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Defining the Adverse Drug Reaction Sequence
Study examines " disease of medical progress" in which AOR begets AOR
Defining the Adverse Drug Reaction Sequence
Adverse drug reactions (ADR) frequently accompany pharmacotherapy and complicate the patient's clinical condition . The incidence of ADRs in hospitalized medical patients has been reported to range from 10 to 18 percent, 1- 9 with a mortality of up to 13 percent. 1- 3 .5 .9 Drug-induced diseases have been responsible for between 1.7 to 4.5 percent of the admissions to medical wards. 2- 4.6 , 10 This study was supported in part by Food and Drug Administration Contract 7 1- 12. Part of thi s study was prese nted as " Iatroge ni c Sequence: A Definition and Case Report" to the Secti on on Clinica l Practi ce, Academy of Ge neral Practi ce (now Academy of Pharmacy Practi ce) at the APhA Annual Meeting, San Fra ncisco, Californ ia, April 2 1, 1975.
more drugs. Seidl, et al. 12 found that patients who experienced ADRs had received an average of 14 drugs. May, et al. 13 found that hospitalized patients received an average of 8.0 drugs and Jick, et al. 14 determined an average of 8.4 drugs . The occurrence of ADR among hospitalized patients also has been related to the patient ' s immediate history of adverse reactions to drug therapy. Cluff, et al. 11 found that 30 percent (11 of 36) of the patients admitted to the hospital with an ADR developed subsequent ADRs while hospitalized. Two of the authors have noted a similarly high incidence of ADRs among hospitalized pe-
Adverse Drug Reaction Sequence Cases
Table I Patient
Factors which predispose patients to the risk of developing an adverse reaction to drug therapy include age, sex, race and physiological condition. Associations also have been made between the incidence of ADR and the manner in which drugs are utilized. Multiple drug therapy, for example, is a significant determinant for ADR, and the rate of adverse effects observed increases disproportionately with an increase in the number of drugs given to the patient. Cluff, et al. 11 observed a 4 .2 percent incidence of reactions in patients receiving 6 to 10 drugs; 24.2 percent with 11 to 15 drugs; 40 percent with 16 to 20 drugs, and 45 percent with 21 or
Age
Drug A
ADR
Sequence
Drug B
ADR
l.
39
Methicillin (inj)
Rash
A lte rnative dr ug B precipi tates A DR
Ceph alothin (inj)
Rash
2.
61
Hyd ro ch loro thiaz id e(po)
Hypokalem ia
Over-correct ion with dru g B
Potassium Chlorid e(po)
Hyperk alemia
3.
10
Chlorpro pamide(po)
Hypoglycem ia
Increased no . drugs In creased no. ADR
Glu cago n(inj )
Na usea / vo mi t
4.
49
Pro pra nolol (po)
Heart fa ilure
Di scon tinuati on of drug A = A DR from dr ug 13 (A & B used conco mi ta ntl y)
Hydralazine(po)
Angina pectori s
5.
67
Insulin (inj)
Hypogl y cem ia
Alternative drug B precip i ta tes A DR
To lbu ta mide(po)
Hypogl ycemia
6.
68
Digox in (po)
In tox icat ion
Over-correction with drugB
Potassium Chloride(po)
Hyperk alemia
7.
59
Digox in (po)
Intox ica tion
Increased no. drugs Increased no. A DR
=
Potassium Chloride (po)
Nausea/vomit
8.
75
Furose mide(po)
Hypo kalemia
Increased no. dru gs In creased no. A DR
=
Potassium Chloride(po)
Nausea
9.
73
Aminoph yllin(po)
Tremor s, ner vo usness
Over-co rrection with drug B
Chlordiazepoxide(po)
Somnolence
10.
15
Dial ysate (intraperit oneal)
Perit onitis
Increased no. drugs Increased no. AD R
Oxacillin (inj)
Rash
11.
75
Lactated Ringer's(inj) and /or Pack ed Red Bloo d Ce\l s(inj )
Edema, shortness of breath and hear t fa ilure
Over-correction with drug B
Furosemide(po) and Digoxin(po)
Digita lis toxi city
12.
24
Gentam i cin (inj) or Potassium Chlorid e(inj) or Penicillin (inj)
Phlebiti s
In creased no. drugs Increased no. AD R
=
Ampicillin (po) and /or Genta mi cin (inj )
Diarrh ea
13.
64
Digoxin (po)
Intoxicat ion
Increased no. drugs Increased no. ADR
=
Potassium Chlorid e(po)
Nausea
14.
24
Digoxin (po)
Intoxi catio n
=
3
Chlorpropamide(po)
Hypoglycem ia
Quinidine(po) and/ or Potassium Chloride(po ) 10% Dex trose(inj) and Vasopressin (inj )
Nausea
15.
Increased no. drugs Increased no. ADR Over-correction wi th drug B
16.
40
Hydrochlorothiazide(po)
Hypo kal emia
17.
