AMERICAN JOURNAL or EPIDEMIOLOGY
Copyright © 1979 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Vol 110, No 2 Printed m USA.
DRUG UTILIZATION AND REPORTED ADVERSE REACTIONS IN HOSPITALIZED CHILDREN ALLEN A. MITCHELL,1-1 PETER GOLDMAN,1 SAMUEL SHAPIRO1 AND DENNIS SLONE' Mitchell, A. A. (Children's Hospital Medical Center, Boston, MA 02115), P. Goldman, S. Shapiro and D. Slone. Drug utilization and reported adverse reactions in hospitalized children. Am J Epidemiol 110:196-204, 1979. An intensive drug surveillance program has been developed to study the clinical effects of drugs In hospitalized children. This program collects Information on drug exposures and the occurrence of adverse clinical events. The 1669 children monitored to date received an average of 7.6 drugs during an average hospital stay of 8.4 days. A group of specified adverse clinical events, whether or not drug attributed, occurred In 45.7% of the patients; drug-attributed events (adverse drug reactions) occurred in 16.8%. Both drug use and reported adverse reactions tended to Increase with age, except that newborns received many drugs but had the lowest reported adverse reaction rates. Newborns, however, had the highest rate of adverse events not attributed to drugs, suggesting that perhaps some of these latter events Include presently unrecognized adverse drug reactions. drug evaluation; drug utilization; pediatrics
Rational drug therapy requires an understanding of the benefits and hazards of drugs. The practitioner must therefore have information not only on the benefits to be expected from a given drug but also Received for publication September 6, 1978, and in final form December 26, 1978. Abbreviation: PeDS, Pediatric Drug Surveillance Program. 1 Clinical Pharmacology Unit, Children's Hospital Medical Center, the Departments of Pediatrics and Pharmacology, Harvard Medical School, the Center for the Analysis of Health Practices, Harvard School of Public Health, and 1 The Drug Epidemiology Unit, Boston University Medical Center, Boston, MA. Repnnt requests to Dr. Mitchell, Children's Hospital Medical Center, 300 Longwood Ave., Boston, MA 02115. This work was initiated under a Special Award from the Burroughs Wellcome Fund and was then supported by Contracts 223-74-3196 and 223-753036 from the US Food and Drug Administration. Dr. Mitchell was supported in part by a grant from the Robert Wood Johnson Foundation, through the Center for the Analysis of Health Practices. The authors thank the following individuals for their assistance: Marguerite Angeloni, R.N., Linda Bauer Cottier, R.N , Kathleen Carr, R.N , Clare Cavallero Kenny, R.N., Jo-Ellen Quinlan, R.N., Mr. Leonard F. Gaetano and Stuart Hartz, Sc.D.
on the nature, frequency and severity of adverse reactions that such a drug might cause. In addition, appropriate therapy for any individual requires an awareness of factors which may enhance the possible therapeutic benefits or increase the risk of an adverse reaction from the use of any drug. While the expected benefits of a prescribed drug are usually known, its hazards are frequently less well defined. An intensive Pediatric Drug Surveillance (PeDS) Program has been established on selected wards of the Children's Hospital Medical Center, Boston, Massachusetts, to obtain information on the clinical effects of drugs in children. This program uses methods modified from those developed by the Boston Collaborative Drug Surveillance Program to monitor hospitalized adults (1, 2). MATERIALS AND METHODS
Patients and data collection The Children's Hospital Medical Center is a 340-bed pediatric teaching hospital. Approximately one-half of the patients on
196
DRUG USE AND ADVERSE REACTIONS IN CHILDREN
the medical service have acute, selflimited illnesses that might be found in a community pediatric hospital. In addition to general medical and surgical wards, the hospital has sub-specialty wards that include the oncology, neurology and cardiology services. Further, patients with certain conditions (such as cystic fibrosis) tend to be referred selectively to this institution. Four wards have been monitored to date—two general medical wards, the oncology ward and the neonatal intensive care unit. Patients excluded from study are those who (a) have been previously monitored by the PeDS Program, (b) are under the care of physicians working on other wards, (c) are admitted to the ward for less than 24 hours, or (d) are transfers from unmonitored wards. Specially-trained pediatric nurses systematically collect data on patients admitted to the monitored wards. The nursemonitor stationed on the ward has no clinical responsibilities, and interviews the patient and/or parent upon admission, attends daily ward rounds, interviews doctors and nurses and reviews both doctors' orders and the complete medical record. Admission data are collected in three categories: general medical data, medication history, and admission laboratory information. General medical data include age, sex, race, height, weight, allergy history, immunizations, and exposure to pets. Medication history pertains to all drugs used in the three months prior to admission. Where appropriate, to enhance recall the nurse asks if drugs were taken either for specific indications (e.g., "fever") or by drug groups (e.g., "antibiotics"). The name of each drug is recorded, along with the frequency and duration of use ("6 years"). Laboratory test results obtained within 48 hours of admission are recorded, and include, when available, complete blood count, urinalysis, electrolytes, blood sugar, blood urea nitrogen,
197
