PLATFORM * TRIBUNE

Excipi)ents, adverse dirugr reactionsand patients' rights

Edward Napke, MD, BSc, DPH

In an article published in CMAJ in 1984 (131:1449-1452), Dr. Edward Napke outlined the hidden haz-

ards of excipients and additives in drug formulations. Inthis update, Napke argues that the problem still existsand offers possible solutions to ensure the safe use ofthese products. Ed.

A 11 components of prescription drug formu-lations- excipients, additives and active ingre-dients- should be listed on the label, where

they can be read by physicians, nurses, pharmacists andpatients or their caregivers. Without easy access to thisinformation one cannot recognize and appropriately treatadverse reactions, and the safety and efficacy of any

drug formulation cannot be established. It is unaccept-able that health care professionals or patients must query

a third party (the manufacturer) to determine the ingredi-ents in a drug formulation.

An excipient is any inert substance added to a drugformulation to confer suitable consistency or form to theactive drug.' Excipients may include diluents, binders,lubricants, disintegrators, colouring agents and flavours.Despite the general perception that excipients are harm-less there is growing evidence of adverse reactions tothese so-called inert substances.

Adverse drug reactions (ADRs) were studied exten-sively from the 1960s through the early 1980s, primarilyin hospitals. The problem of ADRs was found to bewidespread and serious enough that in 1968 the WorldHealth Organization (WHO) started an ADR surveil-lance program, which continues today. Canada was one

of the 10 countries that founded the program.Barr2 published a retrospective study in 1955 in-

volving 1000 inpatients, 50 of whom had serious com-

Dr. Napke is a retired physician. He was the medical officer in charge of the Federal Adverse Drug Reaction Voluntary Reporting Program andthe Federal Poison Control Program for 25 years, until 1990. He was also the Canadian designate to the Drug Monitoring Program of theWorld Health Organizationfor 20 years.

Reprint requests to: Dr. Edward Napke, 124 Amberwood Cres., Nepean, ON K2E 2H8

CAN MED ASSOC J 1994; 151 (5) 529

Resume: Les effets indesirables des excipients et desadditifs dans les formules de medicament posent desrisques senieux pour la sante des patients. Toutefois, onne connait pas l'etendue du probleme. Les reactions auxexcipients et aux additifs peuvent ne pas etre reconnuesou signal6es parce que les professionnels de la sante neconnaissent pas les ingredients de la plupart des for-mules de medicament. Mais le plus grave est que cemanque d'information, outre l'opinion repandue selonlaquelle les excipients sont inertes et sans danger, porteles intervenants a chercher ailleurs ou a jeter le blamesur l'ingredient actif quand se produit un effet indesi-rable. Les renseignements relatifs aux ingr6dients dansles formules des medicaments devraient etre transmisnon seulement aux medecins mais aussi aux patients.Ceux qui sont allergiques ou hypersensibles aux exci-pients ont le droit de se prot6ger contre ces substances.Par cons6quent, tous les ingredients d'un medicamentdevraient obligatoirement etre imprimes sur l'6tiquettedu produit. L'6tiquetage est d'autant plus necessaire queles excipients de bon nombre de medicaments se re-trouvent egalement dans les aliments, les medicamentsgrand public, les produits de beaut6 et autres produits.Par consequent, s'ils ne sont pas informes par un etique-tage approprie des medicaments et de tous les autresproduits, les patients peuvent imgerer une quantite toxi-que d'excipients provenant de nombreuses sources.

*-- For prescribing information see page 681

plications of therapeutic or diagnostic procedures.Schimmel' followed 1000 patients over 8 months andfound that 148 had had reactions to drugs. For 1 yearOgilvie and Ruedy4 followed patients admitted to a 53-bed general medical ward and found that 18% had oneor more adverse reactions while in hospital. Another 8%of patients were admitted because of an adverse reaction,and 1% were admitted for other problems but had beensuffering an adverse reaction at the time. Hospital staysof patients with drug reactions were almost twice as longas those of patients with no reactions.

Hurwitz and Wade5 diagnosed reactions in 118 of1268 patients examined. They found an exponential rela-tion between the number of medications a patient wastaking and the likelihood of an ADR.

