SPECIAL ARTICLE

HAZARDS OF MODERN DIAGNOSIS AND "THERAPY-THE PRICE WE PAY

FRANK BILLINGS MEMORIAL LECTURE

- David P. Barr, M.D., New York

"First of all, be sure you do no harm: Primum non nocere." In all ages this admonition has been fundamental to the practice of medicine. It applied to the use of all the empirical drugs of ancient and medieval times. Failure to regard it inspired the scathing satires of Molière and was responsible for the research of Pierre Louis and the reforms of Oliver Wendell Holmes and Ignaz Semmelweis. The admonition applied in the age of nihilism, when most of the useless drugs of the past had been abandoned and when Osler could find only a dozen or so to recommend for detailed study by his students. Even then, the few great drugs were as well known for their toxic as for their therapeutic effects. Mercury, the recognized specific for syphilis, could cause salivation and loosening of teeth as well as irreparable renal damage. In slight overdosage, digitalis, so helpful in dropsy, was responsible for frequent discomfort and occasional sudden death. The admonition applied during the last half century, when we saw enthusiastic introduction of many therapeutic measures later recognized as unkind, futile, or hazardous. We can shudder now when we remember outdoor treatment of pneumonia, cold tub baths for typhoid, starving of fevers, and withdrawal of water in cholera. We hesitate to think of the harm unwittingly done by the use of aminopyrine, cinchophen, and dinitrophenol. Their wrongful use and many other errors plague our recent past and make us insecure in our present judgments.

Today, when multitudes of new and relatively untried diagnostic and therapeutic procedures form an integral part of the practice of medicine, the admonition "Be sure you do no harm" applies more than ever before. Diagnostic methods formerly simple are becoming increasingly complex and formidable. Sanctioned practice includes use of injections of organic substances for visualization of liver, gallbladder, urinary tract, bronchi, lungs, heart, blood vessels, and spinal canal; air injections for visualization of the brain; cystoscopies, bronchoscopies, esophagoscopies, and gastroscopies; punctures with large needles of bone marrow, liver, and even of lungs, spleen, and kidneys; and catheterization of the great vessels and heart. Therapeutic preparations are confusingly numerous and varied. In the lists of 1953, more than 140,000 medicaments were available to practitioners, and 14,000 new preparations were added during the year. Accretion is still far greater than deletion, although it has been estimated that perhaps 90% of drugs now in common use have been introduced within the last 25 years.'

Although incalculable benefits have come to mankind with the introduction of these newer diagnostic and therapeutic procedures, hazards of medical management have at the same time enormously increased. Not one of the occasionally indispensable diagnostic tests may be undertaken without risk. The simplest as well as the most complicated possesses inherent danger. Infection may be introduced by a needle; sudden death may follow the intravenous administration of such a relatively inert. substance as dehydrocholic acid (Decholin). Furthermore, no agent that can modify the internal environment or organic integrity of the body can be used without hazard. As yet no drug has been found with a single action, and no human body with a single reaction. Risks accompany the use even of those remedies that are regarded as safest. Acetylsalicylic acid is usually given with apparent impunity; yet coryza, bronchospasm, conjunctival injection, eruptions, thrombocytopenic purpura, fever, shock, cardiovascular collapse, and death have followed its use. Although penicillin is correctly regarded as the least toxic of potent chemotherapeutic agents, Welch, Lewis, and Kerlan estimated that from its use 100 to 200 acute anaphylactic-like reactions Occur each year."

These accidents, risks, and dangers may be regarded as the price that we, as responsible physicians must pay for the inestimable benefits of modern diagnosis and therapy. They are the hazards to which, with best intent and most correct practice, we must occasionally subject our patients. In the following discussion about the price we must pay for modern management of disease, care has been taken to exclude from consideration all examples of carelessness, misconduct, malpractice, as well as the use of nostrums, patent medicines, and other unacceptable or condemned remedies. It is believed that all the herein-cited accidents and misfortunes may result on occasion even with enlightened thoughtful use of diagnostic and therapeutic measures by conscientious and well-informed physicians earnestly trying to help their patients. Since even a list of possible dangers would be too cumbersome, examples have been chosen arbitrarily as illustrative of the extent and variety of hazards in our daily work. For orderly presentation, they have been arranged under headings representative both of types of unfavorable responses and of special accidents that may arise in the use of single agents or groups of agents having similar actions.

ACCIDENTAL DRUG INTOXICATION

One of the great hazards in the use of potent drugs is their inherent toxicity that, with wide individual variation, will develop intoxication in any patient if the dose is large enough. An outstanding example is digitalis, in the use of which only a narrow margin separates thera

Read before the Section on Internal Medicine at the 104th Annual Meeting of the American Medical Association, Atlantic City, June 8, 1955. 1. Brown, E. A.: Problems of Drug Allergy, J.A.M.A. 1571814 (March 5) 1955.