70
Ethacrynic acid (po) and Digoxin (po)
Digita lis intoxi cat ion
244
Incr eased In creased Increased Increased
=
=
no. drugs = no. A DR no . drugs = no. ADR
Water in toxi cation, hypo natremia, co nvulsions
Potassium Chloride(po )
Nausea
Lid ocaine HCI(inj)
Conf u sion
Journal of the American Pharmaceutical Association
By Kenneth J . Bender, Michael W. McKenzie and Ronald B. Stewart
diatric patients admitted for drug-induced diseases. 15 That adverse reactions appear to be an inseparable component of drug therapy led Moser 16 to describe ADRs as " diseases of medical progress ." Moser postulated a " domino theory of therapeutics" in which drugs required to treat the adverse effects of other drugs will precipitate their own adverse effects . This extreme " disease of medical progress " in which ADR begets ADR is examined in this study. The incidence of the ADR sequence is determined, the mechanism of each sequence is described and the value of
Patient
clinical monitoring efforts to prevent the occurrence of the sequence is questioned. Although it is essential to identify the factors which contribute to the occurrence of ADRs and shift clinical monitoring efforts to negate them, many hazards of therapy appear to be unavoidable, and judgment of r isk versus benefit must continually be exercised. Methods
Data were obtained from a pharmacistbased epidemiologic study of adverse drug reactions conducted at Shands Teaching Hospital in Gainesville, Florida. The procedures of this epidemiological surveillance
program and the criteria for determining adverse drug reactions have been described previously .9 Data analyzed in this study were collected on medicine and pediatric patients from August 1969 to March 1973. Cases described were identified from printouts from the centralized hospital computer system and the adverse drug reaction sequence was verified through chart review after the patient was discharged. Defining the Sequence
An adverse reaction was defined as any undesired or unintended response to medi-
Drug B
ADR
Potassium Chloride(po)
Nausea
Furosemide(po)
Uric ac id in crease
=
Diazepam(inj)
CNS dep ress ion
In creased no . dru gs In creased no . ADR
=
Ox acillin (inj) Oxa cillin(inj) and /or Trimethobenzam ide Oxac illin (inj) and/ or Chloramphenicol(inj) and /or Met hicillin (inj) and /or Dicloxacillin(inj)
Rash Cho lestat ic jaund ice Secondary candida albi cans infec tion
Steve ns-Johnso n Syndrome
In creased no. drugs Increased no. ADR
=
Methy lprednisolone(inj)
Agitation
Vincristine(inj)
Seconda ry infection
In creased no. drugs Increased no. ADR
=
Cephalothin(inj)
Flush (vasod ilation) and rash
Asparaginase (inj) and/or Predn iso ne(po) and /or Vin cristine(inj)
Secondary infection
In creased no. drugs In creased no . ADR
=
Amp icillin (inj) and Gentamicin(inj)
Seco ndary ca ndida albica n s infection
Mephobarb ital and /or Ph enyto in
Ataxia
Codeine(inj)
Co nst ip ation
Insu lin (inj)
Hypog lycemia
Age
Drug A
ADR
Seq uence
18.
78
Ch loroth iaz ide(po) and Digoxin(po)
Hypokalemia and digitalis intoxication
Increased no. drugs Increased no . ADR
19 .
55
Et hacrynic acid (po)
Nausea
Alternative drug B precipitates ADR
20 .
14 mos.
Aspirin (po)
Aspirin intoxication
Increased no . drugs In creased no . ADR
2l.
18
Omiza sh un t for Amphotericin B (inj)
Secondary stap hylococcus infection
22.
50
Tetracycline(po)
23.
2
24.
3
=
25.
21 mos.
Phenobarbital(po)
Hyperkinesia
Alternative drug B precipitates ADR
26.
60
Phenylbutazone(po)
Thrombocytopenia and po lyarteritis nodosa with associa ted pain
Increased no. drugs In creased no. ADR
27.
14
Methy lpred niso lone(inj)
Hyperglycemia
Over-correction with drug B
28.
21 mos.
Vincristine(inj)
Secondary infection
Increased no. drugs Increased no. ADR
=
Ampic illin (po)
Diarr h ea
29.
S4
Indomethacin (po) and/or Aspir in (po)
G I hemorrhage
Increased no. drugs Increased no. ADR
=
Al-Mg Hydro xide(po) and/or Co lchicin e(po)
Diarrhea
30
61
Digitoxin (po)
Intoxicatio n
Increased no. drugs Increased no. ADR
=
Quinidine(po)
Diarrh ea
3l.
41
Ch loramphenicol(inj)
Agran ulocytosis
Penicillin (inj)
Fever
32
23 mos.
Ch loral hydrate(po)
Hyperkinesia
Alterna tive drug B precipitates ADR Alterna tive drug B precipitates ADR
Secobarbital(inj)
Hyperkine sia
33.
15
Propylthiouracil (po)
Hypo th yroid ism
Alternative drug B precipitates ADR Over-correction with drug B
Methimazole(po) Thyroid (po)
Agranulo cytosis Th y rotoxicosis
Vol. NS 16, No. 5, May 1976
=
245
Defining the Adverse Drug Reaction Sequence
cations which required treatment or alteration of therapy. An ADR sequence was defined when an ADR from drug A resulted in the administration of drug B, which then produced an additional ADR. Drug B was used either to treat the adverse effects of drug A, directly or symptomatically, or to serve as an alternative for drug A. Over-correction resulted in several cases when drug B was used to treat the ADR from drug A. Hyperkalemia, for example, was produced when potassium was given to correct the hypokalemia secondary to hydrochlorothiazide therapy (patient number two, Table I, page 244). The ADR sequence was not used, however, to describe the prophylactic use of drug B (e.g., potassium) to prevent an ADR from drug A (e.g., hypokalemia from thiazide); excessive use of potassium was only included as a sequence case when it was administered as corrective treatment for frank, drug-induced hypokalemia. In most sequences in which drug B was used to treat the ADR from drug A, the second reaction was unrelated to the first (patient number three). This is the "domino" effect 16 in which one ADR has necessitated the administration of additional drugs, which sub-
sequently precipitate additional reactions. The first ADR has created the need for an increased number of drugs, and an increase in the number of adverse reactions results. When a reaction to drug A resulted in drug B being used as an alternative, secondary reactions were either identical to the first (patient number one), or unrelated (patient number 19). The ADR sequence was not applied to cases when combination therapy of pharmacologically similar drugs produced similar side effects (e.g., orthostatic hypotension from combinations of antihypertensive agents). In one patient (patient number four), an adverse reaction to a drug combination which was considered as "drug A" resulted in one component of the combination being continued as the alternative "drug B." The drugs, reactions and mechanism for each ADR sequence are included in Table I. In several cases, the components of the sequence involved more than one drug or more than one reaction. When it was difficult to determine the drug responsible for the adverse reaction, the possible drugs were listed with " and/or" notation . When it appe..ared that multiple drugs or multiple reactions were involved, they were so listed. Patient number
Kenneth J. Bender
Kenneth J. Bender, PharmD, MA, is a clinical associate professor of pharmacy practice, University of illinois, Chicago. At the time this study was conducted, he was assistant professor of clinical pharmacy at the University of Florida. He earned his PharmD at University of Southern California and MA in human behavior at U.S. International University, San Diego . Current activities include coordinating the development of clinical curriculum for the HEW-funded Investigational Project for Self-Directed Study; serving on the scientific review panel of APhA's Drug Interactions Evaluation Program, and as contributing editor for International Pharmaceutical Abstracts.