Caranasos, Stewart and Cluff6 followed 7423 pa-tients and found that 12.5% had adverse reactions.Borda, Stapleton and IF examined 936 patients admittedover 3 years to an intensive monitoring ward that wasparticipating in the Boston Collaborative Drug Surveil-lance Program and found 535 adverse reactions. Duringthose years a total of 75 373 patients were admitted tothe hospital and the hospital's voluntary reporting pro-gram identified 350 reactions. The rate of life-threaten-ing ADRs was 0.6% per drug exposure, lower than thatreported in Israel or the United States as a whole. In1969 the US National Institutes of Health (Bethesda)estimated that direct hospital costs to treat ADRs wereabout US $3 billion.8

Thus, ADRs are a widespread and serious problem.What portion of the problem is due to excipients is notknown, but I believe it is much larger than generallythought. Rarely is a patient given a pure chemical or "ac-tive ingredient" as a therapeutic agent. Each formulationmay contain 1 to about 30 excipients or additives. Excipi-ents include fluorotrichloromethane (Freon 11), dichloro-difluoromethane (Freon-12), phenol, benzyl alcohol,formaldehyde, sorbic acid, thimerosal, tartrazine and otherdyes, gluten, ethanol, aspartame, lactose, propylene gly-col, talc, povidone, polyethylene glycol, perfumes, lano-lin, polyethoxylated castor oil and sulfites.9

Although practitioners know the active ingre-dient- the therapeutic agent- in a drug formulation,they do not know the unlisted excipients. Inpatients inthe study by Borda and associates7 were taking morethan seven medications on average, meaning that eachpatient was exposed to some 8 to 100 substances. Someof these substances may have been in several of the for-mulations, which would increase the risk of a toxic reac-tion in a sensitive patient.

Outbreaks of ADRs or poisonings causedby excipients

There have been a number of serious ADRs causedby excipients. Geiling and Cannon'° reported 76 deathsfrom acidosis and renal failure following the use of elixir

of sulfanilamide. The excipient diethylene glycol wasfound to be the cause. There were later reports of morethan 100 deaths."' 12

The toxic nature of diethylene glycol was recog-nized again some 50 years later by Cantarell and collab-orators.' They described oliguria and acidosis in patientswith burns who were treated with topical antibacterialscontaining diethylene glycol. One could safely assumethat adverse reactions to diethylene glycol had continuedduring the intervening 50 years; failure to diagnose thesereactions may have resulted from diverse factors, includ-ing the belief that excipients were safe and ignoranceabout which excipients were found in drug formulations.

Dilantin, a brand of phenytoin, had been sold formany years in Australia and New Zealand when themanufacturer decided to change the formulation to theone used in the United States.'4 As a result, 51 patientswhose epilepsy was stable with the use of the old formu-lation had severe and serious adverse reactions, includ-ing coma, with the new product. The reformulation in-volved replacement of calcium sulfate dehydrate withlactose, a seemingly innocuous change. However, it ap-peared that the calcium salt slowed absorption of thephenytoin, whereas lactose speeded it up.

In 1982 benzyl alcohol was implicated in the "gasp-ing" syndrome and the deaths of premature infants whoreceived medication containing this excipient.' 156 Benzylalcohol was also the culprit in the exacerbation of asth-ma following intravenous administration of a hydrocorti-sone formulation.'

Single cases of adverse reactionsto excipients

The adage "out of sight, out of mind" almost al-ways holds true in the attribution of an adverse reactionto an unknown or undisclosed excipient in a drug formu-lation. In many investigations of an ADR, when the pa-tient showed a positive result of a challenge with thesuspected drug formulation, investigators concluded thatthe cause of the reaction was the active ingredient be-cause it was the only constituent known; the rest of theformulation was considered inert. Fortunately, a fewsceptics in the medical community investigated not onlythe drug formulation but also each substance in it andcombinations of ingredients.

In 1984 advice and help were sought in the man-agement of a recurrent upper respiratory tract infectionin a child.'8 The infection tended to be refractory becausethe patient was hypersensitive to penicillin and its deriv-atives. A liquid oral erythromycin preparation (125mg/mL) was prescribed. Immediately after taking thefirst dose, the patient suffered severe abdominal pain,nausea and vomiting. Doubting that the child had an al-lergy to erythromycin, the physician prescribed anotherformulation of erythromycin (250 mg/mL). With thisformulation the child suffered no adverse reaction; how-

530 CAN MED ASSOC J 1994; 151 (5) LE I er SEPTEMBRE 1994

ever, some time later, a local phannacist disregarded thephysician's "no substitution" order and substituted the125 mg/mL formulation. The child again experiencedthe pain, nausea and vomiting. When told of the conse-quences, the pharmacist responded, "The active ingredi-ent is the same; the colouring and flavour don't matter."In fact, the child had reacted to the tincture of orangeused as a colouring and flavouring agent in the 125mg/mL formulation. The 250 mg/mL preparation did notcontain tincture of orange, although the products weremanufactured by the same company.