creatinine, and bilirubin. Additional laboratory data are recorded from selected wards; for example, liver function test results are collected on the oncology ward. Hospitalization data. For each drug ordered during the period of surveillance, the date started, dose, route of administration, frequency, instruction (standing, statim, pro re nata, etc.) and indication for use are recorded. This information is obtained from doctors' orders supplemented, where appropriate, by interviews with the prescribing physician. When a drug order is stopped, the date and reason for stopping are recorded, and an efficacy rating ("satisfactory," "unsatisfactory," "don't know") is elicited from the physician, and, where appropriate, from the patient. During the patient's hospitalization, the nurse-monitor systematically seeks information concerning the occurrence of a large number of specified adverse events. Examples of such events include fever, coma, convulsions, renal failure, arrhythmia or electrocardiogram (EKG) changes, hypoglycemia, electrolyte changes, leukopenia, decreased hematocrit, and rash. A given adverse event may be attributed by some observers to drug therapy (i.e., an "adverse drug reaction," denned as an unintended or undesired effect of a drug) while others might not relate this event to drug therapy and consider it simply a manifestation of the patient's illness. For example, a rash occurring during ampicillin therapy for otitis media might be regarded by some as due to ampicillin and by others as due to a viral exanthem associated with the otitis itself. When an adverse event is considered by the observer to be drugattributed, the nurse-monitor fills out an "Adverse Reaction Report Sheet" for the implicated drug(s). This report includes a detailed description of the reaction and information on the drug order implicated. In addition, a judgment on causality is obtained from both the patient's physician
198
MITCHELL, GOLDMAN, SHAPIRO AND SLONE
and an investigator from the PeDS Program. Adverse events not attributed to therapy are noted on a separate "Event List" that identifies certain clinical occurrences, as cited above, which might constitute unrecognized adverse drug reactions. Each observed event is described in detail on an "Event Report Sheet." Discharge data. When a patient is discharged from the monitored ward, the date of discharge and outcome of hospitalization (death, return home, transfer to another ward, etc.) are recorded. In addition, the first four discharge diagnoses are recorded and coded (International Classification ofDiseases, Eighth Revision (3)). Data processing The nurse-monitor assembles and checks the data forms of each completed record and forwards them to the Drug Epidemiology Unit where they are reviewed by a nurse and then a physician for completeness and internal consistency. The data are then transferred directly to keypunch cards. Prior to entry onto computer file, the data are subjected to a variety of computer tests that validate the consistency of dates, the legitimacy of drug and diagnosis code numbers, and the presence of all required data sheets. This review procedure is designed to identify errors or inconsistencies in the data; alterations are not made without specific review of the information in question. A number of standard computer programs are used to describe and evaluate the data contained on magnetic tape, and ad hoc analyses are conducted when appropriate. RESULTS
Data from 1669 patients monitored between 1974 and 1977 have been analyzed. Of these, 833 were from a general medical infant/toddler ward, 573 from a general medical older children's ward, 141 from an oncology ward, and 122 from an intensive care newborn nursery. The mean age
on admission of this population was 6.8 years; 57 per cent were males and 77 per cent were white. The diagnoses most commonly encountered in the study population (table 1) reflect both the nature of the Children's Hospital Medical Center and the wards selected for study. Thus, 9.3 per cent of all patients had asthma and 7.0 per cent had cystic fibrosis. Infectious diseases accounted for a majority of the remaining diagnoses. Monitored patients stayed in the hospital an average of 8.4 days and were given an average of 7.6 drugs. Both the duration of hospital stay and number of drugs received varied among the monitored wards (table 2); newborn infants in the intensive care nursery received the most drugs (mean, 10.4) and had the longest stay (mean, 10.2 days), whereas children on the general medical wards received the fewest drugs (6.0 on the infant/toddler ward and 8.9 on the older children's ward) and stayed in the hospital an average of approximately 8.4 days. In addition, hospital stay and drug utilization also varied by diagnosis. For example, patients with a primary diagnosis of cystic fibrosis received an average of 15.6 drugs over a hospital stay of 11.1 days. Table 3 lists the drugs most frequently used during the period of surveillance. Intravenous dextrose 5 per cent - 0.2 per cent saline was given to approximately 60 per cent of children, potassium chloride to 38 per cent and acetaminophen to 31 per cent. Oxygen, antibiotics and bronchodilators were also given frequently, as were other intravenous fluids. The most common indications for the use of drugs in the hospital (table 4) are as follows: 15.6 per cent of all drug orders were for infection whereas 17.9 per cent were for fluid/electrolyte therapy; approximately 6 per cent were written for the sole purpose of maintaining the patency of an intravenous line ("keep vein open"). Drugs ordered for this last indication in-
199
DRUG USE AND ADVERSE REACTIONS IN CHILDREN TABLE 1
Most common discharge diagnoses among 1669 hospitalized children* Boston, MA, 1974-1977 No. of patients
Discharge diagnosis
Pneumonia Asthma Gastroenteritis/diarrhea Otitis media Cystic fibrosis Convulsions/seizure disorder Upper respiratory infection Cancer (excludes leukemia) Leukemia Anemia—iron deficient & unspecified Dehydration Failure-to-thrive Meningitis Prematurity Viral infection
159 156 142 124 117 87 81 80
79 77 77 65 61 58 51
95 93 8.5 74 7.0 5.2 4.9 4.8 4.7 46 4.6 3.9 37 35 31
* Categories are not mutually exclusive. TABLB 2
Mean duration of hospitalization and mean number of drugs administered, by ward and selected diagnoses, among 1669 hospitalized children, Boston, MA, 1974-1977 Category
All patients By ward Older children Infantstoddler Oncology Newborn By primary diagnosis Asthma Cystic fibrosis
No of patients
Mean duration of hospitaluation (days)
1669
84
7.6
573 833 141 122
83 85 6.6 10.2
89 6.0 10.1 10.4
145 115
5.5 11.1
8.5 15.6
eluded heparin, sodium bicarbonate and hydrocortisone. Thefrequencyof various adverse events, whether or not attributed to drug therapy, is presented in table 5; 45.7 per cent of the children monitored experienced one or more of these events. Fever developed or increased beyond the admission value in 20.8 per cent of the children. When fever is excluded, adverse events were recorded in 36.1 per cent. Onset or worsening of anemia was observed in 7.0 per cent of the monitored patients. Disturbed liver function tests, urinary abnormalities and rash