Michael W. McKenzie
Michael W. McKenzie, MS, is assistant professor of clinical pharmacy at the University of Florida college of pharmacy in Gainesville. He received his BS in pharmacy from Samford University in 1969 and his MS in pharmacy from the University of Florida in 1972. He has worked as a researcher in pediatriCS on, the epidemiologic study of adverse drug reactions conducted jOintly by the University of Florida college of pharmacy and department of medicine . He is a member of APhA, ASHP, AACP, Rho Chi , Florida Pharmaceutical Association and the Florida Society of Hospital Pharmacists.
Ronald B. Stewart
Ronald B. Stewart, MS, is associate professor and chairman of the department of clinical pharmacy at the University of Florida. He earned his BS and MS in pharmacy from that schoOl as well. Since 1969 he has served as a research associate on an epidemiologic study of adverse drug reactions conducted jointly by the University of Florida college of pharmacy and department of medicine. He serves on the scientific review panel of the APhA Drug Interactions Evaluation Program, and is contributing editor for Drug Intelligence and Clinical Pharmacy. He is a member of APhA, ASHP and AACP.
246
15 illustrates the latter situation, where "drug B" consisted of both dextrose solution and vasopressin, and the corresponding ADR included water intoxication, hyponatremia and convulsions. A brief description of this case follows. Results During the period of August 1969 to March 1973, 9,983 patients admitted to adult and pediatric medicine services at Shands Teaching Hospital were monitored for adverse drug reactions. Of 7,423 adult patients, 923 (13 percent) had either presented on admission with an ADR, or had subsequently developed an ADR in the hospital. In the pediatric population, 264 (10 percent) of 2,560 patients had either presented with, or developed an ADR during hospitalization. Of the total population experiencing an ADR, 426 patients (35.7 percent) had multiple adverse reactions (two or more reactions). An ADR sequence in which the initial adverse reaction resulted in altered or additional treatment with subsequent additional adverse reaction was found in 33 patients (2.8 percent of the population experiencing an ADR). Adult patients who developed an adverse drug reaction were found to have received an average of 12 drugs during hospitalization (not including different dosage forms for the same drug), and the pediatric patients received an average of seven drugs. The 426 patients who had experienced multiple adverse drug reactions had each received approximately 16 drugs, and the 33 patients whose multiple adverse reactions were linked in sequence had received an average of 12 drugs during hospitalization. Case Report (Patient Number 15) A 3Y2-year-old Caucasian female with panhypopituitarism and diabetes insipidus secondary to removal of a brain tumor (craniopharyngioma) at 21 months of age was admitted to Shands Teaching Hospital with hypoglycemia from chlorpropamide. Chlorpropamide had been administered for its antidiuretic action after inadequate response was obtained from the use of Iypressin (Iysine-8 vasopressin administered as a nasal spray). Treatment included glucagon, in addition to glucose solutions and pitressin which subsequently produced acute water intoxication and hyponatremia (serum sodium of 116 mEq/L) with resultant seizures. The patient responded to parenteral hypertonic saline. Medications on discharge included Euthroid, cortisone acetate, phenobarbital elixir and pitressin in oil, 1%u to be administered intramuscularly by the patient's
Journal of the American Pharmaceutical Association
Bender, McKenzie and Stewart
mother if the patient's urine specific gravity dropped below 1.005. Although the ADR sequence was noted to have begun with chlorpropamide-induced hypoglycemia at the time of admission to the hospital , inconsistent effects from the nasal vasopresSin (possibly due to erratic absorption or inaccurate dosing) could be considered to have initiated the sequence by providing the indication for chlorpropamide use. This patient was predisposed to hypoglycemia with use of the sulfonylurea because of the deficient growth' hormone, and would have frequently required glucagon to counter hypoglycemia if chlorpropamide had been continued. The intravenous solutions which led to water intoxication had been indicated because of poor oral intake and hypoglycemia . Comment Empirically, there is good reason to agree with Moser ,16 and to assume that the ADR sequence is an insidious component of modern drug therapy. An adverse reaction is po ssible with any drug, and may serve to exacerbate a patient's clinical condition and predispose the patient to further adverse effects from subsequent therapy. In the study it was found that the ADR sequence occurs and, unlike multiple adverse reactions which are unrelated, is not necessarily a function of the number of drugs rec eived by the patient. Sequence patients received an average of 12 drugs, while each of the patients having experiencing multiple drug reactions received approximately 16 drugs. The number of patients who experie nc ed an ADR sequence , however, was extremely small. In the total population monitored , 11.9 percent had developed an ADR (1,192 of 9,983); 4.3 percent had experienced multiple adverse reaction s (426 of 9,983), and 0.3 percent had experienced an ADR sequence (33 of 9,983). Of the patients who developed multiple adverse reactions, then, 7.7 percent (33 to 426) had at least one adverse reaction resulting from therapy being adjusted because of a previous adverse reaction . Further evidence of the low incidence of ADR sequences among the population who received treatment for an ADR is gained by comparing the number of reactions which were categorized in the surveillance process as moderately severe, severe or fatal (most of which could be assumed to have necessitated corrective or alternative therapy) with the number of reactions which led to a sequence . Of a total 1,780 ADRs in this population of adult and pediatric medicine patients , 1,124 (63 percent) reactions so cat-
Vol. NS 16, No. 5. May 19 76
egorized easily dwarf the 37 reactions which evoked an ADR sequence in 33 patients. The low incidence of secondary reactions from corrective therapy may reflect the physician 's sensitization to the possibility of adverse reactions because of the initial ADR, and the resulting tendency to monitor the patient more closely. Although the literature indicates that patients who incur an ADR are at-risk for subsequent adverse reactions, and that an increase in the number of drugs will result in an increased risk of adverse reactions, specific treatment of the ADR with additional drugs in patients of this study did not carry a uniquely high risk for subsequent reactions . Over-correction may occur (e.g., administration of potassium for hypokalemia, producing hyperkalemia), but it is doubtful that there is greater chance of this occurring when potaSsium is given to correct the ADR of hypokalemia than when it is given in routine use to prevent it. It would not appear necessary to delay, or apply an unusual degree of caution , when treating an adverse drug reaction in order to reduce the possibility ·of creating further adverse reactions to the corrective treatment. The altered regimens were indicated in each of the sequence cases, and the potential for secondary reactions did not outweigh the requirement for treatment.