Kwee and Dolovich'9 investigated the case of a man36 years of age who had suffered five episodes of unex-plained anaphylaxis over 6 years. The last attack, whichfollowed ingestion of a multivitamin tablet, had causedunconsciousness and a major generalized seizure, andthe patient had required treatment in an intensive careunit. The patient also had a history of hives after the useof some aftershave lotions. Ingestion of a multivitamin1 week later produced urticaria. The patient was givenskin tests for various substances in the multivitamintablet and had a positive result of a test for polyethyleneglycol, which was also found in the aftershave lotions.

Metabisulfite ingestion was a public hazard duringone period because vegetables in restaurant salad barswere sprinkled with the chemical to keep them fresh-looking. Ingestion of the treated vegetables resulted inanaphylaxis and death in some people.20 Allen and Col-lett2' reported respiratory arrest in a patient who hadbeen treated with an intravenous preparation of dexa-methasone, which, at the time, was formulated withmetabisulfite. In a study of 53 patients who had adversereactions and 20 control patients, Yang, Purchase andRivington22 found that at least some of the adverse reac-tions to metabisulfite were IgE-mediated.

Gross, Kitzman and Adams23 investigated an acuteand sometimes fatal collapse syndrome in humans,horses and cattle that had been attributed to reactions tooxytetracycline. Intravenous solutions of propylene gly-col, propylene glycol and oxytetracycline, and oxytetra-cycline alone were given to conscious calves fitted withintravascular catheters and electromagnetic flowmetertransducers in and on the pulmonary and renal arteries.The investigators found that the cardiac effects werecaused by the propylene glycol rather than by oxytetra-cycline. Janzen and McManus24 administered an oxy-tetracycline preparation to 395 steers and a controlpreparation that contained no oxytetracycline to 386. Re-actions occurred immediately in three of the steerstreated with oxytetracycline and in four steers in the con-trol group, two of which died. Something in the controlpreparation (placebo) was as toxic as the ingredients inthe oxytetracycline formulation.

Hamilton25 noticed an increase in adverse reactionsto the contrast media he used in a private diagnostic ra-diology clinic. After several years of investigation heconcluded that the additional ADRs were caused by 2-

mercaptobenzothiazole (MBT), a rubber vulcanizationagent that had leaked from stoppers and disposable sy-ringes into the solution.26

Lockey27 reported a case of a woman who was re-ferred to him after suffering adverse reactions to a conju-gated estrogen formulation. He found that by washingoff the colouring (tartrazine, also known as Food, Drugand Cosmetic Act- USA yellow dye no. 5) she couldtake her medication without ill effects. The formulationcontained 28 chemicals, 7 of which were known to havea toxic effect in humans.

Total chemical load of excipients

Total excipient intake and the total intake of specificexcipients by hospital inpatients and outpatients requirefurther study. As I discussed earlier, Hurwitz and Wade'found an exponential relation between the number of drugformulations a patient is exposed to and the chance of anadverse reaction. In the study by Borda and associates7 thepatients were exposed to more than seven drug formula-tions on average. Since the number of excipients in anyformulation ranges from a few to about 30, a patient maybe exposed to from 8 to 100 excipients. In addition, differ-ent products could contain one or more of the same excip-ients. Since these substances may also be contained infoods and beverages generally regarded as safe, the totalamount ingested by a patient taking several drug formula-tions is greatly increased and may reach toxic levels.

Articles on ADRs focus on acute episodes; chronicADRs, which especially affect people undergoing long-term drug therapy, have been insufficiently studied.Chronically ill patients may accumulate large amountsof excipients, to which are added the quantities in foods,beverages, other drugs, confections, cosmetics and otherpersonal products. The stress on the body's detoxifica-tion capacity may be enormous, particularly in patientswho are ill. Many substances have been judged "safe"on the basis of studies involving healthy animals, the re-sults of which must not be generalized to ill humans.The use of ill animals in parallel toxicity studies mayprovide a broader understanding of the toxicity factor.