Mean no of drugs
each occurred in more than 5 per cent of the subjects. Adverse events that were attributed to drugs (i.e., adverse drug reactions) are shown in table 6. Vomiting was attributed to drug therapy in 4.2 per cent of all patients, rash in 2.6 per cent and complications related to intravenous, intramuscular or subcutaneous injections in. 2.2 per cent. Although adverse reactions were reported in 16.8 per cent of all children, certain groups of patients were more likely to be considered to have such reactions. Thus, adverse drug reactions were re-
200
MITCHELL, GOLDMAN, SHAPIRO AND SLONE TABLE 3
Drugs used most frequently among 1669 hospitalized children* Boston, MA, 1974-1977 No of patients
Drugt Dextrose 5%-NaCl 0.2% Potassium chloride Acetaminophen Ampicillin Oxygen Gentamicin Oxacillin NaCl, 0.9% Aminophylline Multivitamins Hydrocortisone Chloramphenicol Dextrose 5% -water Heparin Packed red blood cells Penicillin G Prednisone
995 637 523 394 381 286 268 265 238 221 183 180 179 179 179 179 169
59.6 38.2 31.3 23 6 22 8 17.1 16.1 15.9 14.3 13.2 11.0 10 8 10 7 10 7 10.7 10.7 10.1
• Categories are not mutually exclusive. t The term drug was taken to include agents such as oxygen, ophthalmic solutions, intravenous additives and local anesthetics. TABLE 4
Most common indications for drug therapy among 1669 hospitalized children* Boston, MA, 1974—1977 (18,416 drug orders in 1669 patients) Indication
Infection Dehydration/fluid maintenance Electrolyte therapy Broncho8pasm "Keep vein open" Pre-medication Fever Prophylaxis, vitamin depletion Convulsions/seizures Tumor therapy Diabetes Hypoxemia Drug vehicle Anesthesia Pain
No of orders 2877
1740 1568 1474 1058 858 749 581 511 482
461 386 377 330 305
15 6 9.4 85 8.0 5.7 4.7 4.1 3.2 2.8 26 2.5 2.1 2.0 1.8 1.7
* Categories are not mutually exclusive.
ported in 52.5 per cent of oncology patients, while one or more such drugattributed events were noted in approximately 13.5 per cent of 1528 patients without cancer. Adverse drug reaction rates reported for 12 drugs given to at least 50 patients are
listed in table 7. Over one-third of children receiving vincristine were noted to have an adverse drug reaction, as were more than 10 per cent of patients exposed to phenytoin, chlorpromazine or furosemide. Age relationships. The relationship of
201
DRUG USE AND ADVERSE REACTIONS IN CHILDREN TABLE 5
Most common adverse events among 1669 hospitalized children* Boston, MA, 1974-1977, irrespective of drug attribution Adverse event
No of patients
%
Fever Anemia Disturbed liver function testa Urinalysis abnormalities! Rash/hives Gastrointestinal bleeding} Infection Arrhythmia/EKG abnormality Convulsions Electrolyte imbalance Leukopenia
347 117 92 92 90 82 71 70 59 49 49
20.8 7.0 55 55 5.4 4.9 43 42 3.5 29 2.9
• Categories are not mutually exclusive. t Includes hematuna, pyuria, proteinuria, glycosuria. t Includes occult blood loss TABLE 6
Most common drug-attributed events (adverse drug reactions) reported among 1669 hospitalized children,* Boston, MA, 1974-1977 Drug-attributed event
No of patients
Vomiting Rash Injection site complication Nausea Leukopenia Diarrhea Tachycardia/arrhythmia Drowsiness Drug-related infection Fluid retention
70 44 36 33 28 22 18 17 14 12
42 2.6 2.2 20 17 13 1.1 1.0 0.8 07
* Categories are not mutually exclusive.
drug use to patient age in the monitored population is presented in figure 1. After the newborn period, the average number of drugs received during hospitalization increased with age, going from 5.9 among infants to 11.9 among patients 17 years of age and older. Newborns, both in the intensive care nursery and on the other wards received, on average, 9.4 drugs. The age distribution of adverse events, both those attributed and those not attributed to drugs, is shown in figure 2. Drug-attributed events (adverse drug reactions) ranged in frequency from 10.6 per cent in newborns to 23.6 per cent in
patients over 16 years of age. On the other hand, the frequency of events not attributed to drugs tended to decline with increasing age: whereas such adverse events occurred in 74 per cent of newborns, they occurred in 35 per cent of older children. DISCUSSION
Patients in this study received an average of 7.6 drugs during a hospital stay which averaged 8.4 days, a drug use higher than that described previously. Reports of drug surveillance efforts in the early 1970s (4, 5), which monitored ap-
202
MITCHELL, GOLDMAN, SHAPIRO AND SLONE TABLE 7
Adverse reaction rates to drugs received by at least 50 hospitalized children* Boston, MA, 1974-1977 Reported adverse reactions/ no exposed
Drug Vincrifltine Phenytoin Chlorpromazine Furosemide Phenobarbital Prednisone Packed RBC Theophylline Ampicillin Penicillin Morphine Carbenicillin
31/85 8/69 7/67 8/78 10/102 15/169 14/179 12/163 28/394 17/268 6/113 4/80
36.5 11.6 10.4 10.3 9.8 8.9 78 7.4 7.1 6.3 5.3 5.0
* Rates are in descending order of frequency
proximately 1000 pediatric patients, indicated that 4.3 drugs were used during a hospital stay of about nine days. One review of records from a neonatal intensive care unit noted that newborns received 3.4 drugs over 14 days (6). Part of the difference in drug use may be explained by changing therapeutic practices in the time between the completion of previous surveillance programs and initiation of the PeDS Program. The greater use of drugs in the present study may also be explained in part by the definition of a
\ 1 NEWBORN
3
5
7
9
ti
13
15
£17
AGE (YEARS)
FIGURE 1. Average drug exposure among 1669 hospitalized children, by age, Boston, MA, 1974-1977.
drug as used by the PeDS Program. This definition has deliberately been made broader than that used in previous studies, and thus includes agents such as supplemental oxygen, ophthalmic solutions, intravenous additives and local anesthetics. The broader definition serves to facilitate the identification of agents which are often considered innocuous, but which may in fact have direct or indirect adverse effects (e.g., supplemental oxygen can produce retrolental fibroplasia (7)). One or more of a set of specified adverse events occurred during the hospital stay in almost one-half of the monitored population. Even when fever (the most com-
t 1 NEWBORN
3
S
7
9
11
13
15
»17
AGE tYEARS
FIGURE 2. Rates of adverse events (both attributed and not attributed to drugB) among 1669 hospitahxed children, by age, Boston, MA, 1974-1977.
