assessment of factors contributing to toxicity was made by imFrom Cook County Hospital, Chicago, Illinois. For current plicit review by two internists. These factors were then cateauthor addresses, see end of text. gorized and each case was reviewed again using these explicit criteria to determine their frequency. Patient Characteristics 1 heophylline has a well-known narrow therapeutictoxic ratio. In recent years, dosing strategies have been re-assessed (1, 2), and the drug's clinical indications have been questioned (3-8). Central to the risk-benefit question are the frequency, clinical consequences, and potential for avoidance of theophylline toxicity (9-11). Although studies of the drug's efficacy are generally done under well-controlled conditions, use in less carefully monitored settings increases the potential for toxicity. Acute, often intentional, overdose had been the subject of many reports on theophylline's toxicity (12-14). Increasingly, however, iatrogenic factors are being emphasized (15-17). Aitken and Martin reported that 65% of toxic theophylline levels received by their toxicology laboratory occurred in patients who were not toxic at admission (18). We did a quality assurance study to characterize the epidemiology of this iatrogenic problem in our institution and to identify factors contributing to inpatient 748

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Of 40 adult theophylline-intoxicated inpatients, 22 were women and 18, men. The mean age was 56.5 years (range, 26 to 83 years). The primary diagnoses for which patients received methylxanthines were bronchial asthma (18 patients), chronic obstructive pulmonary disease (15 patients), and other cardiorespiratory diseases (7 patients). Surprisingly, no patients presented with a history of overdose or suicide attempt. Thirteen patients had levels over 140 /xmol/L (25.0 mg/L) when presenting, whereas 27 either became toxic during their hospitalization (21 patients) or as a result of therapy in the emergency department (6 patients). Of 13 patients presenting with toxic levels, 1 had been discharged 24 hours earlier. Morbidity and Mortality Nine patients died during the admission being studied. One death that was classified as probably related to toxicity was a 66-year-old man with chronic lung disease who developed agitation and a heart rate of 170 associated with a theophylline level of 220 /Ltmol/L (39.5 mg/L). He died from a refractory supraventricular arrhythmia 12 hours later. Four patients' deaths were possibly related to toxicity. All had underlying conditions with poor prognoses (malignancy [2 patients], sepsis with gastrointestinal bleeding [1 patient], and cardiomyopathy [1 patient]), but the immediate cause of death was arrhythmias or seizures that occurred in association with toxicity. Morbid-

Table 1. Morbidity

Associated

with Theophylline

Sign or Symptom

Toxicity Number

Cardiovascular system Arrhythmias Sinus tachycardia Premature ventricular contractions Supraventricular tachycardia Premature atrial contractions, multifocal atrial tachycardia Atrial fibrillation Chest pain Hypotension Gastrointestinal system Vomiting Nausea Diarrhea Central nervous system Tremors Nervousness Irritability Seizures Altered behavior Headache Others: unusual manifestations Severe hypokalemia Acute psychosis Dysphagia Acute urinary retention Acute renal failure Right upper quadrant pain simulating biliary colic

26 7 12 2 1 3 1 12 7 5 5 6 5 3 2 2 2 2 1 1 1 1

ity was classified as due to toxicity in 30 of the 40 patients (Table 1). It was rated as substantial in 14 and minor in 16. There were no problems or symptoms discovered in 10 patients. When we reviewed the charts, we discovered recurring management errors and classified these errors into ten categories (Table 2). We illustrate each with the following case summaries and comments Delay in Taking Action after Toxic L e v e l s W e r e Measured An 82-year-old man was hospitalized with heart failure. He received slow-release theophylline, 200 mg orally twice daily on hospital days 2 through 8. He was scheduled to be discharged when he developed supraventricular tachycardia (heart rate, 150) and dysphagia. A theophylline level of 110 /xmol/L (20.4 mg/L) measured on day 7 had not been noted. A level of 170 /xmol/L (31.2 mg/L) measured on day 8 was not noted or acted on for 24 hours. The patient's scheduled discharge was cancelled and the theophylline was withheld. His cardiac and renal status deteriorated and he died on day 30. We found an interval of more than 10 hours between the drawing of a toxic level and physician action (to reduce or discontinue the drug or to give activated charcoal) in half of the patients. This excessive delay, clearly multifactorial in cause, represented an important preventable factor contributing to toxicity. Inappropriately High D o s e s with H e a r t Failure or L i v e r Disease A 54-year-old, 65-kg man was hospitalized for decompensated alcoholic cardiomyopathy and given his usual slow-release theophylline 300-mg tablet twice daily. An admission theophylline level of 130 /xmol/L (22.8 mg/L) was not noted for 72 hours. On day 3 he developed tachycardia and diarrhea, and his theophylline level was 170 /xmol/L (30.0 mg/L). Theophylline was withheld for several days and then restarted at 200 mg twice daily. He was discharged on day 9. A level measured on the morning of discharge was 110 /xmol/L (19.8 mg/L). It was apparently never seen.