The ubiquity of some excipients in drug fonnula-tions is remarkable. For example, in one study sulfites(including sodium or potassium bisulfite, sodium orpotassium metabisulfite, sodium sulfite and sulfur di-oxide) were found in 113 drug formulations.28 Miyata,Schuster and Schellenberg29 identified more than 130drug formulations in Canada in 1991 that contained sul-fites. Metabisulfites are also added to fresh and pro-cessed foods and to beverages such as wines.

Lactose, which is widely used in drug formulations,foods and beverages, causes adverse reactions usuallyclassified as lactose intolerance or sensitivity. In whitepeople 5% to 15% have various degrees of lactase defi-ciency and may experience abdominal pain, distensionor diarrhea after lactose ingestion.30 Lactase deficiency

CAN MED ASSOC J 1994; 151 (5) 531SEPTEMBER 1, 1994

affects 60% to 90% of people of other races.30 Lactoseintolerance in subjects may affect clinical studies inwhich lactose is used as a placebo or as a filler in a drugformulation. How many trial results have been con-founded by reactions to so-called placebos?

The need for reform

Prescription of a drug formulation is a form of"chemical surgery:" all of the ingredients in the productmay intrude on the body's functioning. We regard sur-gery as a serious procedure and ensure that the patient iswell informed of its harms and consequences. Prescrip-tion of drugs may be more serious, yet not even healthcare professionals are aware of the possible effects onthe patient.

I believe there is a need to review not only theprocess of putting a drug formulation on the market butalso the ADR surveillance system. To speed up identifi-cation and to prevent adverse reactions, the labels of allprescription drugs should disclose fully not only the ac-tive ingredients but also all excipients and additives.This will allow patients, their families and health careprofessionals to take the first step toward solving drug-efficacy or adverse-reaction problems. It is imperative toknow what chemicals have been prescribed for a patientwithout having to ask the manufacturer. Full disclosureon the drug label will also be invaluable to poison-control and emergency-treatment measures.

There have been arguments that such disclosureposes difficulties; however, Searle Canada Inc. (Oak-ville, Ont.) announced in 1988 a voluntary policy of fulldisclosure on the labels of its products. McNeil Con-sumer Products Company (Guelph, Ont.) soon followedsuit. Other companies have listed all of the excipients intheir products in the 1993 Compendium of Pharmaceuti-cals and Specialties.28 These are positive steps; however,all manufacturers should fully disclose excipients intheir products. As well, this information should be avail-able not only to physicians but also to patients so thatthey can question pharmacists and physicians. I believethat patients have the right to know what chemicals, inaddition to active ingredients, are unwittingly prescribedfor them. This may necessitate a change in pharmacypractice to dispensing from the original product packageor to providing a printout of all the excipients in drugformulations that have been removed from the package.

Mandatory inclusion of nonmedicinal ingredientson product labels has been debated in the House ofCommons.333 In 1989 a motion was passed to amend theFood and Drug Regulations to require such labelling.34As a result, the Department of National Health and Wel-fare (now Health Canada) sponsored amendments to theregulations; however, these amendments have remainedat the proposal stage.35 36

Full disclosure on labels of all ingredients in a drugproduct will allow knowledgeable patients, pharmacists

and physicians to prevent adverse reactions from knowncauses and to discover the cause of many reactions.

I thank Cyril Nair for word processing of this article.

