Some Adverse Drug Reactions Common in the Postoperative Period

Some Adverse Drug Reactions Common in the Postoperative Period GUSTAVUS A. PETERS, M.D. J. PAUL MARCOUX, M.D.

The incidence of adverse drug reactions among hospitalized patients has been reported as 15% and 10% by Cluff and by Schimmel, respectively. Beaty and Petersdorf emphasized the importance of iatrogenic factors in the treatment of infectious disease and made suggestions for their elimination. For various reasons, physicians in general tend to under-report adverse drug reactions, which probably occur more often than is actually reported. This paper will review some of the more common types likely to be seen in the postoperative patient. Koch-Weser and associates have defined an adverse drug reaction as "any noxious change in a patient's condition which a physician suspects may be due to a drug, which occurs at dosages normally used in man, and which (1) requires treatment, or (2) indicates decrease or cessation of therapy with the drug, or (3) suggests that future therapy with the drug carries an unusual risk in this patient." They do not include trivial or expected side effects, nor results of accidental or deliberate overdosage. In contrast, the Food and Drug Administration (FDA) defines an adverse experience as "any noxious-pathologic and unintended change in the structure (signs), function (symptoms), and chemistry (laboratory data) of the body that is not a part of the disease and is linked with any substance used in the prophylaxis, diagnosis, or therapy of disease or for the modification of the physiologic state." And further, "an adverse experience is a suspected adverse reaction but has inadequate though authentic backing, whereas an adverse drug reaction is one with both adequate and authentic backing." In the 41f2 years since our adverse drug reporting program was started at the Mayo Clinic-that is, from July 1964 to December 31, 1968-there have been 761 adverse reactions reported. Of these, 264 were due to antibiotics: penicillin and its analogues caused 181, erythromycin and cephalothin 12 each, tetracycline 7, and streptomycin 6. Next came the tranquilizers and hypnotics with 85 reactions, of which the Surgical Clinics of North America- Vol. 49, No.5, October, 1969

1123

1124

GUSTAVUS

A.

PETERS,

J.

PAUL MARCOUX

phenothiazines caused 31, glutethimide (Doriden) 10, and ethchlorvynol (Placidyl) 10. The diagnostic media produced 76 reactions, half of which were due to Renovist (meglumine and sodium diatrizoate). The sulfa drugs caused 52, and the thiazides 22, the remainder being of scattered distribution. We do not believe that these are all the adverse drug reactions that occurred at the Mayo Clinic and the affiliated hospitals, but all of the 761 were bona fide instances checked not only by the resident but also by the consultant, by an FDA reporter, and finally by the coordinator of the program (G.A.P.). There was an average of about 15 adverse drug reactions per month.

INCOMPATIBILITIES POSSIBLE IN INTRAVENOUS THERAPY Studying adverse drug reactions from the standpoint of the postoperative patient, we can start with the incompatibilities that arise from intravenous therapy, since the patient has to rely on parenteral fluids for his nutrition, electrolytes, and drugs in the immediate postoperative period. The postoperative patient almost always has an indwelling intravenous catheter, which not uncommonly causes local phlebitis with associated soreness and inflammation. Polyvinyl chloride tubing contains stabilizing compounds which may leach out during use and cause tissue irritation. It has been pointed out that only plastics which have passed the USP rabbit-muscle implantation test should be used. (Several of the antibiotics-amphotericin B, tetracyclines, erythromycin, vancomycin, cephalothin, and nafcillin - irritate the veins and can cause chemical phlebitis. Sulfa salts irritate the tissues because of their alkalinity. Levarterenol [Levophedl is well known to cause tissue sloughing if it escapes from the veins.) Sometimes the 5% glucose solution produces phlebitis because of an adjustment of its pH by the manufacturer to prevent caramelization of the glucose during sterilization. Often drugs, electrolytes, glucose, and vitamins are added to the intravenous bottle, and various intravenous fluids may have physical, chemical, or pharmacologic incompatibilities. 20 ,30 Proper attention has to be paid to the pH and temperature of the solution at the time of mixing, and also attention must be given to the time elapsed after mixing, because the ingredients can become inactivated. If tetracycline and novobiocin are mixed in the same bottle, the fluid turns cloudy, demonstrating a physical incompatibility. Various oxidants and buffers can change the pH of a solution and inactivate the drugs. For instance-as pointed out by Conrad O. Thompson, Research Pharmacist, Rochester (Minn.) Methodist Hospital-if the surgeon should decide to mix 500 mg of tetracycline hydrochloride, 1 vial of vitamin B complex with C, 20,000,000 units of potassium penicillin G, and 40 mEq of potassium chloride solution, the yellow solution that results is clear, but its components are incompatible, and the solution

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1125

is unstable. The tetracycline is acid and contains 1500 mg of ascorbic acid as the buffer. Ascorbic acid inactivates the penicillin G, which is stable at a pH of 6.4. The potassium penicillin G contains 34 mEq of potassium which - together with the 40 mEq of potassium chloride that is added to the bottle-makes 74 mEq of potassium, which may be

Table 1.