DRUG USE AND ADVERSE REACTIONS IN CHILDREN
mon event) was excluded, over one-third of the hospitalized patients developed adverse events such as anemia, disturbed liver function tests, urinalysis abnormalities, rashes or gastrointestinal bleeding. Adverse events were attributed to drug therapy in 16.8 per cent of the study population, and were four times higher in oncology patients (52.5 per cent) than in children without cancer (13.5 per cent). These findings agree with previous studies which reported adverse reaction rates of 10.6 per cent (4) and 12.7 per cent (5) among children on general wards, as well as with one study which reported adverse reactions in 56 per cent of 63 children on a hematology-oncology service (8). Drug effects observed in monitored populations are not necessarily meaningful unless the nature of the population is specified. For example, in one study (5) less than 10 per cent of pediatric patients had cancer, asthma or cystic fibrosis, whereas these conditions were present in more than 25 per cent of the population of this study. The present findings are derived from pediatric patients admitted to selected wards in a large teaching hospital and therefore should not necessarily be generalized to all children or even to all hospitalized children. Differences in the population under study clearly affect patterns of drug use, since numerous drugs are used to treat certain conditions (e.g., cancer, cystic fibrosis), while relatively few drugs are used to treat others (e.g., asthma). Patterns of drug utilization and the nature of the study population, in turn, affect the nature and frequency of adverse drug reactions. Thus, it is difficult to compare patterns of drug use and adverse reactions among the few pediatric studies reported to date. Although comparisons among studies are difficult, patterns of drug use and effects can be evaluated within a given study. In the population of this study, drug use appears to increase with increas-
203
ing age, with the notable exception of neonates, among whom the number of drugs used was second only to the oldest patients. This observation is consistent with the age-related nature of disease encountered among patients at the Children's Hospital Medical Center: Most of the newborns were treated in a neonatal intensive care unit specializing in the care of critically ill neonates; infants and toddlers tended to have acute infectious diseases requiring relatively short hospital stays and received the fewest drugs; older children and adolescents tended to have more chronic and severe illnesses, such as asthma, cystic fibrosis, inflammatory bowel disease and renal disease, which require long hospital stays and the use of many drugs. Drug use increased with age from infancy through adolescence, and it is not surprising, therefore, that rates of reported adverse reactions also tended to rise with age. The concordance between drug use and the rate of adverse drug reactions did not apply to neonates, however, where the rate of drug exposure was among the highest while the reported adverse reaction rate was the lowest. On the other hand, adverse clinical events not attributed to drugs occurred twice as frequently among neonates as among other patients, suggesting perhaps that some of these events may be unperceived adverse drug reactions. The neonatal population is relatively new to the hospital and contains many infants who would not have survived only a decade ago. Thus, there is little experience with the nature of adverse drug reactions in this population which, because of immaturity of both drug metabolic capability of the liver and drug elimination by the kidney, may be expected to have different patterns of adverse reactions. A goal of this program is to identify those adverse reactions that now may be perceived simply as adverse clinical events in the neonate and to do the same for certain adverse drug reac-
204
MITCHELL, GOLDMAN, SHAPIRO AND 8LONE
tions that are presently unrecognized in older children as well. To detect unsuspected adverse drug effects, the PeDS Program evaluates all adverse events (whether drug-attributed or not) with the aid of computer programs that are used to compare the frequencies of such events according to exposure or non-exposure to each drug. Specific associations between a given drug and a given outcome, signaled in this way, can then be analyzed in detail to determine whether a causal inference appears to be justified. For example, if the association between ampicillin and rash were unknown or blamed on other drugs, it would be revealed by routine computer programs which compare the frequency of rash among patients exposed to ampicillin with the corresponding frequency of rash among non-exposed (i.e., all other) patients. In this way, reactions may be identified which, because of preconceptions and limited experience of a single observer, may have gone undetected. Such surveillance facilitates the more accurate estimation of rates of adverse drug reactions. Intensive surveillance of hospitalized patients has already provided the clini-
cian with new insights into the clinical effects of drugs in adults. The PeDS Program seeks to obtain similar information for the pediatric population. It is hoped that information gained from systematic studies of drug effects such as those outlined here will improve the pediatrician's ability to assess the risks and benefits of drug therapy in children. REFERENCES
1. Miller RR, Greenblatt DJ (Editors): Drug Effects in Hospitalized Patients. New York, John Wiley & Sons, 1976 2. Jick H, Miettinen OS, Shapiro S, et al: Comprehensive drug surveillance. JAMA 213: 1455-1460, 1970 3. US Department of Health, Education, and Welfare. Eighth revision. International Classification of Diseases. Washington DC, US GPO, 1968 4. McKensie MW, Stewart RB, Weiss CF, et al: A pharmacist-based study of the epidemiology of adverse drug reactions in pediatric medicine patients. Am J Hosp Pharm 30:898-903, 1973 5. Lawson DH, Shapiro S, Slone D, et al: Drug surveillance: problems and challenges. Pediatr Clin North Am 19:117-129, 1972 6 Aranda JV, Cohen S, Neims AH: Drug utilization in a newborn intensive care unit. J Pediatr 89:315-317, 1976 7. Patz A: Oxygen studies in retrolental fibroplasia: Clinical and experimental observations. Am J Ophth 38:291-301, 1954 8 Collins GE, Clay MM, Falletta JM: A prospective study of the epidemiology of adverse drug reactions in pediatric hematology and oncology patients. Am J Hosp Pharm 31:968-975, 1974
Copyright © 1979 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Vol 110, No 2 Printed m USA.