As in the previous case, this patient illustrates multiple error categories. At a weight of 65 kg with congestive heart failure and an elevated prothrombin time suggesting liver disease, he was receiving two times the recommended maintenance theophylline dose of 0.1 to 0.2 mg/kg body weight per hour (1). Although delay in responding to elevated levels was the most common management error observed and frequently resulted in prolongation of morbidity, the overdosing of patients with congestive heart failure was the leading factor that caused toxicity. If these patients had received appropriately reduced theophylline doses, much of the observed toxicity could have been avoided. Warnings (1, 20) about difficulties using this drug safely in such patients are reinforced by our data. Failure T o Recognize Signs of Toxicity A 42-year-old woman with rheumatic heart disease and asthma presented with dyspnea. She was given increasing doses of parenteral and then oral theophylline (initially 250 mg every 8 hours, increased to 300 mg, then 350 mg, then 450 mg, and then 500 mg every 8 hours; then switched to 400-mg slowrelease tablets three times daily). The next day she became psychotic and combative. Physicians evaluating her from the primary service and psychiatry service failed to consider toxicity. Later a level of 160 jwmol/L (28.3 mg/L) was charted. She was sent home without any note on the chart linking the mental changes to the toxicity. Another woman with hypertension, heart failure, and obstructive lung disease was hospitalized for epigastric pain. An abdominal ultrasound showed gallstones, assessed to be an incidental finding, and she was discharged with a diagnosis of gastritis. The next day she returned with dyspnea, palpitations, nausea, diaphoresis, and a heart rate of 156. Theophylline toxicity was suspected and later confirmed with a level of 180 /imol/L (33.3 mg/L). The drug was held for 16 hours and she improved. Oral theophylline was resumed. On day 2 she developed pulmonary edema. She was given diuretics, a "half loading dose" of 150 mg of aminophylline followed by infusion of 25 mg/h. She was transferred to the intensive care unit and found to have an acute myocardial infarction. One hour later she began experiencing nausea, vomiting, and abdominal pain. An emergency surgical consult, called to evaluate her "acute abdomen," noted the abnormal ultrasound results, and transferred her to surgery for an emergency cholecystectomy. She survived a complicated postoperative course. A theophylline

Table 2. Management line Toxicity*

Errors

Error

to

Theophyl-

Number (%)

Delay (> 10 hours) from time toxic level drawn to action by physician Inappropriately high doses (> 1.5 times) administered to patient with congestive heart failure or liver disease Failure to note obvious (gastrointestinal, cardiac, central nervous system) symptoms or signs of toxicity Recurrent toxicity with failure to be aware of, or to adjust dose Dosing confusion and errors for patients without congestive heart failure Emergency department intravenous treatment despite pretreatment levels ultimately found > 110 /Ltmol/L (20.0 mg/L) Inadvertent overlap of intravenous aminophylline and oral theophylline Interacting drugs; failure to adjust dose or closely monitor Patient discharged on same dose despite toxicity Patient discharged with no noted physician awareness of toxicity

20 (50) 17 (42.5) 16 (40) 11 (27.5) 9 (22.5) 6 (15) 6 (15) 5 (12.5) 5 (12.5) 4 (10)

* More than one factor may apply to each case.

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We have implemented a new policy requiring that "mg/h" be used for ordering aminophylline parenterally. A premixed formulation of 250 mg in 250 mL of 5% dextrose in water is now stocked by the pharmacy. Thus, mg/h is equivalent to mL/h. Physicians and nurses can become familiar with orders for 5 to 15 mg per hour as being safe for elderly patients or those with congestive heart failure rather than the 25 to 50 mg/h we frequently discovered. This excessive dosing was obvious to us only when we converted the orders into the standardized "mg/h" format. Administration by t h e E m e r g e n c y D e p a r t m e n t despite Toxic P r e t r e a t m e n t L e v e l s

Figure 1. Examples of lack of standardization in parenteral aminophylline ordering. Over 70 ways that orders for parenteral aminophylline were written were documented. The lack of standardization, apparent from the selected examples quoted above, makes recognition of potentially toxic infusion orders difficult.