Incompatibilities of Commonly Used Drugs for Intravenous Administration':'

AGENT

INCOMPATIBLE AGENTS

Antibiotics Amphotericin Bt Cephalothin Chloramphenicol Methicillin t Nafcillin Potassium penicillin G Polymyxin B Tetracyclines§ Vancomycin

Potassium penicillin G, tetracyclines Calcium chloride or gluconate, erythromycin, polymyxin B, tetracyclines B-complex vitamin preparations, hydrocortisone, polymyxin B, tetracyclines, vancomycin Tetracyclines B-complex vitamin preparations Amphotericin B, ascorbic acid, metaraminol, phenylephrine, tetracyclines, vancomycin Cephalothin, chloramphenicol, heparin, tetracyclines Amphotericin B, cephalothin, chloramphenicol, heparin, hydrocortisone, methicillin, potassium penicillin G, polymyxin B Chloramphenicol, heparin, hydrocortisone, potassium penicillin G

Pressors Ephedrine Epinephrine Mephentermine Metaraminol Phenylephrine"':'

Hydrocortisone Mephentermine Epinephrine Potassium penicillin G Potassium penicillin G

Miscellaneous Aminophylline B-complex vitamin preparations Barbiturates and tranquilizers Calcium chloride or gluconate Heparin Hydrocortisone Sodium bicarbonate

Acidic solutions, B-complex vitamin preparations, barbiturates, calcium or magnesium salts, vancomycin Aminophylline, chloramphenicol, hydrocortisone, nafcillin Many drugs Cephalothin, sodium bicarbonate, tetracyclines Polymyxin B, tetracyclines, vancomycin B-complex vitamin preparations, chloramphenicol, ephedrine, tetracyclines, vancomycin Calcium chloride or gluconate, lactated Ringer's solution

*From Med Lett Drugs Ther 9:68 (Aug. 25) 1967. By permission of the publisher, Drug and Therapeutic Information, Inc. tSpecific instructions for reconstitution are provided by the manufacturer; the agent should always be administered alone. t Physical stability or biological potency may change after reconstitution; the agent should be administered alone soon after it is diluted. §The agent should not be mixed with solutions which contain calcium. Ringer's solution may be used as a diluent because the pH of the solution is acid. "":'Bisulfite is used as an antioxidant in commercial preparations of this agent; bisulfite slowly inactivates penicillin G.

1126

GUSTAVUS

A.

PETERS,

J,

PAUL MARCOUX

irritating to the veins and may lead to hyperkalemia if there is any associated renal insufficiency. The riboflavin inactivates the tetracycline, and itself is subject to photo-oxidation. The penicillin is inactivated rapidly at the lowered pH after the tetracycline has been added. The surgeon will do well to consult with the hospital pharmacist to avoid chemical incompatibilities. As stated, clarity of the solution does not guarantee chemical compatibility or effectiveness. Table 1 shows some incompatibilities of drugs commonly administered intravenously. Note that potassium penicillin G is incompatible with metaraminol, phenylephrine, vancomycin, tetracycline, and amphotericin B, as well as with ascorbic acid.

ANTIMICROBIAL DRUGS Antibiotics PENICILLIN. The first of the antibiotics, penicillin, still produces the highest incidence of allergiC reactions seen today28 and is the most common agent in producing shock. Therefore, prior to its administration, the patient should be questioned thoroughly regarding past adverse reactions to drugs and any indications that he is atopic. For some unknown reason, drug reactions are less common in children than in adults. The allergic reactions to penicillin are diverse/I. 46 there being immediate, accelerated, and delayed types. The immediate reactions -or anaphylactic reactions-develop in a matter of seconds or minutes and usually end in recovery or a fatality. The onset is rapid, associated with dizziness, mlmbness or burning of the tongue, sweating, tachycardia, weakness, and a feeling of impending collapse. The accelerated response comes about half an hour after the injection or within the next 12 to 36 hours. Both the immediate and the accelerated reactions are thought due to antigen-antibody reactions. The penicillin degrades into various products which combine with serum proteins by covalent bonds and act as a conjugate to induce antibody formation. The cellular antibodies or reagins, sometimes called "skin-sensitizing antibodies," are thought to be in the immunoglobulin fraction E and attach to the mast cells or basophils. When penicillin is reintroduced into the body it combines with antibody to form an antigen-antibody complex releasing vasoactive amines such as histamine. These amines cause an increase in capillary permeability, edema formation, and activity of smooth muscle (such as bronchospasm) or stimulation of glandular tissue (causing mucus production, tears, nasal congestion, wheezing, and hives). These effects constitute the pattern of an acute allergic reaction. Antihistaminic drugs block the receptor sites and are likely to be more effective when given before the reaction occurs, but they help to some extent even after the reaction has occurred. Epinephrine in 1: 1000 solution is the drug of choice, however, to combat an immediate allergic reaction. For moderate reactions, 0.3 to 0.5 ml given subcutaneously is usual, but for severe anaphylactic reactions, 0.5 to 1 ml intravenously may be required. The third group of adverse reactions to penicillin are the delayed