DRUG UTILIZATION AND REPORTED ADVERSE REACTIONS IN HOSPITALIZED CHILDREN ALLEN A. MITCHELL,1-1 PETER GOLDMAN,1 SAMUEL SHAPIRO1 AND DENNIS SLONE' Mitchell, A. A. (Children's Hospital Medical Center, Boston, MA 02115), P. Goldman, S. Shapiro and D. Slone. Drug utilization and reported adverse reactions in hospitalized children. Am J Epidemiol 110:196-204, 1979. An intensive drug surveillance program has been developed to study the clinical effects of drugs In hospitalized children. This program collects Information on drug exposures and the occurrence of adverse clinical events. The 1669 children monitored to date received an average of 7.6 drugs during an average hospital stay of 8.4 days. A group of specified adverse clinical events, whether or not drug attributed, occurred In 45.7% of the patients; drug-attributed events (adverse drug reactions) occurred in 16.8%. Both drug use and reported adverse reactions tended to Increase with age, except that newborns received many drugs but had the lowest reported adverse reaction rates. Newborns, however, had the highest rate of adverse events not attributed to drugs, suggesting that perhaps some of these latter events Include presently unrecognized adverse drug reactions. drug evaluation; drug utilization; pediatrics
Rational drug therapy requires an understanding of the benefits and hazards of drugs. The practitioner must therefore have information not only on the benefits to be expected from a given drug but also Received for publication September 6, 1978, and in final form December 26, 1978. Abbreviation: PeDS, Pediatric Drug Surveillance Program. 1 Clinical Pharmacology Unit, Children's Hospital Medical Center, the Departments of Pediatrics and Pharmacology, Harvard Medical School, the Center for the Analysis of Health Practices, Harvard School of Public Health, and 1 The Drug Epidemiology Unit, Boston University Medical Center, Boston, MA. Repnnt requests to Dr. Mitchell, Children's Hospital Medical Center, 300 Longwood Ave., Boston, MA 02115. This work was initiated under a Special Award from the Burroughs Wellcome Fund and was then supported by Contracts 223-74-3196 and 223-753036 from the US Food and Drug Administration. Dr. Mitchell was supported in part by a grant from the Robert Wood Johnson Foundation, through the Center for the Analysis of Health Practices. The authors thank the following individuals for their assistance: Marguerite Angeloni, R.N., Linda Bauer Cottier, R.N , Kathleen Carr, R.N , Clare Cavallero Kenny, R.N., Jo-Ellen Quinlan, R.N., Mr. Leonard F. Gaetano and Stuart Hartz, Sc.D.
on the nature, frequency and severity of adverse reactions that such a drug might cause. In addition, appropriate therapy for any individual requires an awareness of factors which may enhance the possible therapeutic benefits or increase the risk of an adverse reaction from the use of any drug. While the expected benefits of a prescribed drug are usually known, its hazards are frequently less well defined. An intensive Pediatric Drug Surveillance (PeDS) Program has been established on selected wards of the Children's Hospital Medical Center, Boston, Massachusetts, to obtain information on the clinical effects of drugs in children. This program uses methods modified from those developed by the Boston Collaborative Drug Surveillance Program to monitor hospitalized adults (1, 2). MATERIALS AND METHODS
Patients and data collection The Children's Hospital Medical Center is a 340-bed pediatric teaching hospital. Approximately one-half of the patients on
196
DRUG USE AND ADVERSE REACTIONS IN CHILDREN
the medical service have acute, selflimited illnesses that might be found in a community pediatric hospital. In addition to general medical and surgical wards, the hospital has sub-specialty wards that include the oncology, neurology and cardiology services. Further, patients with certain conditions (such as cystic fibrosis) tend to be referred selectively to this institution. Four wards have been monitored to date—two general medical wards, the oncology ward and the neonatal intensive care unit. Patients excluded from study are those who (a) have been previously monitored by the PeDS Program, (b) are under the care of physicians working on other wards, (c) are admitted to the ward for less than 24 hours, or (d) are transfers from unmonitored wards. Specially-trained pediatric nurses systematically collect data on patients admitted to the monitored wards. The nursemonitor stationed on the ward has no clinical responsibilities, and interviews the patient and/or parent upon admission, attends daily ward rounds, interviews doctors and nurses and reviews both doctors' orders and the complete medical record. Admission data are collected in three categories: general medical data, medication history, and admission laboratory information. General medical data include age, sex, race, height, weight, allergy history, immunizations, and exposure to pets. Medication history pertains to all drugs used in the three months prior to admission. Where appropriate, to enhance recall the nurse asks if drugs were taken either for specific indications (e.g., "fever") or by drug groups (e.g., "antibiotics"). The name of each drug is recorded, along with the frequency and duration of use ("6 years"). Laboratory test results obtained within 48 hours of admission are recorded, and include, when available, complete blood count, urinalysis, electrolytes, blood sugar, blood urea nitrogen,
197