level concurrent with her gastrointestinal symptoms was found to be 150 /xmol/L (26.2 mg/L). The pathology report showed "chronic" but no acute cholecystitis. Although neither case is absolutely conclusive, both patients had findings suggesting theophylline toxicity. In neither case was toxicity suspected. Particularly for the second patient, who was hospitalized for theophylline toxicity, this should have been a primary consideration. Instead, she had high-risk surgery for symptoms quite possibly due to her adverse drug reaction. L a c k of A w a r e n e s s of P r e v i o u s Toxicity A 76-year-old man with obstructive lung disease was taking theophylline slow release, 200 mg twice daily. He was hospitalized for exacerbation and was given aminophylline, 300 mg every 8 hours intravenously. Five days later he was discharged on 300 mg twice daily. Rising levels of 110 /xmol/L (20.0 mg/L) and 130 /xmol/L (23.5 mg/L) before discharge were not noted. He returned the next day with dyspnea and tachycardia. The theophylline level was 170 /xmol/L (31.3 mg/L). He was given activated charcoal and did well. During the chart review, two other admissions (one 9 months earlier, another 3 months after the index admission) for theophylline toxicity were incidentally discovered. We found evidence of recurrent intoxication in one quarter of the patients. The physicians were unaware of this patient's previous admission for theophylline toxicity. In addition, he was again hospitalized with toxicity just 3 months later—an obvious failure of patient education and inattention to careful dosing and monitoring of a high-risk patient. Two patients became toxic on three separate occasions during the study hospitalization. One patient had six separate episodes of toxicity during a 4.5 month hospitalization. Dosing Confusion and E r r o r s An important finding was the varied fashion in which orders for parenteral aminophylline were written. We documented over seventy different ways that the drug was ordered (Figure 1). This lack of standardization contributed to dosing confusion. Although the dose should be individualized (based on weight, age, smoking, cardiac disease, or interacting drugs), the ordering and administration needs to be standardized. The multiple conversions from pounds to kilograms, to milligrams per kilogram per hour, from milligrams of theophylline to milligrams of aminophylline, to milligrams to be added to x millilitres of fluid, to run over x hours, leads to an error-prone situation (21). Without a common "currency" there is no easy way to recognize an ordered dose as being excessive. 750

1 May 1991 • Annals of Internal Medicine

A 38-year-old man came to the emergency department for asthma treatment, was discharged in improved condition but returned the next day. He was then "1/2 loaded" with aminophylline and an infusion was begun. He was found to have ventricular trigemeny and hypokalemia. His pre-infusion theophylline level was found to be 180 /xmol/L (33.2 mg/L) with a post-treatment level of 190 /xmol/L (35 mg/L). Whether to give additional methylxanthines to a patient with an acute attack who is already taking this drug, and, if so, at what dose, is a frequently encountered dilemma in the emergency department. Arbab and colleagues (22) warn that estimations of aminophylline doses in this setting, without access to theophylline levels, are unreliable and hazardous (22). Because this factor contributed to toxicity in six patients, we have discontinued the practice of giving additional aminophylline before receiving a level from the laboratory. I n a d v e r t e n t O v e r l a p of Oral and I n t r a v e n o u s Administration A 66-year-old woman with asthma presented with increasing dyspnea. She was treated with aminophylline, 240 mg every 12 hours; the dose was then increased to 250 mg every 7 hours. On hospital day 5, when being switched to oral therapy, a level of 31 /xmol/L (5.5 mg/L) was noted. She was therefore given an additional intravenous dose of 250 mg and 400 mg of oral theophylline slow release immediately and then every 12 hours. The infusion, however, was not discontinued. An overlap of 16 hours of intravenous and oral therapy occurred. The patient's level rose to 140 /xmol/L (26.1 mg/L) and she developed tachycardia and vomiting, which was complicated by hyponatremia and hypokalemia. Although standard reviews do not offer advice on how to best make the transition from intravenous to oral therapy (1), we documented six instances of prolonged (> 6 hours) overlap. In two instances the overlap occurred when patients were switched from oral to intravenous therapy. With use of the slow-release oral product, the overlap period was thus potentially even longer. Interacting D r u g s : Failure to Adjust D o s e and M o n i t o r A 66-year-old woman with hypertension and heart failure was hospitalized for an acute myocardial infarction and a cerebrovascular accident. On hospital day 8 she was transferred out of the cardiac care unit, was having fever and pulmonary congestion, and was begun on erythromycin. On day 9 an aminophylline infusion, 600 mg every 24 hours, was ordered. On day 10 the patient had vomiting and chest pain. No drug levels were obtained. On day 12 she had a cardiac arrest due to "aspiration" and four episodes of "refractory ventricular tachycardia." A theophylline level drawn at this time was 160 /xmol/L (29.3 mg/L). She was successfully resuscitated. This patient was one of five whose medications included drugs reported to interact with theophylline. These drugs included erythromycin (3 patients) as well as cimetidine and ranitidine (1 patient each) (23). Patients Discharged on the S a m e D o s e despite Toxicity A 47-year-old woman with asthma, taking oral theophylline slow release, 300 mg twice daily, presented with a 2-day history of exacerbation of asthma and symptoms of an upper