Summary
Of 9,983 patients admitted to adult and pediatric medicine during the period of August 1969 to March 1973, 1, 192 incurred at least one adverse drug reaction (11 .9 percent), and 426 had multiple adverse drug reactions (4.3 percent) . An adverse drug reaction sequence in which an ADR resulted from therapy administered for a previous ADR was found in 33 patients (0 .3 percent). Although a literature search revealed an ADR risk among patients with a history of an ADR , and an increasingly higher risk with an increase in the number of drugs received , it does not appear to be justified to withhold appropriate treatment for an adverse reaction in order to reduce the possibility of further reactions to the corrective therapy . Further, the postulation of a "domino effect" 16 in which adverse reactions are treated with drugs which cause additional adverse reactions has been shown to be of min imal significance in this studied population . • Acknowledgment
The authors gratefully acknowledge Mac Steger for his assistance in gathering the data for this article.
References 1. Schimmel. E.M ., " The Hazards of Hospita lizati on," Ann. Intern. Med .• 60, 100 (1964)
2. Seidl. L.G.. Thornton. S.F.. Smith. JW .. and Cluff. L.E.. "Studies on the Epidemiology of Adverse Drug Reacti ons, III. Reactions in Patients on a General Medica l Serv ice, " BUll. JOhns Hopkins Hosp .• 119, 299 (1966)
3. Smith, JW .. Seidl, L.G., and Cluff, L.E., "Studies on the Epidemiology of Adverse Drug Reactions, V. Clinical Factors Influencing Susceptibility, " A nn. Intern Med., 65, 629 (1 966) 4. Sidel, VW., Koch-Weser, J., Barnett, G.O., and Eaton, A., " Drug Utilization and Adverse Reactions in a General
Hospital," Hosp itals, 41, 80 (June 1967) 5. Hoddinott, B.C. , Gowdy, CW., Coulter, WK, and Parker, J.M., " Drug Reaction s and Errors in Ad mini strati on on a
Medical Ward," Can. Med. Assoc. J , 97, 1001 (1967) 6. Oglivie, R.I., and Ruedy, J., "Adverse Drug Reactions During Hospitalization," Can. Med. Assoc. J, 97, 1450 (1967) 7. Simmons, M. , Parker, J.M. , Gowdy, CW., and Coulter, WK, "Adverse Drug Reactions During Hospitalization, " correspondence, Can. Med. Assoc. J, 98, 175 (1968) 8. Hurw itz, N., and Wade, D.L. , " Intensive Hospital Monitoring of Adverse Reactions to Drugs," Br. Moo. J , 1,531(1969) 9. Gardner , P., and Watso n, l.J ., " Adver se Drug Reactio ns: A Pharmaci st-Based Monitoring System, " Glin. Pharmacal. Ther., 11,802 (1970) 10. Hurwit z, N. , "Admissions to a Hospital Due to Drugs," Br. Med. J, 1, 539 (1969)
11 . Cluff, LE., Thornton, G.. Seidl, L , and Smith, J.. "Epidemiologica l Study of Adverse Drug Reactions," Trans. Assoc. Am. Physicians, 78, 255 (1965)
12. Seidl, L.G .. Thornton, G.F., Smith, FW., and Cluff, L.E. , " Studies on the Epidemiology of Adverse Drug Reacti ons," Bull. John Hopkins Hosp ., 119, 229 (1966) 13. May, FE, Stewart, R.B., and Cluff, L.E., "Drug Use in the Hospital: Eva luati on of Determinants," Glin. Pharmacol. Ther., 16, 834 (1974)
14. Jick, H., Miettinen, O.S., Shapiro, S., Lewis, S.P., Sisking, V. , and Slone, 0 ., "Comprehensive Drug Surve illance," JA MA, 213, 1455 (1 970)
15. McKenzie, MW., Stewart, R.B.. Weise. C.F., and Cluff, L.E., "A Pharmacist-Based Study of the Epidemiology of Adverse Drug Reactions in Pediatric Medicine Patients," Am. J. Hasp. Pharm. , 30, 898 (1973) 16. Moser, R. H., " IatrogeniC Di sorders," Military Medicine. 135,
61 9 (1970)
Med-i-Quiz Answers
1. 2. 3. 4. 5. 6. 7.