creatinine, and bilirubin. Additional laboratory data are recorded from selected wards; for example, liver function test results are collected on the oncology ward. Hospitalization data. For each drug ordered during the period of surveillance, the date started, dose, route of administration, frequency, instruction (standing, statim, pro re nata, etc.) and indication for use are recorded. This information is obtained from doctors' orders supplemented, where appropriate, by interviews with the prescribing physician. When a drug order is stopped, the date and reason for stopping are recorded, and an efficacy rating ("satisfactory," "unsatisfactory," "don't know") is elicited from the physician, and, where appropriate, from the patient. During the patient's hospitalization, the nurse-monitor systematically seeks information concerning the occurrence of a large number of specified adverse events. Examples of such events include fever, coma, convulsions, renal failure, arrhythmia or electrocardiogram (EKG) changes, hypoglycemia, electrolyte changes, leukopenia, decreased hematocrit, and rash. A given adverse event may be attributed by some observers to drug therapy (i.e., an "adverse drug reaction," denned as an unintended or undesired effect of a drug) while others might not relate this event to drug therapy and consider it simply a manifestation of the patient's illness. For example, a rash occurring during ampicillin therapy for otitis media might be regarded by some as due to ampicillin and by others as due to a viral exanthem associated with the otitis itself. When an adverse event is considered by the observer to be drugattributed, the nurse-monitor fills out an "Adverse Reaction Report Sheet" for the implicated drug(s). This report includes a detailed description of the reaction and information on the drug order implicated. In addition, a judgment on causality is obtained from both the patient's physician
198
MITCHELL, GOLDMAN, SHAPIRO AND SLONE
and an investigator from the PeDS Program. Adverse events not attributed to therapy are noted on a separate "Event List" that identifies certain clinical occurrences, as cited above, which might constitute unrecognized adverse drug reactions. Each observed event is described in detail on an "Event Report Sheet." Discharge data. When a patient is discharged from the monitored ward, the date of discharge and outcome of hospitalization (death, return home, transfer to another ward, etc.) are recorded. In addition, the first four discharge diagnoses are recorded and coded (International Classification ofDiseases, Eighth Revision (3)). Data processing The nurse-monitor assembles and checks the data forms of each completed record and forwards them to the Drug Epidemiology Unit where they are reviewed by a nurse and then a physician for completeness and internal consistency. The data are then transferred directly to keypunch cards. Prior to entry onto computer file, the data are subjected to a variety of computer tests that validate the consistency of dates, the legitimacy of drug and diagnosis code numbers, and the presence of all required data sheets. This review procedure is designed to identify errors or inconsistencies in the data; alterations are not made without specific review of the information in question. A number of standard computer programs are used to describe and evaluate the data contained on magnetic tape, and ad hoc analyses are conducted when appropriate. RESULTS
Data from 1669 patients monitored between 1974 and 1977 have been analyzed. Of these, 833 were from a general medical infant/toddler ward, 573 from a general medical older children's ward, 141 from an oncology ward, and 122 from an intensive care newborn nursery. The mean age
on admission of this population was 6.8 years; 57 per cent were males and 77 per cent were white. The diagnoses most commonly encountered in the study population (table 1) reflect both the nature of the Children's Hospital Medical Center and the wards selected for study. Thus, 9.3 per cent of all patients had asthma and 7.0 per cent had cystic fibrosis. Infectious diseases accounted for a majority of the remaining diagnoses. Monitored patients stayed in the hospital an average of 8.4 days and were given an average of 7.6 drugs. Both the duration of hospital stay and number of drugs received varied among the monitored wards (table 2); newborn infants in the intensive care nursery received the most drugs (mean, 10.4) and had the longest stay (mean, 10.2 days), whereas children on the general medical wards received the fewest drugs (6.0 on the infant/toddler ward and 8.9 on the older children's ward) and stayed in the hospital an average of approximately 8.4 days. In addition, hospital stay and drug utilization also varied by diagnosis. For example, patients with a primary diagnosis of cystic fibrosis received an average of 15.6 drugs over a hospital stay of 11.1 days. Table 3 lists the drugs most frequently used during the period of surveillance. Intravenous dextrose 5 per cent - 0.2 per cent saline was given to approximately 60 per cent of children, potassium chloride to 38 per cent and acetaminophen to 31 per cent. Oxygen, antibiotics and bronchodilators were also given frequently, as were other intravenous fluids. The most common indications for the use of drugs in the hospital (table 4) are as follows: 15.6 per cent of all drug orders were for infection whereas 17.9 per cent were for fluid/electrolyte therapy; approximately 6 per cent were written for the sole purpose of maintaining the patency of an intravenous line ("keep vein open"). Drugs ordered for this last indication in-
199
DRUG USE AND ADVERSE REACTIONS IN CHILDREN TABLE 1
Most common discharge diagnoses among 1669 hospitalized children* Boston, MA, 1974-1977 No. of patients
Discharge diagnosis
Pneumonia Asthma Gastroenteritis/diarrhea Otitis media Cystic fibrosis Convulsions/seizure disorder Upper respiratory infection Cancer (excludes leukemia) Leukemia Anemia—iron deficient & unspecified Dehydration Failure-to-thrive Meningitis Prematurity Viral infection
159 156 142 124 117 87 81 80
79 77 77 65 61 58 51
95 93 8.5 74 7.0 5.2 4.9 4.8 4.7 46 4.6 3.9 37 35 31
* Categories are not mutually exclusive. TABLB 2
Mean duration of hospitalization and mean number of drugs administered, by ward and selected diagnoses, among 1669 hospitalized children, Boston, MA, 1974-1977 Category
All patients By ward Older children Infantstoddler Oncology Newborn By primary diagnosis Asthma Cystic fibrosis
No of patients
Mean duration of hospitaluation (days)
1669
84
7.6
573 833 141 122
83 85 6.6 10.2
89 6.0 10.1 10.4
145 115
5.5 11.1
8.5 15.6
eluded heparin, sodium bicarbonate and hydrocortisone. Thefrequencyof various adverse events, whether or not attributed to drug therapy, is presented in table 5; 45.7 per cent of the children monitored experienced one or more of these events. Fever developed or increased beyond the admission value in 20.8 per cent of the children. When fever is excluded, adverse events were recorded in 36.1 per cent. Onset or worsening of anemia was observed in 7.0 per cent of the monitored patients. Disturbed liver function tests, urinary abnormalities and rash
Mean no of drugs