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1127

allergic reactions, which are manifested by erythema, measles-like rash, erythrovesicular changes, maculopapular eruptions, generalized urticaria, or angioedema. Also more complex reactions can occur-such as erythema nodosum, erythema multiforme, severe exfoliative dermatitis, or even periarteritis no do sa. Serum sickness develops frequently, and is characterized by hives, lymphadenopathy, joint pain and swelling, and onset 5 to 10 days after the beginning of the therapy. This type of reaction may last for weeks or months. Among countermeasures, penicillinase has been used for relief of some of these reactions, with variable success. In our experience with 20 cases, there has been a distinct indication that it can be helpful even when used without other agents such as antihistaminics and steroids. It is a protein substance and capable of acting as an antigen and creating its own antibodies. It should not be used again for a new reaction. We have had no serious complications in response to intramuscular administration of 800,000 units and a similar dose 2 or 3 days later for relief of penicillin reactions. Severe serum sickness or exfoliative reactions may require the use of steroids or ACTH for their relief. Another form of delayed allergic reaction to penicillin is contact dermatitis. Ointments containing penicillin are highly sensitizing and should be avoided. There have been a few cases of renal damage as well as hepatic and myocardial damage from large parenteral doses of penicillin, and even chronic brain syndrome. R As for the mechanism and laboratory testing, in almost all cases of penicillin reaction, the hemagglutinating titer rises to high levels. This antibody is thought to be mainly in the IgG fraction of the immunoglobulins, but its significance is not fully understood. In fact, the titer goes up in all patients receiving penicillin, whether they experience adverse reactions or not. When patients receive huge doses of penicillin G, as in treatment for subacute bacterial endocarditis, they may give a positive response to the Coombs test or develop hemolytic anemia. 33 In the latter situation the anti penicillin antibodies combine with the penicillin and complement to destroy red blood cells. The skin-sensitizing antibodies specific for the major penicilloyl antigenic determinants are associated mainly with immediate and urticarial reactions that develop in 2 or 3 days after the renewal of treatment with penicillin G. Parker and associates showed that penicilloyl polylysine (PPL) testing frequently demonstrated these antibodies and, because it is nonsensitizing, is safer than testing with the minor determinant mixture (MDM), which is made up mainly of benzyl penicillin, sodium benzyl penicilloate, benzyl penicilloate, and sodium and benzyl-penicilloyl amine. The skin-sensitizing antibodies are thought to be responsible for the anaphylactic reactors, according to Voss, Redmond, and Levine. Periodically one faces the problem of the penicillin-allergic patient, and wonders whether to give penicillin despite a history positive for penicillin allergy. Substitutes or alternative drugs should be tried first. If the disease is life-threatening, however, like subacute bacterial endocarditis, one may be forced to use penicillin.

1128

GUSTAVUS

A.

PETERS,

J

PAUL MARCOUX

In such cases, one should determine by sensitivity studies which antibiotic is the most specific for the infecting organism, and if penicillin proves to be the drug of choice, then one should check its safety by skintesting with penicillin G, using a scratch test first-i.e., a drop of a solution of 1000 units/ml on the forearm. If this is negative, 0.02 ml of penicillin (100 units/ml) is injected intradermally. A positive reaction is a wheal greater than 4 mm in diameter at 15 minutes after injection. Benzyl penicilloyl-polylysine (BPL) also can be employed in this manner if available in a solution of 5 x 10-6 molar, but so far it is available only for investigational use. If the skin tests produce negative responses to both agents, it is quite likely that the patient can tolerate the drug in full therapeutic dosage. Levine and Zolov studied 218 patients who had positive histories of penicillin allergy but required penicillin therapy, using as skin-test agents benzyl penicilloyl-polylysine and an MDM solution. They found that negative reactions to intradermal injections of BPL and MDM virtually exclude the possibility of an immediate (and anaphylactic) allergic reaction to penicillin and markedly reduce the probability of an accelerated reaction. On the other hand, if the skin tests show a positive reaction to BPL or to MDM, there is a very high probability of an immediate or accelerated allergic reaction to penicillin, especially if given in high dosage. Bierman and VanArsdel also concluded that negative skin-test reactions are useful in determining whether a child can tolerate penicillin. If the response to the skin tests is positive, however, and still penicillin is desperately needed for therapy, it is possible to try the cautious administration of penicillin G in a solution containing 100 units/ml, beginning with 1 or 2 units, subcutaneouslY,H, 36 then waiting 15 minutes (during which pulse and blood pressure are monitored and an anaphylactic tray is kept at hand) and doubling the dose every 15 minutes until the therapeutic range is attained, and then switching immediately to the intravenous route, giving the drug at the dosage necessary for proper treatment. Before attempting penicillin therapy in a case with a positive history of penicillin allergy, it is advisable that the physician discuss the risks involved with the patient or the nearest relative, and get consent for the intended treatment and record it in the medical history. Whether actual desensitization occurs is debatable, but this cautious way of proceeding has been practical in use. It is possible to work up to high levels in a matter of a few hours, and frequently one can reach therapeutic dosage levels without any reaction, but one must be quite careful if the responses to both skin tests are positive, since a reaction is likely to occur. Antihistaminic drugs and steroids may be used for additional coverage if needed. Awareness and forethought could help to avoid sensitization in many cases. There is a tendency to forget that penicillin has many homologues these days, all of which have the potentiality of crossreactivity, and that if a patient is reactive to penicillin, these homologues should not be used. Ampicillin, for example, is an excellent, broadly effective antibiotic, but it can cross-react in the penicillin-allergic patient. All of the various penicillin products share a common 6 amino-