2. Brown, E. A.: Drug Allergy, Quart. Rev. Allergy 7:51, 1953. 3. Welch, H.; Lewis, C. N., and Kerian, I.: Blood Dyscrasias: A Nationwide Survey, Antibiotics & Chemother. 41 607, 1954.

"pyrazinamide," methyltestosterone," phenyl"one," and other agents whose toxic or idiosyncratic ɔns are as yet only partially evaluated.

SPECIAL INSTANCES OF INTOXICATION ibiotics.-Because of the enormous usage of antiintoxication assumes a prominent role even 1 it may be statistically infrequent. No antibiotic yet been found free from hazards or disadvanThe side-actions and toxic effects of penicillin have numerous. In addition to the sometimes fatal anatic responses, there are eruptions of the most e type, all manifestations of serum sickness, disices of renal function, hypotension, cardiovascular se, or unconsciousness; there may be hematological Dances as various as anemia, agranulocytosis, philia, and hypothrombinemia.

their entirety, toxic reactions attributable to antiand chemotherapy are impressive." Anaphylactic ons have been reported occasionally from most, ali, of the agents derived from fungi. Hepatic dyson has followed the use of streptomycin, chlortetra(Aureomycin), oxytetracycline (Terramycin), loramphenicol. Renal impairment has been noted treptomycin therapy and appears as a toxic effect ing administration of bacitracin, neomycin, and yxin. The incidence of aplastic anemia and other ological dyscrasias developing during the use of mphenicol has been subjected to searching ination by Welch and associates. Difficulties inherattribution of toxic action to any drug appeared ir study. In this instance, as in others, history of ure did not establish proof of causation of unfae symptoms. While circumstantial evidence indithat administration of chloramphenicol was folby an increased incidence of bone marrow depresstatistical proof of its action was not established, remained questionable whether chloramphenicol entially more toxic than some other antibiotics record of toxicity has excited less attention. orable actions of sulfonamides that in some measive been lost to view because of their replacement er agents in many therapeutic situations are numer nd include fever, eruptions, blood dyscrasias, and

is.

the least of the toxic symptoms associated with otics is irritation of the gastrointestinal tract that is ularly severe after the use of tetracycline derivaNot infrequently, administration of these drugs has ollowed by invasion of the intestinal tract by drugint staphylococci causing infection that may be inless administration of the offending drugs is dissued and erythromycin therapy instituted." Less s effects of antibiotics are the development of myinfections in the mouth and in the gastrointestinal ind of vitamin deficiencies attributable to bacterioaction on the normal intestinal flora.

isone, Hydrocortisone, and Corticotropin (ACTH). favorable reactions from the long-term adminis1 of cortisone, hydrocortisone, and corticotropin H) are well known. In addition to the obesity, tension, hirsutism, and osteoporosis of adrenal coryperfunction (Cushing's syndrome), reactions may

include increased susceptibility to infection, hindrance of wound healing, or exacerbation of ulcers in the stomach and intestinal tract. A considerable danger results also from rapid withdrawal of the agents after prolonged

use."

Antihistaminics.-The antihistaminic agents, of which there are now no less than 20, must be regarded as serious causes of intoxication, more particularly since their use is chiefly among patients who are not seriously ill. Several fatalities have been attributed to them. Their side-effects, especially those observed on the nervous system, are so numerous and sometimes so severe as to suggest that their use is actually more hazardous than that of sulfonamides and antibiotics employed for the most part in treatment of infections that might otherwise result in death."

Phenylbutazone and Chlorpromazine.—Phenylbutazone is a congener of aminopyrine, and its toxic effects, particularly on bone marrow, are reminiscent of the unfortunate experiences with aminopyrine. Side-effects are numerous and sometimes serious; they include edema, eruptions, and unfavorable actions on the gastrointestinal tract, hematopoietic system, central nervous system, and heart. Fatal hepatitis has recently been reported." It is perhaps illustrative of illogical practice that the use of aminopyrine was sharply limited by disclosure of rare instances of intoxication, while the use of a phenylbutazone may now be actually increasing. Current brochures describing clinical uses of chlorpromazine under the name of Thorazine mention its applicability for relief of nausea and vomiting, mental and emotional disturbances, alcoholism, intractable pain, and hiccoughs. Suggestions are included for its use in correction of nausea and vomiting caused by other drugs, such as diethylstilbestrol (Stilbestrol), digitalis, nitrogen mustards, broad-spectrum antibiotics, and general ancs