References

1. Dorland's Illustrated Medical Dictionary, 27th ed, WB Saunders,Philadelphia, 1988

2. Barr DP: Hazards of modem diagnosis and therapy- the pricewe pay. JAMA 1955; 159: 1452-1456

3. Schimmel EM: The hazards of hospitalization. Ann Intern Med1964; 60: 100-110

4. Ogilvie R, Ruedy J: Adverse drug reactions during hospitaliza-tion. Can Med Assoc J 1967; 97: 1450-1457

5. Hurwitz N, Wade OL: Intensive hospital monitoring of adversereactions to drugs. BMJ 1969; 1: 531-536

6. Caranasos GJ, Stewart RB, Cluff LE: Drug induced illness lead-ing to hospitalization. JAMA 1974; 228: 713-717

7. Borda IT, Napke E, Stapleton C: Drug surveillance data in aCanadian hospital. Can Med Assoc J 1976; 114: 517-522

8. Melmon KL: Preventable drug reactions - causes and cures.N EngliJ Med 1971; 284: 1361-1368

9. Golightly LK, Smolinski SS, Bennet ML et al: Pharmaceutical ex-cipients. Med Toxicol 1988; 3: 128-165

10. Geiling EMK, Cannon PR: Pathologic effects of elixir of sulfanil-amide (diethylene glycol) poisoning; clinical and experimentalcorrelations: final report. JAMA 1939; 1 1 1: 919-926

11. Leech PN: Elixir of sulfanilamide-Massengil: II. JAMA 1937;109: 1724-1725

12. Calvery HO, Flump TG: The toxicity for human beings of di-ethylene glycol with sulfanilamide. South Med J 1939; 32:1105-1109

13. Cantarell MC, Fort J, Camps J et al: Acute intoxication due totopical application of diethylene glycol. Ann Intern Med 1987;106: 473-479

14. Tyrer JH, Eadie MJ, Sutherland JM et al: Outbreak of anticonvul-sant intoxication in an Australian city. BMJ 1970; 4: 271-273

15. Gershanik J, Boecler B, Ensley H et al: The gasping syndromeand benzyl alcohol poisoning. N Engl J Med 1982; 307:1384-1388

16. Brown WJ, Buist NRM, Gipson HTC et al: Fatal benzyl alcoholpoisoning in a neonatal intensive care unit. [abstract] Lancet1982; 1:1250

17. Grant JA, Bilodeau PA, Guernsey BG et al: Unsuspected benzylalcohol hypersensitivity. [letter] N Engl J Med 1982; 306: 108

18. Napke E, Stevens DGH: Excipients and additives: hidden hazardsin drug products and in product substitution. Can Med Assoc J1984; 131: 1449-1452

19. Kwee YN, Dolovich J: Anaphylaxis to polyethylene glycol (PEG)in a multivitamin tablet, part 2. [abstract 181] J Allergy Clin Im-munol 1982; 69 (suppl): 138

20. Sulfite uptake. FDA Drug Bull 1984; 14: 2421. Allen DH, Collett P: Life threatening asthmatic reactions to food

and drug preservative sodium metabisulfite. J Allergy Clin Im-munol 1981; 68: 67-71

22. Yang WH, Purchase ER, Rivington RN: Positive skin tests andPrausnitz-Kustner reactions in metabisulfite-sensitive subjects.J Allergy Clin Immunol 1986; 78: 443-449

23. Gross DR, Kitzman JV, Adams HR: Cardiovascular effects of in-travenous administration of propylene glycol and of oxytetracy-dline in propylene glycol in calves. Am J Vet Res 1974; 40:783-791

24. Janzen ED, McManus RF: Observations on the use of a long-act-ing oxytetracycline for intact prophylaxis of undifferentiatedbovine respiratory disease in feedlot steers under Canadian condi-tions. Bovine Pract 1980; 15: 87-90

25. Hamilton G: Contamination of contrast agent by MBT in rubber

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seals. [letter] Can Med Assoc J 1987; 136: 1020-102126. Hazards from use of disposable syringes. Alert Medical Services

no 60, Health Protection Branch, Department of National Healthand Welfare, Aug 31, 1983

27. Lockey SD Sr: Reactions to hidden agents in foods, beveragesand drugs. Ann Allergy 1971; 29: 461-466

28. Compendium of Pharmaceuticals and Specialties, 28th ed, Can-adian Pharmaceutical Association, Ottawa, 1993: B70-B71

29. Miyata M, Schuster B, Schellenberg R: Sulfite-containing Can-adian pharmaceutical products available in 1991. Can Med AssocJ 1992; 147: 1333-1338

30. Toskes PP: Malabsorption. In Wyngaarden JB, Smith LH Jr, Ben-

nett JC (eds): Cecil Textbook ofMedicine, 19th ed, WB Saunders,Philadelphia, 1992: 687-699

31. Canada, HC Debates, 157 at 8183-8192 (Aug 18, 1987)32. Canada, HC Debates, 55 at 3238-3249 (June 19, 1989)33. Minutes of Proceedings and Evidence of the Standing Committee

in National Health and Welfare: Proposed Drug Labelling Regu-lations, House of Commons, Ottawa, July 14, 1988