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1129

penicillanic acid nucleus and a beta lac tam ring. Even the cephalosporins have a beta lac tam ring and may produce cross-reactivity.4, 15,45 We believe that penicillin should be saved for those occasions where it is specific and should not be used indiSCriminately when other broadly effective antibiotics would serve the purpose just as well. In this way the incidence of allergic reactions to penicillin would be minimized. TETRACYCLINES AND OTHERS. The tetracyclines are broadly effective antibiotics that usually produce little in the way of adverse reactions. They may interfere with protein synthesis, inhibiting certain enzyme systems. Demethylchlortetracycline (Declomycin) can cause photosensitivity reactions, but these are usually not serious. Degradation products of tetracycline or outdated tetracycline can affect renal tubular function, causing kidney damage and an acute Fanconi type of syndrome, characterized by albuminuria, glycosuria, aminoaciduria, nausea, vomiting, hypophosphatemia, hypokalemia, and acidosis. Another reason not to use outdated tetracycline drugs or not to use them for a prolonged time in patients with renal insufficiency is the possibility that hepatic and pancreatic damage will result. Novobiocin causes such a high incidence of skin rash (5 to 10% ) that some physicians prefer not to use it. However, ampicillin also produces a high incidence of skin-rash reactions. (Also, the postoperative patient may develop contact dermatitis from thimerosal [Merthiolatel used for skin sterilization prior to surgery. Reisman recently reported on 10 cases of delayed hypersensitivity reactions to thimerosal. In the past 41f2 years of adverse drug reporting, we have had 24 cases of skin reactivity attributed to this agent. Even adhesive tape may produce reactions of the skin, but this can be avoided by using 3M micropore tape #530 if there is any indication of reaction from the adhesive tape. The severe reactions seem to arise from the resins in the pigmented gum.) Some of the antibiotic drugs, such as kanamycin, dihydrostreptomycin, neomycin, and vancomycin, may cause cochlear involvement and deafness. 12 Streptomycin is more likely to produce vestibular dysfunction and dizziness. It has been found recently that ethacrynic acid (Edecrin) has an ototoxic quality which may be strengthened by combination with kanamycin. Polymyxin Band colistimethate (Colistin) have caused vertigo and ataxia as well as transient speech disturbances. All these drugs can set off a curariform type of reaction causing a neuromuscular blockade and possible respiratory and cardiac arrest. 34 Of all the antibiotics, chloramphenicol is probably the most likely to produce a severe bone-marrow effect in the form of agranulocytosis, since-according to Weisberger and associates-it inhibits protein synthesis by interfering with the binding of the mRN A to the ribosomes. This drug should not be used indiscriminately, but it is used far too freely. It may cause the so-called gray syndrome (due to low levels of the enzyme glucuronyl transferase), which is responsible for glucuronide conjugation of bilirubin as frequently seen among infants. The syndrome is further characterized by abdominal distention, progressive pallid cyanosis, and vascular collapse. Aplastic anemia with pancytopenic

1130

GUSTAVUS

A.

PETERS, ]. PAUL MARCOUX

reactions occurs more often with chloramphenicol than with any other drug. As with other antibiotics, an overgrowth of nonsusceptible organisms may occur. Despite repeated medical warnings regarding its potential severe bone-marrow effects, it continues to be used widely by the medical profession. 5 , 19

Sulfa Drugs The next most likely offenders are the sulfa drugs, whose potential for harm has been known since before the advent of the antibiotics. They produce erythematous rashes, fever, headache, photosensitivity, urticaria, leukopenia, hemolytic anemia, coagulation defects, erythema multiforme, and erythema nodosum as well as hepatotoxic jaundice and collagen disease. A patient with sulfa reactivity may react adversely when given procaine (Novocain) because these two chemicals have a similar para-amino grouping and chemical structure. If long-lasting sulfa drugs such as sulfamethoxazole (Gantanol), sulfamethoxypyridazine (Kynex), or sulfadimethoxine (Madribon) are used, a StevensJohnson syndrome may occur. It is thought that the sulfa agents may be converted into quinone compounds which can then act as haptenes and induce drug hyperreactivity. The sulfonylureas, such as chlorpropamide (Diabenese), tolbutamide (Orinase), the thiazides, and carbonic acid anhydrase also are sulfa derivatives and can cross-react with other sulfa drugs. It is worth noting that either sulfa drugs or barbiturates may precipitate porphyria, creating an acute abdomen that mimics perforation of a viscus and often occasions unnecessary exploratory laparotomy.

Nitrofurantoin Frequently, nitrofurantoin (Furadantin) is given for genitourinary infections and is effective against some Proteus organisms, but it can produce nausea and vomiting as well as peripheral neurotoxic effects. A few anaphylactoid reactions to it have occurred, and several cases of allergic pulmonary infiltrations with effusion and eosinophilia have been reported.1. 21. 38, 40

DIURETICS The next group of drugs likely to give trouble in the postoperative state are diuretics. The thiazides are commonly given not only for diuresis but for control of hypertension. Most of them will cause a state of hypokalemia which, if the patient is receiving digitalis, can lead to a digitalis toxicity state. Furosemide (Lasix) and ethacrynic acid also are extremely potent diuretics and can lead to electrolyte imbalance. Patients receiving them in the postoperative period require careful electrolyte monitoring. Metabolic alkalosis is often produced by thiazides because of loss of potassium and chloride. Again, furosemide and ethacrynic acid can cause alkalosis, and by depleting the hydrogen ion they aggravate it, with compensatory depression of alveolar ventilation.