11. (u) Zatuchni, J., and Miller, G.; Jaundice During Chlorpromazine Therapy, New England J. Med. 251: 1003, 1954. (b) Lemire, R. E., and Mitchell, R. A.: Regurgitation Type Jaundice Associated with Chlorpromazine ("Thorazine," SKF 2601-A) Administration, J. Lab. & Clin. Med. 44: 825, 1954. (c) van Ommen, R. A., and Brown, C. H: ObstrucLive-Type Jaundice Due to Chlorpromazine (Thorazine): Report of 3 Cases, J.A.M.A. 157:321 (Jan. 22) 1955. (d) Hodges, H H., and LuZerte, G. D. Jaundice and Agranulocytosis with Fatality Following Chlorpromazine Therapy, ibid. 158: 114 (May 14) 1955.

12. McDermott, W., and others: Pyrazinamide-Isoniazid in Tuberculosis, Am. Hev. Tuberc. GD: 119, 1954.

13. Werner, S. C.; Hanger, F. M., and Kritzler, R. A.: Jaundice During Methyl Testosterone Therapy, Ain. J. Med. 8:325, 1950.

14. Engleman, E. P., and others: Hepatithy Following the Ingestion of Phenylbutazune, J.A.M.A. 154:98 (Sept. 11) 1954.

15. Wilensky, A. O.: Fatal Delayed Anaphylactic Shock After Penicillin, Correspondence, JAMA. 131:1384 (Aug. 17) 1946. Waldbott, G. L.; Anaphylactic Death from Penicillin, ibid. 139: 526 (Fcb. 19) 1949, Thornson, W. O.: Sudden Death Following an Injection of Penicillin, Lot M. J. 2: 73, 1952. Christensen, W. N., Hedrick, G. W., and Schugmann, R. F. Fatal Anaphylactic Reaction Following Penicillin Injection, U. S. Armed Forces M. J. 4:249, 1953.

16. Kutscher, A. H.; Lane, S. L., and Segall, R.: The Clinical Toxicity of Antibiotics and Sulfonamides: A Comparative Review of the Literature Based on 104,672 Cases Treated Systemically, J. Allergy 25: 135, 1954, 17. Jackson, G. G., and others: Terramycin Therapy of Pneumonia: Clinical and Bacteriologic Studies in 91 Cases. Ann. Int. Med. 3511175, 1951. Williams, E.: Staphylococcal Pseudomembranous Enterocolitis Complivating Treatment with Aureomycin. Lancet 2: 999, 1954.

18. Ragan, C.: Corticotropin, Cortisone, and Related Steroids in Clinical Medicine: Practical Considerations, Bull. New York Acad. Med. 291 355, 1951.

19. Wyngaarden, J. B., and Seevers, M. H.: The Toxic Effects of Antihistaminic Drugs, J.A.M.A. 143: 277 (Feb. 3) 1951.

20. Hlemming. A. and Kuzell, W. C.: The Pharmacologic and Clinical Characteristics of Phenylbutazone (Butazolidin), Antibiotics & Chemother. 3:614, 1951.

21. Deleted on proof.

peutic and toxic dosage. In spite of the availability of highly purified crystalline preparations, the dangers of the drug appear to be greater now than ever before. This situation can be attributed to several factors. Among them are dogmatic insistence upon oversimplification of dosage and prevalence of rapid digitalization and intravenous administration. Other factors are related to the use of digitalis in older patients in whom life has been prolonged by other measures and in whom the myocardium is more susceptible to the action of the drug because the failure is more severe. Also implicated is the variable responsiveness to digitalis that results from increasing dependence in cardiac therapy on the manipulation of electrolytes by restriction of sodium in the diet, the stimulation of sodium excretion by mercurial diuretics, and the use of ammonium chloride, cation exchange resins, carbonic anhydrase inhibitors, and cortisone. Whatever may be the factors, the use of digitalis constitutes today one of the most frequent causes of "iatrogenic" disease. Toxic actions are illustrative of the dangers that may be encountered with less well studied and newer drugs. Similar hazards are inherent in the administration of such drugs as scopolamine, curare, and bishydroxycoumarin (Dicumarol), the dangers of which are less important only because these drugs are less frequently used.