34. Canada, HC Debates, 81 at 1 (Oct 23, 1989)35. Food and Drug Regulations-Amendment, C Gaz 1989.1.5215 at

522436. Food and Drug Regulations-Amendment, C Gaz 1994.1.859 at

872

Conferencescontinuedfrom page 526

Sept. 16-18, 1994: 6th National Conference on OutreachEducation: the Changing Colours of Outreach Education(presented by the Four Corners Coalition on ContinuingEducation)

Durango, Colo.Study credits available.Joann Bauer, conference coordinator, Office of Continuing

Medical Education, University of Colorado Health SciencesCenter, PO Box C-295, 4200 E 9th Ave., Denver, CO 80262;tel (303) 372-9050 or 1-800-882-9153, fax (303) 372-9065

Sept. 16-19, 1994: Quality of Life: Women and BreastCancer

TorontoRegistration coordinator, Community Resources and

Initiatives, 106-344 Dupont St., Toronto, ON M5R 1V9;tel (416) 924-8998, fax (416) 924-8352

Du 17 au 21 sept. 1994: 10e Congres international sur lessoins aux malades en phase terminale (presente par laDivision des soins palliatifs, Departement d'oncologie,Universite McGill, et co-commandite par l'Organisationmondiale de la sante)

MontrealLes Services de congres GEMS, 10e Congres international,

710-759, Square Victoria, Montreal, QC H2Y 2J7;tel (514) 485-0855, fax (514) 487-6725

Sept. 17-21, 1994: 10th International Congress on Care ofthe Terminally Ill (presented by the Palliative CareDivision, Department of Oncology, McGill University, andcosponsored by the World Health Organization)

MontrealGEMS Conference Services, 10th International Congress,

701-759 Victoria Square, Montreal, PQ H2Y 2J7; tel (514)485-0855, fax (514) 487-6725

Sept. 18-23, 1994: 12th International Congress ofNeuropathology (in conjunction with the annual meetingsof the Canadian Association of Neuropathologists and theAmerican Association of Neuropathologists)

TorontoDr. J.J. Gilbert, Department of Pathology, Victoria Hospital,PO Box 5375, London, ON N6A 4G5; tel (519) 667-6649,fax (519) 667-6749

Sept. 23-24, 1994: 3rd Annual International Sports MedicineSymposium- Instabilities: a-Global Approach (presentedwith the Sports Medicine Council of Alberta)

EdmontonDr. Lisa Stevenson, Glen Sather Sports Medicine Clinic, E-05Van Vliet Centre, University of Alberta, Edmonton, ABT6G 2H9; tel (403) 492-4752, fax (403) 492-1637

Sept. 24-30, 1994: 14th World Congress of Gynecology andObstetrics (FIGO '94)

MontrealOfficial languages: English, French and SpanishStudy credits available.FIGO '94 Congress Secretariat, 100-4260 Girouard Ave.,

Montreal, PQ H4A 3C9; tel (514) 485-0855, fax (514)487-6725

Du 24 au 30 sept. 1994: 14e congres mondial de gynecologieet d'obstetrique (FIGO '94)

Montr6alLangues officielles : l'anglais, leffrangais et l'espagnolCredits d'education medicale continue.Secretariat du congres FIGO '94, 100-4260, ave. Girouard,

Montr6al, QC H4A 3C9; tel (514) 485-0855, fax (514)487-6725

Du 29 sept. au Ier oct. 1994 : Conference intemationale surles effets preventifs et therapeutiques des supplementsnutritionnels dans le traitement des maladies chroniques

TorontoSecretariat de la conf6rence sur les supplements nutritionnels,

a/s Association des hopitaux du Canada, 100-17, rue York,Ottawa, ON KIN 9J6; tel (613) 241-8005, fax (613)241-5055

Sept. 29-Oct. 1, 1994: International Conference on AdjuvantNutrition and Chronic Disease: Preventive and TherapeuticEffects

TorontoAdjuvant Nutrition Conference Secretariat, c/o Canadian

Hospital Association, 100-17 York St., Ottawa, ONKIN 9J6; tel (613) 241-8005, fax (613) 241-5055

continued on page 542

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