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1131

The thiazides, furosemide, and ethacrynic acid can cause hyperuricemia too, and possibly aggravate gout. When these diuretics are used, administration of potassium and chloride in the form of 10% KCI solution is strongly recommended. The KCI solution is better and less costly than the potassium acetate or effervescent potassium citrate salts. Another drug, mannitol, is often used as an osmotic diuretic to prevent organic renal failure associated with cardiovascular surgery, as well as for shock and extensive hemorrhage, but patients receiving it must be watched carefully, for it can produce circulatory overload and congestive heart failure. It can cause crenation and agglutination of red blood cells. Adverse effects of mannitol infusion are headaches, chills, fever, thirst, tachycardia, and nausea. Plasma expanders such as lowmolecular-weight dextran help to maintain osmotic pressure of the plasma and also the circulatory blood volume, but anaphylactic reactions have occurred with their use, and they cannot be relied on as entirely innocuous. 3 !

TRANQUILIZERS, HYPNOTICS, ANTIDEPRESSANTS Another group of drugs that may give trouble are the tranquilizers, hypnotics, and antidepressantsY These are likely to be used postoperatively for control of tension, for sedation, or for countering marked anxiety reactions or depression. The tranquilizers may be divided into major and minor, with chlordiazepoxide (Librium), diazepam (Valium), and meprobamate being in the minor group. Meprobamate is not so safe as the former two, since its lethal dose is only 10 to 20 times the usual daily dose. 29 In the major tranquilizer group there are the phenothiazines/ B which have many adverse effects. However, because they are so tremendously valuable in the treatment of psychiatric conditions they have not been abandoned. They are used in many forms with many names, such as chlorpromazine (Thorazine), promazine, prochlorperazine (Compazine), promethazine (Phenergan), perphenazine (Trilafon), thiopropazate (Dartal), thioridazine (Mellaril), trifluoperazine (Stelazine), triflupromazine (Vesprin), methdilazone (Tacaryl), trimeprazine (Temaril), thiethylperazine (Torecan), pimpamazine (Mornidine), and propiomazine (Largon). They can be categorized as tranquilizers, antihistaminics, antiemetics, and adjuncts to anesthesia. From the psychiatric standpoint, thioridazine appears to be the safest of the phenothiazines, only rarely causing extrapyramidal-tract signs. But it can cause retinal pigmentation in large doses, and since it also can produce agranulocytosis, as reported by Rosenthal and associates, its use has to be supervised carefully. Phenothiazines can cause partial alpha-adrenergic blockage, which can lead to serious hypotension and cardiorespiratory arrest when epinephrine is given afterward as we have noted in a recent report. 24 Before leaving the phenothiazines, it should be noted that they can potentiate the analgesic effects of morphine, meperidine (Demerol), and

1132

GUSTAVUS

A.

PETERS,

J.

PAUL MARCOUX

other opiates. Sudden deaths have occurred with use of phenothiazines,39 and death has resulted also when combinations of phenothiazines and opiates were administered too liberally in treatment for asthma. Van Metre has reported that among 15 asthmatic patients who died, seven had received phenothiazine drugs. If a phenothiazine is given with analgesics, the dosage of each should be decreased because of the synergism of their action. It should also be mentioned that phenothiazines can cause enough skin pigmentation to make patients purplish. Prolonged use can lead to extrapyramidal signs (especially dystonia), and this is seen not uncommonly in patients receiving prochlorperazine (Compazine). The side effects of phenothiazines are numerous: (1) antihistaminic influence, (2) anticholinergic action, (3) cholestatic jaundice, (4) agranulocytosis, (5) photosensitivity, (6) endocrine effects such as diabetes mellitus and feminization, (7) convulsive seizures, (8) Parkinson's or extrapyramidaltract signs along with dyskinesia, dystonia, or akathisia, (9) ventricular arrhythmia and cardiac arrest, and (10) adrenergic blocking and epinephrine reversal. is Among hypnotics, the barbiturates are known to be addicting, and so are some of the nonbarbiturates such as glutethimide and ethchlorvynol. Few physicians are aware that glutethimide can become addicting in only small doses, and severe withdrawal symptoms may occur. We believe that glutethimide is one of the more dangerous hypnotic drugs on the market, though this is not well recognized by many physicians. Acute brain syndrome, characterized by seizures, respiratory failure, and death, may ensue when long-time use of it is stopped abruptly.26 The LD50 is about 10 gm/day, which amounts to only about 20 tablets, so it is convenient for the purpose of suicide. 29 It is a wise rule not to let a patient continue taking any hypnotic for an extended time. An interchange of sedatives or hypnotics at periodic intervals seems advisable to prevent tolerance or dependence from developing. It should be remembered that the monoamine oxidase (MAO) inhibitors can cause hypertensive crises in certain patients.i3 When the inhibitors prevent those enzymes from their usual destruction of tyramine, phentolamine (Regitine), dopamine, serotonin, norepinephrine, and related catecholamines, the latter are free to elevate the blood pressure to high levels, even causing strokes. Patients who are taking MAO inhibitors must avoid eating such foods as cheddar cheese, sour cream, and pickled herring.