MODIFICATION OF INTERNAL ENVIRONMENT

Although the homeostasis of the body is modified by a vast number of drugs in ways but vaguely appreciated, it is most strikingly changed by parenteral injection of fluids of variable composition and by agents that modify the rate of excretion of water, electrolytes, and other substances through kidneys or intestine. Modifications that can be produced by these measures are alarming in variety and degree and only partially predictable. Sodium may be seriously depleted, not only by the sweating that results from hot weather and by restriction of sodium in the diet, but by mercurial and other diuretics. Potentially serious hypopotassemia, with its muscular weakness and cardiac complications, may be promoted by many factors, including acidosis, intravenous injection of glucose and insulin, and the administration of ammonium chloride, commonly used resins, a carbonic anhydrase inhibitor, cortisone, or desoxycorticosterone acetate. Alkalosis and hypochloremia with their baffling nervous and mental symptoms may follow administration of large amounts of alkalis, such as sodium bicarbonate and sodium lactate or may result from gastric suction with removal of excessive amounts of gastric hydrochloric acid. Severe hyperchloremic acidosis with its simulation of cerebral vascular accidents, terminal renal disease, and other forms of acidosis may accompany treatment of heart failure with mercurial diuretics. Acidosis with many troublesome symptoms may follow the administration of ammonium chloride." These and many other reactions from the use of parenterally given fluids and diuretics are illustrative of the general principle that no modification of homeostasis can be simple and that the manipulation of one factor by drugs or fluids may have unpredictable and subtle effects on another.

INTRODUCTION OF INFECTION

Entry by needles or other instruments into tissues, vessels, or cavities of the body always involves some risk of infection. After cystoscopy bacteremia is not infrequent, and infection of the urinary tract, with or without septicemia, is an occasional complication. It is sus pected that the virus of homologous serum jaundice has been introduced by insufficiently sterilized needles in punctures of fingers, ears, or veins. Transfusions may be the source of serious blood stream infections. Recent reports have shown that blood banking, a practice that has saved many lives by making blood readily available, has also introduced new hazards of infection. The pos sibility of carrying bacteria into the blood du ing its removal from the donor can not be entirely excluded, and, in rare instances, relatively nonpathogenic bacteria of the Pseudomonas group may accumulate in blood stored at icebox temperature in amounts sufficient to cause fatal intoxication. A much more frequent accident from transfusions is the introduction of the virus of homologous serum jaundice. It is known that a healthy person with no history of hepatitis or jaundice and exhibiting no clinical or laboratory evidence of liver dis ease may nevertheless carry the virus in his blood. Danger is great from transfusions of whole blood and is much greater from the use of plasma from plasma pools. Since there is at present no known effective method of prevention, hepatitis must be regarded as one of the cal culated risks of blood transfusion.10

ALLERGIC REACTIONS

More than 500 separate drugs are known to cause allergic reactions.' The unfavorable effects may be expressed by simulation of serum sickness, by the more violent reactions of anaphylaxis, or by affection of one or more of the organs of the body: the skin, bone mar row, lungs, liver, or kidneys. There is great variety and separateness in the response of individual patients to individual drugs. While many drugs cause reactions, there are only a few ways in which the body can react. Thus, the function of bone marrow can be seriously disturbed in an almost identical manner by antibiotic agents, sulfonamides, antihistaminic agents, antimalarials, barbiturates, some heavy metals, amphetamine, urethane, phenylbutazone, glyceryl trinitrate (nitroglycerin), meperidine hydrochloride, and thiouracil.' Drugs causing urticaria and other allergic skin reactions are still mor numerous. Injury of the liver by action thought to be allergic is encountered with increasing frequency and has been reported after the use of chlorpromazine (Thora

4. Lown, B., and Levine, S. A.: Current Concepts in Digitalis Therap Boston, Little, Brown & Company, 1954.

5. Schroeder, H. A.: Renal Failure Associated with Low Extracellular Sodium Chloride: The Low Salt Syndrome, J.A.M.A. 141: 117 (Sept. 1 1949.

6. Darrow, D. C.: Medical Progress: Body-Fluid Physiology The Relation of Tissue Composition to Problems of Water and Electrab Balance, New England J. Med. 233191, 1945. Lown and Levine' 7. Grace, W. J., and Barr, D. P.: Complications of Alkalosis, An J. Med. 4:331, 1948.

8. Schwartz, W. B., and Wallace, W. M.: Electrolyte Equilibrium During Mercurial Diuresis, J. Clin. Invest. 30: 1089, 1951.

9. Slelsenger, M. H., and Freedberg, A. S.: Ammonium Chleria Acidosis: Report of 6 Cases, Circulation 1837, 1951.

10. (a) Wiener, A. S.: Prevention of Accidents in Blood Transfusion. J.A.M.A. 156: 1301 (Dec. 4) 1954. (b) Stevens, A. R., Jr., and other Fatal Transfusion Reactions from Contamination of Stored Blood by Call Growing Bacteria, Ann. Int. Med. 30: 122, 1953.