247
B A and Band D A , and D D B
e
e
e
8. 9. 10. 11. 12. 13. 14.
e e e
e
A , B, and D Band D
e
D
Defining the Adverse Drug Reaction Sequence
Adverse drug reactions (ADR) frequently accompany pharmacotherapy and complicate the patient's clinical condition . The incidence of ADRs in hospitalized medical patients has been reported to range from 10 to 18 percent, 1- 9 with a mortality of up to 13 percent. 1- 3 .5 .9 Drug-induced diseases have been responsible for between 1.7 to 4.5 percent of the admissions to medical wards. 2- 4.6 , 10 This study was supported in part by Food and Drug Administration Contract 7 1- 12. Part of thi s study was prese nted as " Iatroge ni c Sequence: A Definition and Case Report" to the Secti on on Clinica l Practi ce, Academy of Ge neral Practi ce (now Academy of Pharmacy Practi ce) at the APhA Annual Meeting, San Fra ncisco, Californ ia, April 2 1, 1975.
more drugs. Seidl, et al. 12 found that patients who experienced ADRs had received an average of 14 drugs. May, et al. 13 found that hospitalized patients received an average of 8.0 drugs and Jick, et al. 14 determined an average of 8.4 drugs . The occurrence of ADR among hospitalized patients also has been related to the patient ' s immediate history of adverse reactions to drug therapy. Cluff, et al. 11 found that 30 percent (11 of 36) of the patients admitted to the hospital with an ADR developed subsequent ADRs while hospitalized. Two of the authors have noted a similarly high incidence of ADRs among hospitalized pe-
Adverse Drug Reaction Sequence Cases
Table I Patient
Factors which predispose patients to the risk of developing an adverse reaction to drug therapy include age, sex, race and physiological condition. Associations also have been made between the incidence of ADR and the manner in which drugs are utilized. Multiple drug therapy, for example, is a significant determinant for ADR, and the rate of adverse effects observed increases disproportionately with an increase in the number of drugs given to the patient. Cluff, et al. 11 observed a 4 .2 percent incidence of reactions in patients receiving 6 to 10 drugs; 24.2 percent with 11 to 15 drugs; 40 percent with 16 to 20 drugs, and 45 percent with 21 or
Age
Drug A
ADR
Sequence
Drug B
ADR
l.
39
Methicillin (inj)
Rash
A lte rnative dr ug B precipi tates A DR
Ceph alothin (inj)
Rash
2.
61
Hyd ro ch loro thiaz id e(po)
Hypokalem ia
Over-correct ion with dru g B
Potassium Chlorid e(po)
Hyperk alemia
3.
10
Chlorpro pamide(po)
Hypoglycem ia
Increased no . drugs In creased no. ADR
Glu cago n(inj )
Na usea / vo mi t
4.
49
Pro pra nolol (po)
Heart fa ilure
Di scon tinuati on of drug A = A DR from dr ug 13 (A & B used conco mi ta ntl y)
Hydralazine(po)
Angina pectori s
5.
67
Insulin (inj)
Hypogl y cem ia
Alternative drug B precip i ta tes A DR
To lbu ta mide(po)
Hypogl ycemia
6.
68
Digox in (po)
In tox icat ion
Over-correction with drugB
Potassium Chloride(po)
Hyperk alemia
7.
59
Digox in (po)
Intox ica tion
Increased no. drugs Increased no. A DR
=
Potassium Chloride (po)
Nausea/vomit
8.
75
Furose mide(po)
Hypo kalemia
Increased no. dru gs In creased no. A DR
=
Potassium Chloride(po)
Nausea
9.
73
Aminoph yllin(po)
Tremor s, ner vo usness
Over-co rrection with drug B
Chlordiazepoxide(po)
Somnolence
10.
15
Dial ysate (intraperit oneal)
Perit onitis
Increased no. drugs Increased no. AD R
Oxacillin (inj)
Rash
11.
75
Lactated Ringer's(inj) and /or Pack ed Red Bloo d Ce\l s(inj )
Edema, shortness of breath and hear t fa ilure
Over-correction with drug B
Furosemide(po) and Digoxin(po)
Digita lis toxi city
12.
24
Gentam i cin (inj) or Potassium Chlorid e(inj) or Penicillin (inj)
Phlebiti s
In creased no. drugs Increased no. AD R
=
Ampicillin (po) and /or Genta mi cin (inj )
Diarrh ea
13.
64
Digoxin (po)
Intoxicat ion
Increased no. drugs Increased no. ADR
=
Potassium Chlorid e(po)
Nausea
14.
24
Digoxin (po)
Intoxi catio n
=
3
Chlorpropamide(po)
Hypoglycem ia
Quinidine(po) and/ or Potassium Chloride(po ) 10% Dex trose(inj) and Vasopressin (inj )
Nausea
15.
Increased no. drugs Increased no. ADR Over-correction wi th drug B
16.
40
Hydrochlorothiazide(po)
Hypo kal emia
17.