SEVERAL CAUTIONS A word of caution should be said about giving steroids to patients who, because of rheumatoid arthritis or asthma or any other reason, have received a course of steroids lasting even as briefly as a few days to a week or two within the 6 months prior to contemplated surgery. These patients should be given adequate amounts of steroids to withstand the stress of the operation, thus preventing a possible state of adrenal in-

I

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1133

sufficiency in the postoperative period. Our routine for the patient about to undergo a major surgical procedure has been to give 200 mg of cortisone acetate each morning for 2 days prior to surgery and on the morning of surgery, thus forming a pool or depot of cortisone that counters the surgical stress. Postoperatively, the patient who has been receiving steroids for some time may need extra amounts daily, but these can be supplied by either intramuscular or oral administration of steroid supplements. Through the first 24 hours after operation, such a patient should be checked hourly for blood pressure, pulse, and temperature. For minor procedures, a rapid steroid preparation may be accomplished by intramuscular injection of 100 mg of prednisolone half an hour prior to surgery. In patients with diabetes, probenecid, salicylates, sulfa drugs, MAO inhibitors, and oxyphenbutazone all enhance the effect of sulfonylureas and may cause hypoglycemia. Chlorpropamide can cause thrombocytopenia, leukopenia, agranulocytosis, diarrhea, and skin rash. Tolbutamide can cause similar blood effects, and also produce gastrointestinal disturbances, weakness, paresthesia, tinnitus, and headache. Allergic dermatologic reactions - pruritus, erythema, urticaria, and morbilliform eruptions - may occur too. Usually these adverse effects will disappear if administration of the drug is stopped. Neither chlorpropamide nor tolbutamide should be given to the patient with definite liver disease. Recently it has been shown that diphenylhydantoin (Dilantin) may potentiate the effects of tolbutamide. 22 Certain drugs also have a propensity to produce cholestatic jaundice: aminos'alicyclic acid, chlorpropamide, erythromycin estolate (Ilosone), phenothiazines-especially chlorpromazine (Thorazine)steroids of the anabolic-androgenic type, sulfadiazine, and triacetyloleandomycin. Hepatotoxic jaundice may result from the use of othershalothane, iosoniazid, oxyphenbutazone, phenelzine (Nardil), promethazine, and sulfa drugs. Erythromycin is not toxic in its basic form, but seems to acquire a hepatotoxic effect when the simple OH grouping is replaced by a propionyl grouping. The inclusion of aspirin in many oral analgesic agents given postoperatively can precipitate severe attacks of asthma or angioedema or laryngeal edema. Such cases often include a triad of symptoms - namely, nasal polyps, vasomotor rhinitis, and aspirin sensitivity-in addition to the asthma. 42 Also, aspirin can cause gastric ulceration and bleeding, which lead to a puzzling type of secondary anemia. One should use substitutes such as acetaminophen (Tylenol, Apamide), plain propoxyphene (Darvon), or Percogesic tablets (acetaminophen, phenyltoloxamine). If aspirin is to be used, it should be given after meals or in a buffered form. Indomethacin has been reported .to produce asthma in the aspirin-sensitive patient, raising the question of cross-reactivity. Finally, the interaction of drugs is being seen more commonly these days,44.47 especially since multiple-drug therapy is given in almost every hospital case. Some patients may receive anywhere from half a dozen to three dozen drugs-an average figure is 14-during one hospitalization. 7

1134

GUSTAVUS

A.

PETERS,

J

PAUL MARCOUX

The postoperative patient may need anticoagulant therapy to prevent thromboembolic complications, but various drugs affect the coumarin compounds and derivatives in different ways (Table 2).9. 10. 16H is believed that the barbiturates stimulate the hepatic microsomal enzymes in the smooth part of the endoplasmic reticulum, speeding up the degradation of the coumarin derivatives and thus increasing the amounts of warfarin or coumarin derivatives required for the proper effect.27 Phenobarbital is known to do this, as well as other hypnotics such as glutethimide, ethchlorvynol, chloral hydrate, and meprobamate. Phenobarbital and other hypnotics may reduce the warfarin plasma half-life by about 50%. It may take 2 weeks to 2 months for the enzyme activity of the liver to return to normal. The coumarin derivatives are influenced also by factors in the gastrointestinal tract, by protein carriers, and by receptor sites as well as by kidney excretion. Phenylbutazone may affect the concentration of warfarin by displacing it from receptor sites, thus making it more available. D-Thyroxine has no effect on warfarin binding or on blood clotting levels. Blood coagulation factors II, VII, IX, and X are synthesized by the liver cells and of course are sensitive to vitamin K. Large doses of salicylate (6 gm or more for a person weighing 70 kg) may also increase the prothrombin time. 22 Koch-Weser and associates pointed out that warfarin may be potentiated by quinidine and may cause bleeding, as may also propylthiouracil. Warfarin has been shown to potentiate the effects of diphenylhydantoin and tolbutamide, increasing the half-life of both. To conclude, in this era of polypharmacy, the practicing physician needs to be more knowledgeable concerning drug effects. He needs to know the contents of the printed inserts which come with drugs, telling how they act, what are the effective doses, and what are the possible adverse reactions to them. He should know their indications-and to avoid iatrogenic disease, he should know their contraindications. The practicing physician must be alert to signs and symptoms of adverse reactions, especially for any unexplained rash or fever, abnormallaboratory data, such as elevation of the concentrations of serum glutamicoxaloacetic transaminase, alkaline phosphatase, or bilirubin, leukopenia, thrombocytopenia, the presence of hemorrhage or petechiae, changes in blood pressure or pulse rate, or abnormal urinary findings. Physicians Table 2.