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respiratory infection. In the emergency department, she was "half loaded" with intravenous aminophylline. Her pretreatment level was 120 /imol/L (21.6 mg/L); post-treatment, 150 /xmol/L (27.0 mg/L). She was hospitalized with a pulse rate of 160. Theophylline was held and the level returned to normal. She was restarted on intravenous theophylline and discharged on theophylline slow release, 300 mg twice daily. This patient was discharged on the same dose on which she had presented with a toxic level. Although levels can rise when a patient becomes acutely ill (24), the assumption should be that when a patient develops toxicity, the chronic dose should be reduced. Patients Discharged with No Noted Awareness of Toxicity A 42-year-old woman with idiopathic interstitial lung disease presented with dyspnea and edema. She received theophylline slow release, 300 mg orally twice daily, during her 7-day hospitalization. On hospital day 6 she had an episode of vomiting. A theophylline level drawn the next morning was 150 /xmol/L (27.0 mg/L). She was discharged several hours later on the same dose. There was no evidence in the chart that the level was seen or acted on. It was often difficult to determine if or when the physicians were aware of a toxic level. In the absence of comments in the notes, we had to infer awareness based on when the drug was discontinued or dose decreased. There is no note on this patient's chart, for example, indicating that the patient received a telephone call changing her prescription. The lack of documentation is an important quality issue that we frequently observed. Discussion In reviewing charts of 40 adult inpatients with elevated theophylline levels, we uncovered a set of management errors that helped to cause or prolong toxicity. Without a nontoxic control group, the exact effect of each of these contributing factors cannot be measured. As a quality-assurance audit, however, our primary purpose was not to determine "what is the right thing to d o " but rather "was the right thing done" (25). Our finding is that, in these cases, it often was not. The illustrative cases are examples of the most glaring management errors. It would be a mistake, however, to dismiss these errors as being so obvious that one would be unlikely to commit them in one's own practice or institution. Although we have no data on the generalizability of our findings, we suspect the problems are not isolated because our institution's overall quality is rated highly (26). Unless a hospital has carefully designed systems in place to prevent these errors, it is easy to envision how busy physicians could make similar mistakes. There are few published data detailing inpatient management errors contributing to this iatrogenic problem. Understandably, there is an inhibition about publicly sharing such data. Mountain and Nefif (16) examined physician error causing theophylline intoxication in 21 inpatients, concluding that it was the primary mechanism in 9 patients. Identified errors included prescribing inappropriately high doses or concurrent interacting drugs, monitoring levels inadequately, and educating patients insufficiently. Bertino and Walker (27) reviewed 19 patients with theophylline toxicity and noted that few had levels monitored before the onset of toxic symptoms. Aitken and Martin (18) identified 54 toxic patients, of whom 24 had heart disease and 5 had liver

disease. They did not comment on whether appropriate dose adjustments were made. They did note that in 7 patients, the toxicity was never recognized, an incidence that is similar to ours and that of others (28). There is a report on use of charcoal hemoperfusion (29) for a patient who presented to the emergency department and who was given additional aminophylline before a pretreatment level of 220 /xmol/L (40 mg/L) (rising to 280 jLtmol/L [50 mg/L] after treatment) was discovered. Our study confirms the findings of Aitken and Martin (18) that two thirds of inpatients became toxic in the hospital. Although Mountain and Nefif (16) identified antecedent self-overmedication as the most common cause of toxicity, if we used their cut-off value (110 )itmol/L [20 mg/L]), our results are also consistent with their finding that in only half of the patients were toxic levels present at admission. They underscore the preventable nature of these outpatient cases but do not examine the role of inpatient factors contributing to toxicity. Finally, although drug interactions are frequently cited (1, 30, 31), these were less important than other problems we identified. Several limitations to our study should be noted. Because it was a retrospective chart review, it depended on the quality of documentation. Some of the gastrointestinal, cardiac, or neurologic symptoms may have been recognized as toxic symptoms even though they were not noted as such in the progress notes. Such symptoms may have even led to action being taken— ordering a theophylline level—a level that ultimately signaled the case for inclusion in our study. However, because there was no change in the drug dose, we felt justified in citing management as a quality issue. On the other hand, toxic patients whose levels were never checked are under-represented in the study. Finally, we have no control group. If errors occurred with equal frequency in nontoxic patients receiving the drug, the significance of the errors would be diminished. If the errors were unusual, however, occurring only in the small group of study patients, the generalizability of these findings would likewise be limited. Tognoni and Bonati (32) argue that clinical pharmacology has strayed from its original mandate—the improvement of medical care by safer and more effective use of drugs. They advocate a "second generation" of clinical pharmacology, one that goes beyond preoccupation with the laboratory and pharmacokinetics and instead gives increased attention to the "natural laboratory" of real-world prescribing. As opposed to a drug's efficacy (how it performs under controlled experimental conditions), a drug's effectiveness (performance in actual clinical practice) (33) can be compromised by the management errors we documented. For a drug such as theophylline, with a narrow margin of safety, these can be decisive, particularly in situations where its efficacy is questionable (11). Discussions of risk versus benefit must therefore take into account how well physicians comply with recommendations offered for safe use of the drug. To the extent that our findings are representative, inpatient use of theophylline is associated with hazards that require a higher level of vigilance than we observed.