70
Ethacrynic acid (po) and Digoxin (po)
Digita lis intoxi cat ion
244
Incr eased In creased Increased Increased
=
=
no. drugs = no. A DR no . drugs = no. ADR
Water in toxi cation, hypo natremia, co nvulsions
Potassium Chloride(po )
Nausea
Lid ocaine HCI(inj)
Conf u sion
Journal of the American Pharmaceutical Association
By Kenneth J . Bender, Michael W. McKenzie and Ronald B. Stewart
diatric patients admitted for drug-induced diseases. 15 That adverse reactions appear to be an inseparable component of drug therapy led Moser 16 to describe ADRs as " diseases of medical progress ." Moser postulated a " domino theory of therapeutics" in which drugs required to treat the adverse effects of other drugs will precipitate their own adverse effects . This extreme " disease of medical progress " in which ADR begets ADR is examined in this study. The incidence of the ADR sequence is determined, the mechanism of each sequence is described and the value of
Patient
clinical monitoring efforts to prevent the occurrence of the sequence is questioned. Although it is essential to identify the factors which contribute to the occurrence of ADRs and shift clinical monitoring efforts to negate them, many hazards of therapy appear to be unavoidable, and judgment of r isk versus benefit must continually be exercised. Methods
Data were obtained from a pharmacistbased epidemiologic study of adverse drug reactions conducted at Shands Teaching Hospital in Gainesville, Florida. The procedures of this epidemiological surveillance
program and the criteria for determining adverse drug reactions have been described previously .9 Data analyzed in this study were collected on medicine and pediatric patients from August 1969 to March 1973. Cases described were identified from printouts from the centralized hospital computer system and the adverse drug reaction sequence was verified through chart review after the patient was discharged. Defining the Sequence
An adverse reaction was defined as any undesired or unintended response to medi-
Drug B
ADR
Potassium Chloride(po)
Nausea
Furosemide(po)
Uric ac id in crease
=
Diazepam(inj)
CNS dep ress ion
In creased no . dru gs In creased no . ADR
=
Ox acillin (inj) Oxa cillin(inj) and /or Trimethobenzam ide Oxac illin (inj) and/ or Chloramphenicol(inj) and /or Met hicillin (inj) and /or Dicloxacillin(inj)
Rash Cho lestat ic jaund ice Secondary candida albi cans infec tion
Steve ns-Johnso n Syndrome
In creased no. drugs Increased no. ADR
=
Methy lprednisolone(inj)
Agitation
Vincristine(inj)
Seconda ry infection
In creased no. drugs Increased no. ADR
=
Cephalothin(inj)
Flush (vasod ilation) and rash
Asparaginase (inj) and/or Predn iso ne(po) and /or Vin cristine(inj)
Secondary infection
In creased no. drugs In creased no . ADR
=
Amp icillin (inj) and Gentamicin(inj)
Seco ndary ca ndida albica n s infection
Mephobarb ital and /or Ph enyto in
Ataxia
Codeine(inj)
Co nst ip ation
Insu lin (inj)
Hypog lycemia
Age
Drug A
ADR
Seq uence
18.
78
Ch loroth iaz ide(po) and Digoxin(po)
Hypokalemia and digitalis intoxication
Increased no. drugs Increased no . ADR
19 .
55
Et hacrynic acid (po)
Nausea
Alternative drug B precipitates ADR
20 .
14 mos.
Aspirin (po)
Aspirin intoxication
Increased no . drugs In creased no . ADR
2l.
18
Omiza sh un t for Amphotericin B (inj)
Secondary stap hylococcus infection
22.
50
Tetracycline(po)
23.
2
24.
3
=
25.
21 mos.
Phenobarbital(po)
Hyperkinesia
Alternative drug B precipitates ADR
26.
60
Phenylbutazone(po)
Thrombocytopenia and po lyarteritis nodosa with associa ted pain
Increased no. drugs In creased no. ADR
27.
14
Methy lpred niso lone(inj)
Hyperglycemia
Over-correction with drug B
28.
21 mos.
Vincristine(inj)
Secondary infection
Increased no. drugs Increased no. ADR
=
Ampic illin (po)
Diarr h ea
29.
S4
Indomethacin (po) and/or Aspir in (po)
G I hemorrhage
Increased no. drugs Increased no. ADR
=
Al-Mg Hydro xide(po) and/or Co lchicin e(po)
Diarrhea
30
61
Digitoxin (po)
Intoxicatio n
Increased no. drugs Increased no. ADR
=
Quinidine(po)
Diarrh ea
3l.
41
Ch loramphenicol(inj)
Agran ulocytosis
Penicillin (inj)
Fever
32
23 mos.
Ch loral hydrate(po)
Hyperkinesia
Alterna tive drug B precipitates ADR Alterna tive drug B precipitates ADR
Secobarbital(inj)
Hyperkine sia
33.
15
Propylthiouracil (po)
Hypo th yroid ism
Alternative drug B precipitates ADR Over-correction with drug B
Methimazole(po) Thyroid (po)
Agranulo cytosis Th y rotoxicosis
Vol. NS 16, No. 5, May 1976
=
245
Defining the Adverse Drug Reaction Sequence
cations which required treatment or alteration of therapy. An ADR sequence was defined when an ADR from drug A resulted in the administration of drug B, which then produced an additional ADR. Drug B was used either to treat the adverse effects of drug A, directly or symptomatically, or to serve as an alternative for drug A. Over-correction resulted in several cases when drug B was used to treat the ADR from drug A. Hyperkalemia, for example, was produced when potassium was given to correct the hypokalemia secondary to hydrochlorothiazide therapy (patient number two, Table I, page 244). The ADR sequence was not used, however, to describe the prophylactic use of drug B (e.g., potassium) to prevent an ADR from drug A (e.g., hypokalemia from thiazide); excessive use of potassium was only included as a sequence case when it was administered as corrective treatment for frank, drug-induced hypokalemia. In most sequences in which drug B was used to treat the ADR from drug A, the second reaction was unrelated to the first (patient number three). This is the "domino" effect 16 in which one ADR has necessitated the administration of additional drugs, which sub-
sequently precipitate additional reactions. The first ADR has created the need for an increased number of drugs, and an increase in the number of adverse reactions results. When a reaction to drug A resulted in drug B being used as an alternative, secondary reactions were either identical to the first (patient number one), or unrelated (patient number 19). The ADR sequence was not applied to cases when combination therapy of pharmacologically similar drugs produced similar side effects (e.g., orthostatic hypotension from combinations of antihypertensive agents). In one patient (patient number four), an adverse reaction to a drug combination which was considered as "drug A" resulted in one component of the combination being continued as the alternative "drug B." The drugs, reactions and mechanism for each ADR sequence are included in Table I. In several cases, the components of the sequence involved more than one drug or more than one reaction. When it was difficult to determine the drug responsible for the adverse reaction, the possible drugs were listed with " and/or" notation . When it appe..ared that multiple drugs or multiple reactions were involved, they were so listed. Patient number
Kenneth J. Bender
Kenneth J. Bender, PharmD, MA, is a clinical associate professor of pharmacy practice, University of illinois, Chicago. At the time this study was conducted, he was assistant professor of clinical pharmacy at the University of Florida. He earned his PharmD at University of Southern California and MA in human behavior at U.S. International University, San Diego . Current activities include coordinating the development of clinical curriculum for the HEW-funded Investigational Project for Self-Directed Study; serving on the scientific review panel of APhA's Drug Interactions Evaluation Program, and as contributing editor for International Pharmaceutical Abstracts.