Effects of Various Drugs on Prothrombin Time or Plasma Concentrations of Warfarin DECREASE

Barbiturates Glutethimide (Doriden) Ethchlorvynol (Placidyl) Chloral hydrate Meprobamate Griseofulvin

INCREASE

Anabolic steroids Antibiotics Clofibrate (Atromid-S) Phenyramidol (Analexin) Phenylbutazone (Butazolidin) D-Thyroxine Propylthiouracil Quinine Quinidine

ADVERSE DRUG REACTIONS IN THE POSTOPERATIVE PERIOD

1135

and surgeons today would do well to have on hand several drug reference books-namely, the most recent edition of the AMA manual called New Drugs and also the Physicians' Desk Reference (PDR), which lists more than 13,000 drugs-as well as an up-to-date book on pharmacology and therapeutics. Frequently the patient who changes physicians is carrying in his suitcase a miscellany of drugs, unlabeled, whose names he does not know, and the question of what he has been taking is a difficult one for the physician. The PDR often is helpful in this situation. It seems appropriate to suggest that all drugs be labeled and that all patients who have exhibited drug reactions or drug allergy should carry a notice of it, so that further adverse drug reactions will not be induced.

REFERENCES 1. Bayer, W. L., Dawson, R. B., Jr., and Kotin, E.: Allergic tracheobronchitis due to nitrofurantoin sensitivity: Report of a case. Dis Chest 48:429-430 (Oct.) 1965. 2. Beaty, H. N., and Petersdorf, R. G.: Iatrogenic factors in infectious disease. Ann Intern Med 65:641-656 (Oct.) 1966. 3. Bierman, C. W., and VanArsdel, P. P., Jr.: Penicillin allergy in children: The role of immunological tests in its diagnosis. J Allerg43:267-272 (May) 1969. 4. Brandriss, M. W., Smith, J. W., and Steinman, H. G.: Common antigenic determinants of penicillin G, cephalothin and 6-aminopenicillanic acid in rabbits. J Immun 94 :696-704 (May) 1965. 5. Brauer, M. J., and Dameshek, W.: Hypoplastic anemia and myeloblastic leukemia follOwing chloramphenicol therapy: Report of three cases. New Eng J Med 277: 1003-1005 (Nov. 9) 1967. 6. Cluff, L. E.: Higher incidence of adverse drug reaction noted in women than in men. (Medical News section.) JAMA 191 :33-35 (Jan. 18) 1965. 7. Cluff, L. E., Thornton, G. F., and Seidl, L. G.: Studies on the epidemiology of adverse drug reactions. I. Methods of surveillance. JAMA 188:976-983 (June 15) 1964. 8. Cohen, S. B.: Brain damage due to penicillin. JAMA 186:899-902 (Dec. 7) 1963. 9. Cucinell, S. A., Conney, A. H., Sansur, M., and Burns, J. J.: Drug interactions in man. I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (Dicumarol) and diphenylhydantoin (Dilantin). Clin Pharmacol Ther 6:420-429 (July-Aug.) 1965. 10. Dayton, P. G., Tarcan, Y., Chenkin, T., and Weiner, M.: The influence of barbiturates on coumarin plasma levels and prothrombin response. J Clin Invest 40:1797-1802 (Oct.) 1961. 11. De Weck, A. L., and Schneider, C. H.: Allergic reactions to penicillins: Advances in understanding and management. Minn Med 52:137-150 (Jan.) 1969. 12. Freemon, F. R., Parker, R. L., Jr., and Greer, M.: Unusual neurotoxiCity of kanamycin. JAMA 200:410-411 (May 1) 1967. 13. Goldberg, L. I.: Monoamine oxidase inhibitors: Adverse reactions and possible mechanisms. JAMA 190:456-462 (Nov. 2) 1964. 14. Green, G. R., Peters, G. A., and Geraci, J. E.: Treatment of bacterial endocarditis in patients with penicillin hypersensitivity. Ann Intern Med 67:235-249 (Aug.) 1967. 15. Grieco, M. H.: Cross-allergenicity of the penicillins and the cephalosporins. Arch Intern Med (Chicago) 119:141-146 (Feb.) 1967. 16. Hansen, J. M., Kristensen, M., Skovsted, L., and Christensen, L. K.: Dicoumarol-induced diphenylhydantoin intoxication. Lancet 2:265-266 (July 30) 1966. 17. Harris, J. R. [discusser): Use and abuse of tranquilizers and some other psychotropic drugs. Med Sci 18:38-48 (April) 1967. 18. Hollister, L. E.: Adverse reactions to phenothiazines. JAMA 189:311-313 (July 27) 1964. 19. Huguley, C. M., Jr.: Drug-induced blood dyscrasias. JAMA 188:817-818 (June 1) 1964. 20. 1m, S., and Latiolais, C. J.: Physico-chemicalincompatibilities of parenteral admixturespenicillin and tetracyclines. Amer J Hosp Pharm 23:333-343 (July) 1966. 21. Israel, H. L., and Diamond, P.: Recurrent pulmonary infiltration and pleural effusion due to nitrofurantoin sensitivity. New EngJ Med 266: 1024-1026 (May 17) 1962. 22. Kazmier, F.: Personal communication to the authors. 23. Koch-Weser, J., Sidel, V. W., Sweet, R. H., Kanarek, Paula, and Eaton, Ann E.: Factors determining physician reporting of adverse drug reactions: Comparison of 2000 spon-

1136

24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.