each occurred in more than 5 per cent of the subjects. Adverse events that were attributed to drugs (i.e., adverse drug reactions) are shown in table 6. Vomiting was attributed to drug therapy in 4.2 per cent of all patients, rash in 2.6 per cent and complications related to intravenous, intramuscular or subcutaneous injections in. 2.2 per cent. Although adverse reactions were reported in 16.8 per cent of all children, certain groups of patients were more likely to be considered to have such reactions. Thus, adverse drug reactions were re-
200
MITCHELL, GOLDMAN, SHAPIRO AND SLONE TABLE 3
Drugs used most frequently among 1669 hospitalized children* Boston, MA, 1974-1977 No of patients
Drugt Dextrose 5%-NaCl 0.2% Potassium chloride Acetaminophen Ampicillin Oxygen Gentamicin Oxacillin NaCl, 0.9% Aminophylline Multivitamins Hydrocortisone Chloramphenicol Dextrose 5% -water Heparin Packed red blood cells Penicillin G Prednisone
995 637 523 394 381 286 268 265 238 221 183 180 179 179 179 179 169
59.6 38.2 31.3 23 6 22 8 17.1 16.1 15.9 14.3 13.2 11.0 10 8 10 7 10 7 10.7 10.7 10.1
• Categories are not mutually exclusive. t The term drug was taken to include agents such as oxygen, ophthalmic solutions, intravenous additives and local anesthetics. TABLE 4
Most common indications for drug therapy among 1669 hospitalized children* Boston, MA, 1974—1977 (18,416 drug orders in 1669 patients) Indication
Infection Dehydration/fluid maintenance Electrolyte therapy Broncho8pasm "Keep vein open" Pre-medication Fever Prophylaxis, vitamin depletion Convulsions/seizures Tumor therapy Diabetes Hypoxemia Drug vehicle Anesthesia Pain
No of orders 2877
1740 1568 1474 1058 858 749 581 511 482
461 386 377 330 305
15 6 9.4 85 8.0 5.7 4.7 4.1 3.2 2.8 26 2.5 2.1 2.0 1.8 1.7
* Categories are not mutually exclusive.
ported in 52.5 per cent of oncology patients, while one or more such drugattributed events were noted in approximately 13.5 per cent of 1528 patients without cancer. Adverse drug reaction rates reported for 12 drugs given to at least 50 patients are
listed in table 7. Over one-third of children receiving vincristine were noted to have an adverse drug reaction, as were more than 10 per cent of patients exposed to phenytoin, chlorpromazine or furosemide. Age relationships. The relationship of
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DRUG USE AND ADVERSE REACTIONS IN CHILDREN TABLE 5
Most common adverse events among 1669 hospitalized children* Boston, MA, 1974-1977, irrespective of drug attribution Adverse event
No of patients
%
Fever Anemia Disturbed liver function testa Urinalysis abnormalities! Rash/hives Gastrointestinal bleeding} Infection Arrhythmia/EKG abnormality Convulsions Electrolyte imbalance Leukopenia
347 117 92 92 90 82 71 70 59 49 49
20.8 7.0 55 55 5.4 4.9 43 42 3.5 29 2.9
• Categories are not mutually exclusive. t Includes hematuna, pyuria, proteinuria, glycosuria. t Includes occult blood loss TABLE 6
Most common drug-attributed events (adverse drug reactions) reported among 1669 hospitalized children,* Boston, MA, 1974-1977 Drug-attributed event
No of patients
Vomiting Rash Injection site complication Nausea Leukopenia Diarrhea Tachycardia/arrhythmia Drowsiness Drug-related infection Fluid retention
70 44 36 33 28 22 18 17 14 12
42 2.6 2.2 20 17 13 1.1 1.0 0.8 07
* Categories are not mutually exclusive.
drug use to patient age in the monitored population is presented in figure 1. After the newborn period, the average number of drugs received during hospitalization increased with age, going from 5.9 among infants to 11.9 among patients 17 years of age and older. Newborns, both in the intensive care nursery and on the other wards received, on average, 9.4 drugs. The age distribution of adverse events, both those attributed and those not attributed to drugs, is shown in figure 2. Drug-attributed events (adverse drug reactions) ranged in frequency from 10.6 per cent in newborns to 23.6 per cent in
patients over 16 years of age. On the other hand, the frequency of events not attributed to drugs tended to decline with increasing age: whereas such adverse events occurred in 74 per cent of newborns, they occurred in 35 per cent of older children. DISCUSSION
Patients in this study received an average of 7.6 drugs during a hospital stay which averaged 8.4 days, a drug use higher than that described previously. Reports of drug surveillance efforts in the early 1970s (4, 5), which monitored ap-
202
MITCHELL, GOLDMAN, SHAPIRO AND SLONE TABLE 7
Adverse reaction rates to drugs received by at least 50 hospitalized children* Boston, MA, 1974-1977 Reported adverse reactions/ no exposed
Drug Vincrifltine Phenytoin Chlorpromazine Furosemide Phenobarbital Prednisone Packed RBC Theophylline Ampicillin Penicillin Morphine Carbenicillin
31/85 8/69 7/67 8/78 10/102 15/169 14/179 12/163 28/394 17/268 6/113 4/80
36.5 11.6 10.4 10.3 9.8 8.9 78 7.4 7.1 6.3 5.3 5.0
* Rates are in descending order of frequency
proximately 1000 pediatric patients, indicated that 4.3 drugs were used during a hospital stay of about nine days. One review of records from a neonatal intensive care unit noted that newborns received 3.4 drugs over 14 days (6). Part of the difference in drug use may be explained by changing therapeutic practices in the time between the completion of previous surveillance programs and initiation of the PeDS Program. The greater use of drugs in the present study may also be explained in part by the definition of a
\ 1 NEWBORN
3
5
7
9
ti
13
15
£17
AGE (YEARS)
FIGURE 1. Average drug exposure among 1669 hospitalized children, by age, Boston, MA, 1974-1977.
drug as used by the PeDS Program. This definition has deliberately been made broader than that used in previous studies, and thus includes agents such as supplemental oxygen, ophthalmic solutions, intravenous additives and local anesthetics. The broader definition serves to facilitate the identification of agents which are often considered innocuous, but which may in fact have direct or indirect adverse effects (e.g., supplemental oxygen can produce retrolental fibroplasia (7)). One or more of a set of specified adverse events occurred during the hospital stay in almost one-half of the monitored population. Even when fever (the most com-
t 1 NEWBORN
3
S
7
9
11
13
15
»17
AGE tYEARS
FIGURE 2. Rates of adverse events (both attributed and not attributed to drugB) among 1669 hospitahxed children, by age, Boston, MA, 1974-1977.