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Table 3. Corrective

Measures

The iatrogenic problems we identified are not unique

Implemented

to a particular drug or institution (36, 37). We believe Problem

Corrective Actions

Delay from time toxic level was drawn to physician's action

Inappropriately high doses and erratic or confusing dosing

Redesign of panic reporting system, including protocol for reporting if ordering physician not reached or off duty Laboratory-based surveillance by clinical pharmacists Monitoring of internal and external laboratory turnaround time Emergency department toxicology analyzer Medical Grand Rounds Educational pharmacy newsletter Adoption of "mg/h" as standardized format for aminophylline ordering Purchase of commercially prepared aminophylline with standardized concentration of 1 mg per 1 mL

that disproportionate emphasis has been placed on identifying and comparing their rates, rather than probing and preventing their pathogenesis. The former approach leads to attempts to attribute adverse events to physician or patient idiosyncrasies, the latter to efforts

to

modify the underlying processes (38). The Joint Commission on Accreditation of Healthcare Organizations' requirement for drug utilization review met with noncompliance in almost half of hospitals surveyed in 1989 (39), and we suspect few reviews actually stimulate

significant

changes. Theophylline

whose use is ripe for such introspective

is a drug

examination.

On the basis of our analysis of toxic patients, we conclude that there must be increased attention to several factors to prevent toxicity. To the extent that our cases are representative of problems in the use of theophylline, the drug's actual effectiveness

may be less than

that derived from well-controlled studies of its efficacy. Overlooked toxicity symptoms and signs

Physician and nurse education Patient education

Recurrent toxicity

Campaign to increase inclusion of adverse drug reactions on chart problem lists Improved documentation of drug reactions on discharge summary and more readily available computer report of summary (40) Improved discharge patient education

Emergency department giving additional doses to already toxic patients

Withholding of aminophylline until level is known Purchase of level analyzer for emergency department

Interacting drugs, overlapping intravenous and oral doses

New inpatient pharmacy computer system to include features to screen for drug interactions and overlap

Narrow therapeutictoxic margin

Encouragement of use of inhaled beta-agonists and steroids as first-line therapy

Although the errors superficially appear to be management errors by physicians, most are, in fact, hospital " s y s t e m s " problems. The Japanese speak of " t h e five w h y s " in approaching quality issues, each why probing deeper to question, understand, and correct the underlying causes of the problem (34, 35). Why are lab results not seen or acted on in a timely fashion? If the answer is failure to reach the ordering physician with "panic results," then why is this occurring and why was this not detected and corrected earlier? Mere exhortation or education of the (transient resident) physicians is not sufficient. Unless we address the underlying reasons why physicians are making errors in prescribing the drug for cardiac patients or the lack of standardization in ordering, we are unlikely to solve the problems. Although

our

hospital

lacks

a formal

Japanese-style

quality improvement program, we assembled a multidisciplinary team and, using the toxic patients' flow diagrams, analyzed the problems and implemented corrective measures (Table 3).

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Medicine

Requests for Reprints: Gordon D. Schiff, MD, General Medicine Clinic, Cook County Hospital, 1835 West Harrison, Chicago, IL 60612. Current Author Addresses: Dr. Schiff: General Medicine Clinic, Cook County Hospital, 1835 West Harrison, Chicago, IL 60612. Dr. Hegde: 112 Clapp Street, Milton, MA 02186. Ms. LaCloche: 6743 North Artesian, Chicago, IL 60645. Dr. Hryhorczuk: Division of Occupational Medicine, Cook County Hospital, 1835 West Harrison, Chicago, IL 60612.

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