GUSTAVUS

A.

PETERS,

J.

PAUL MARCOUX

taneous reports with surveillance studies at the Massachusetts General Hospital. New Eng J Med 280:20-26 (Jan. 2) 1969. Legge, D. A., Tiede, J. J., Peters, G. A., and Gedge, S. W.: Death from tension pneumothorax and chlorpromazine cardiorespiratory collapse as separate complications of asthma. Ann Allerg 27:23-29 (Jan.) 1969. Levine, B. B., and Zolov, D. M.: Prediction of penicillin allergy by immunological tests. J Allerg 43:231-244 (April) 1969. Lingl, F. A.: Irreversible effects of glutethimide addiction. Amer J Psychiat 123:349-351 (Sept.) 1966. MacDonald, M. G., and Robinson, D. S.: Clinical observations of possible barbiturate interference with anticoagulation. JAMA 204:97-100 (April 8) 1968. Marcoux, A., and Martin, W. J.: Untoward reactions associated with antimicrobial therapy. Minn Med 50:1393-1397 (Sept.); 1571-1573 (Oct.); 1713-1720 (Nov.) 1967. Martin, M. J.: Personal communication to the authors. Mary Edward, Sister: pH-an important factor in the compatibility of additives in intravenous therapy. Amer J Hosp Pharm 24:440-449 (Aug.) 1967. Norman, P. S.: Adverse drug reactions and alternative drugs of choice. In Modell, W.: Drugs of Choice 1968-1969. St. Louis, C. V. Mosby Company, 1967, p. 32. Parker, C. W., Shapiro, J., Kern, M., and Eisen, H. N.: Hypersensitivity to penicillenic acid derivatives in human beings with peniCillin allergy. J Exp Med 115:821-838 (April 1) 1962. Petz, L. D., and Fudenberg, H. H.: Coombs-positive hemolytic anemia caused by penicillin administration. New Eng J Med 274:171-178 (Jan. 27) 1966. Pohlmann, G.: Respiratory arrest associated with intravenous administration of polymyxin B sulfate. JAMA 196:181-183 (April 11) 1966. Reisman, R. E.: Delayed hypersensitivity to Merthiolate preservative. J Allerg 43 :245-248 (April) 1969. Reisman, R. E., Rose, N. R., Witebsky, E., and Arbesman, C. E.: Penicillin allergy and desensitization. J Allergy 33:178-187 (March-April) 1962. Rendell-Baker, L., and Roberts, R. B.: Hazards of ethylene oxide sterilization. (Abstr.) Anesthesiology 30:349-350 (March) 1969. Robinson, B. R.: Pleuropulmonary reaction to nitrofurantoin. JAMA 189:239-240 (July 20) 1964. Rosati, D.: Hypotensive side effects of phenothiazine and their management. Dis Nerv Syst 25:366-369 (June) 1964. Rosenow, E. C., III, DeRemee, R. A., and Dines, D. E.: Chronic nitrofurantoin pulmonary reaction: Report of five cases. New Eng J Med 279:1258-1262 (Dec. 5) 1968. Rosenthal, D. S., Stein, G. F., and Santos, J. C.: Thioridazine agranulocytosis. JAMA 200:81-82 (April 3) 1967. Samter, M., and Beers, R. F., Jr.: Intolerance to aspirin: Clinical studies and consideration of its pathogenesis. Ann Intern Med 68 :975-983 (May) 1968. Schimmel, E. M.: The hazards of hospitalization. Ann Intern Med 60:100-110 (Jan.) 1964. Schrogie, J. J.: Drug interactions. FDA Papers, Nov. 1, 1968, pp. 11-13. Thoburn, R., Johnson, J. E., III, and Cluff, L. E.: Studies on the epidemiology of adverse drug reactions. IV. The relationship of cephalothin and penicillin allergy. JAMA 198: 345-348 (Oct. 24) 1966. VanArsdel, P. P., Jr.: Allergic reactions to penicillin. JAMA 191 :238-239 (Jan. 18) 1965. Van Dam, F. E., Overkamp, M., and Haanen, C.: The interaction of drugs. (Letter to the Editor.) Lancet 2:1027 (Nov. 5) 1966. Van Metre, T. E., Jr.: Adverse effects of inhalation of excessive amounts of nebulized isoproterenolin status asthmaticus. J Allerg43: 101-113 (Feb.) 1969. Voss, H. E., Redmond, A. P., and Levine, B. B.: Clinical detection of the potential allergic reactor to penicillin by immunologic tests. JAMA 196:679-683 (May 23) 1966. Weisberger, A. S., Wolfe, S., and Armentrout, S.: Inhibition of protein synthesis in mammalian cell-free systems by chloramphenicol. J Exp Med 120:161-181 (Aug. 1) 1964.