Michael W. McKenzie
Michael W. McKenzie, MS, is assistant professor of clinical pharmacy at the University of Florida college of pharmacy in Gainesville. He received his BS in pharmacy from Samford University in 1969 and his MS in pharmacy from the University of Florida in 1972. He has worked as a researcher in pediatriCS on, the epidemiologic study of adverse drug reactions conducted jOintly by the University of Florida college of pharmacy and department of medicine . He is a member of APhA, ASHP, AACP, Rho Chi , Florida Pharmaceutical Association and the Florida Society of Hospital Pharmacists.
Ronald B. Stewart
Ronald B. Stewart, MS, is associate professor and chairman of the department of clinical pharmacy at the University of Florida. He earned his BS and MS in pharmacy from that schoOl as well. Since 1969 he has served as a research associate on an epidemiologic study of adverse drug reactions conducted jointly by the University of Florida college of pharmacy and department of medicine. He serves on the scientific review panel of the APhA Drug Interactions Evaluation Program, and is contributing editor for Drug Intelligence and Clinical Pharmacy. He is a member of APhA, ASHP and AACP.
246
15 illustrates the latter situation, where "drug B" consisted of both dextrose solution and vasopressin, and the corresponding ADR included water intoxication, hyponatremia and convulsions. A brief description of this case follows. Results During the period of August 1969 to March 1973, 9,983 patients admitted to adult and pediatric medicine services at Shands Teaching Hospital were monitored for adverse drug reactions. Of 7,423 adult patients, 923 (13 percent) had either presented on admission with an ADR, or had subsequently developed an ADR in the hospital. In the pediatric population, 264 (10 percent) of 2,560 patients had either presented with, or developed an ADR during hospitalization. Of the total population experiencing an ADR, 426 patients (35.7 percent) had multiple adverse reactions (two or more reactions). An ADR sequence in which the initial adverse reaction resulted in altered or additional treatment with subsequent additional adverse reaction was found in 33 patients (2.8 percent of the population experiencing an ADR). Adult patients who developed an adverse drug reaction were found to have received an average of 12 drugs during hospitalization (not including different dosage forms for the same drug), and the pediatric patients received an average of seven drugs. The 426 patients who had experienced multiple adverse drug reactions had each received approximately 16 drugs, and the 33 patients whose multiple adverse reactions were linked in sequence had received an average of 12 drugs during hospitalization. Case Report (Patient Number 15) A 3Y2-year-old Caucasian female with panhypopituitarism and diabetes insipidus secondary to removal of a brain tumor (craniopharyngioma) at 21 months of age was admitted to Shands Teaching Hospital with hypoglycemia from chlorpropamide. Chlorpropamide had been administered for its antidiuretic action after inadequate response was obtained from the use of Iypressin (Iysine-8 vasopressin administered as a nasal spray). Treatment included glucagon, in addition to glucose solutions and pitressin which subsequently produced acute water intoxication and hyponatremia (serum sodium of 116 mEq/L) with resultant seizures. The patient responded to parenteral hypertonic saline. Medications on discharge included Euthroid, cortisone acetate, phenobarbital elixir and pitressin in oil, 1%u to be administered intramuscularly by the patient's
Journal of the American Pharmaceutical Association
Bender, McKenzie and Stewart
mother if the patient's urine specific gravity dropped below 1.005. Although the ADR sequence was noted to have begun with chlorpropamide-induced hypoglycemia at the time of admission to the hospital , inconsistent effects from the nasal vasopresSin (possibly due to erratic absorption or inaccurate dosing) could be considered to have initiated the sequence by providing the indication for chlorpropamide use. This patient was predisposed to hypoglycemia with use of the sulfonylurea because of the deficient growth' hormone, and would have frequently required glucagon to counter hypoglycemia if chlorpropamide had been continued. The intravenous solutions which led to water intoxication had been indicated because of poor oral intake and hypoglycemia . Comment Empirically, there is good reason to agree with Moser ,16 and to assume that the ADR sequence is an insidious component of modern drug therapy. An adverse reaction is po ssible with any drug, and may serve to exacerbate a patient's clinical condition and predispose the patient to further adverse effects from subsequent therapy. In the study it was found that the ADR sequence occurs and, unlike multiple adverse reactions which are unrelated, is not necessarily a function of the number of drugs rec eived by the patient. Sequence patients received an average of 12 drugs, while each of the patients having experiencing multiple drug reactions received approximately 16 drugs. The number of patients who experie nc ed an ADR sequence , however, was extremely small. In the total population monitored , 11.9 percent had developed an ADR (1,192 of 9,983); 4.3 percent had experienced multiple adverse reaction s (426 of 9,983), and 0.3 percent had experienced an ADR sequence (33 of 9,983). Of the patients who developed multiple adverse reactions, then, 7.7 percent (33 to 426) had at least one adverse reaction resulting from therapy being adjusted because of a previous adverse reaction . Further evidence of the low incidence of ADR sequences among the population who received treatment for an ADR is gained by comparing the number of reactions which were categorized in the surveillance process as moderately severe, severe or fatal (most of which could be assumed to have necessitated corrective or alternative therapy) with the number of reactions which led to a sequence . Of a total 1,780 ADRs in this population of adult and pediatric medicine patients , 1,124 (63 percent) reactions so cat-
Vol. NS 16, No. 5. May 19 76
egorized easily dwarf the 37 reactions which evoked an ADR sequence in 33 patients. The low incidence of secondary reactions from corrective therapy may reflect the physician 's sensitization to the possibility of adverse reactions because of the initial ADR, and the resulting tendency to monitor the patient more closely. Although the literature indicates that patients who incur an ADR are at-risk for subsequent adverse reactions, and that an increase in the number of drugs will result in an increased risk of adverse reactions, specific treatment of the ADR with additional drugs in patients of this study did not carry a uniquely high risk for subsequent reactions . Over-correction may occur (e.g., administration of potassium for hypokalemia, producing hyperkalemia), but it is doubtful that there is greater chance of this occurring when potaSsium is given to correct the ADR of hypokalemia than when it is given in routine use to prevent it. It would not appear necessary to delay, or apply an unusual degree of caution , when treating an adverse drug reaction in order to reduce the possibility ·of creating further adverse reactions to the corrective treatment. The altered regimens were indicated in each of the sequence cases, and the potential for secondary reactions did not outweigh the requirement for treatment.
Summary
Of 9,983 patients admitted to adult and pediatric medicine during the period of August 1969 to March 1973, 1, 192 incurred at least one adverse drug reaction (11 .9 percent), and 426 had multiple adverse drug reactions (4.3 percent) . An adverse drug reaction sequence in which an ADR resulted from therapy administered for a previous ADR was found in 33 patients (0 .3 percent). Although a literature search revealed an ADR risk among patients with a history of an ADR , and an increasingly higher risk with an increase in the number of drugs received , it does not appear to be justified to withhold appropriate treatment for an adverse reaction in order to reduce the possibility of further reactions to the corrective therapy . Further, the postulation of a "domino effect" 16 in which adverse reactions are treated with drugs which cause additional adverse reactions has been shown to be of min imal significance in this studied population . • Acknowledgment
The authors gratefully acknowledge Mac Steger for his assistance in gathering the data for this article.
References 1. Schimmel. E.M ., " The Hazards of Hospita lizati on," Ann. Intern. Med .• 60, 100 (1964)
2. Seidl. L.G.. Thornton. S.F.. Smith. JW .. and Cluff. L.E.. "Studies on the Epidemiology of Adverse Drug Reacti ons, III. Reactions in Patients on a General Medica l Serv ice, " BUll. JOhns Hopkins Hosp .• 119, 299 (1966)
3. Smith, JW .. Seidl, L.G., and Cluff, L.E., "Studies on the Epidemiology of Adverse Drug Reactions, V. Clinical Factors Influencing Susceptibility, " A nn. Intern Med., 65, 629 (1 966) 4. Sidel, VW., Koch-Weser, J., Barnett, G.O., and Eaton, A., " Drug Utilization and Adverse Reactions in a General
Hospital," Hosp itals, 41, 80 (June 1967) 5. Hoddinott, B.C. , Gowdy, CW., Coulter, WK, and Parker, J.M., " Drug Reaction s and Errors in Ad mini strati on on a
Medical Ward," Can. Med. Assoc. J , 97, 1001 (1967) 6. Oglivie, R.I., and Ruedy, J., "Adverse Drug Reactions During Hospitalization," Can. Med. Assoc. J, 97, 1450 (1967) 7. Simmons, M. , Parker, J.M. , Gowdy, CW., and Coulter, WK, "Adverse Drug Reactions During Hospitalization, " correspondence, Can. Med. Assoc. J, 98, 175 (1968) 8. Hurw itz, N., and Wade, D.L. , " Intensive Hospital Monitoring of Adverse Reactions to Drugs," Br. Moo. J , 1,531(1969) 9. Gardner , P., and Watso n, l.J ., " Adver se Drug Reactio ns: A Pharmaci st-Based Monitoring System, " Glin. Pharmacal. Ther., 11,802 (1970) 10. Hurwit z, N. , "Admissions to a Hospital Due to Drugs," Br. Med. J, 1, 539 (1969)
11 . Cluff, LE., Thornton, G.. Seidl, L , and Smith, J.. "Epidemiologica l Study of Adverse Drug Reactions," Trans. Assoc. Am. Physicians, 78, 255 (1965)
12. Seidl, L.G .. Thornton, G.F., Smith, FW., and Cluff, L.E. , " Studies on the Epidemiology of Adverse Drug Reacti ons," Bull. John Hopkins Hosp ., 119, 229 (1966) 13. May, FE, Stewart, R.B., and Cluff, L.E., "Drug Use in the Hospital: Eva luati on of Determinants," Glin. Pharmacol. Ther., 16, 834 (1974)
14. Jick, H., Miettinen, O.S., Shapiro, S., Lewis, S.P., Sisking, V. , and Slone, 0 ., "Comprehensive Drug Surve illance," JA MA, 213, 1455 (1 970)
15. McKenzie, MW., Stewart, R.B.. Weise. C.F., and Cluff, L.E., "A Pharmacist-Based Study of the Epidemiology of Adverse Drug Reactions in Pediatric Medicine Patients," Am. J. Hasp. Pharm. , 30, 898 (1973) 16. Moser, R. H., " IatrogeniC Di sorders," Military Medicine. 135,
61 9 (1970)
Med-i-Quiz Answers
1. 2. 3. 4. 5. 6. 7.
247
B A and Band D A , and D D B
e
e
e
8. 9. 10. 11. 12. 13. 14.
e e e
e
A , B, and D Band D
e
D