DRUG USE AND ADVERSE REACTIONS IN CHILDREN
mon event) was excluded, over one-third of the hospitalized patients developed adverse events such as anemia, disturbed liver function tests, urinalysis abnormalities, rashes or gastrointestinal bleeding. Adverse events were attributed to drug therapy in 16.8 per cent of the study population, and were four times higher in oncology patients (52.5 per cent) than in children without cancer (13.5 per cent). These findings agree with previous studies which reported adverse reaction rates of 10.6 per cent (4) and 12.7 per cent (5) among children on general wards, as well as with one study which reported adverse reactions in 56 per cent of 63 children on a hematology-oncology service (8). Drug effects observed in monitored populations are not necessarily meaningful unless the nature of the population is specified. For example, in one study (5) less than 10 per cent of pediatric patients had cancer, asthma or cystic fibrosis, whereas these conditions were present in more than 25 per cent of the population of this study. The present findings are derived from pediatric patients admitted to selected wards in a large teaching hospital and therefore should not necessarily be generalized to all children or even to all hospitalized children. Differences in the population under study clearly affect patterns of drug use, since numerous drugs are used to treat certain conditions (e.g., cancer, cystic fibrosis), while relatively few drugs are used to treat others (e.g., asthma). Patterns of drug utilization and the nature of the study population, in turn, affect the nature and frequency of adverse drug reactions. Thus, it is difficult to compare patterns of drug use and adverse reactions among the few pediatric studies reported to date. Although comparisons among studies are difficult, patterns of drug use and effects can be evaluated within a given study. In the population of this study, drug use appears to increase with increas-
203
ing age, with the notable exception of neonates, among whom the number of drugs used was second only to the oldest patients. This observation is consistent with the age-related nature of disease encountered among patients at the Children's Hospital Medical Center: Most of the newborns were treated in a neonatal intensive care unit specializing in the care of critically ill neonates; infants and toddlers tended to have acute infectious diseases requiring relatively short hospital stays and received the fewest drugs; older children and adolescents tended to have more chronic and severe illnesses, such as asthma, cystic fibrosis, inflammatory bowel disease and renal disease, which require long hospital stays and the use of many drugs. Drug use increased with age from infancy through adolescence, and it is not surprising, therefore, that rates of reported adverse reactions also tended to rise with age. The concordance between drug use and the rate of adverse drug reactions did not apply to neonates, however, where the rate of drug exposure was among the highest while the reported adverse reaction rate was the lowest. On the other hand, adverse clinical events not attributed to drugs occurred twice as frequently among neonates as among other patients, suggesting perhaps that some of these events may be unperceived adverse drug reactions. The neonatal population is relatively new to the hospital and contains many infants who would not have survived only a decade ago. Thus, there is little experience with the nature of adverse drug reactions in this population which, because of immaturity of both drug metabolic capability of the liver and drug elimination by the kidney, may be expected to have different patterns of adverse reactions. A goal of this program is to identify those adverse reactions that now may be perceived simply as adverse clinical events in the neonate and to do the same for certain adverse drug reac-
204
MITCHELL, GOLDMAN, SHAPIRO AND 8LONE
tions that are presently unrecognized in older children as well. To detect unsuspected adverse drug effects, the PeDS Program evaluates all adverse events (whether drug-attributed or not) with the aid of computer programs that are used to compare the frequencies of such events according to exposure or non-exposure to each drug. Specific associations between a given drug and a given outcome, signaled in this way, can then be analyzed in detail to determine whether a causal inference appears to be justified. For example, if the association between ampicillin and rash were unknown or blamed on other drugs, it would be revealed by routine computer programs which compare the frequency of rash among patients exposed to ampicillin with the corresponding frequency of rash among non-exposed (i.e., all other) patients. In this way, reactions may be identified which, because of preconceptions and limited experience of a single observer, may have gone undetected. Such surveillance facilitates the more accurate estimation of rates of adverse drug reactions. Intensive surveillance of hospitalized patients has already provided the clini-
cian with new insights into the clinical effects of drugs in adults. The PeDS Program seeks to obtain similar information for the pediatric population. It is hoped that information gained from systematic studies of drug effects such as those outlined here will improve the pediatrician's ability to assess the risks and benefits of drug therapy in children. REFERENCES
1. Miller RR, Greenblatt DJ (Editors): Drug Effects in Hospitalized Patients. New York, John Wiley & Sons, 1976 2. Jick H, Miettinen OS, Shapiro S, et al: Comprehensive drug surveillance. JAMA 213: 1455-1460, 1970 3. US Department of Health, Education, and Welfare. Eighth revision. International Classification of Diseases. Washington DC, US GPO, 1968 4. McKensie MW, Stewart RB, Weiss CF, et al: A pharmacist-based study of the epidemiology of adverse drug reactions in pediatric medicine patients. Am J Hosp Pharm 30:898-903, 1973 5. Lawson DH, Shapiro S, Slone D, et al: Drug surveillance: problems and challenges. Pediatr Clin North Am 19:117-129, 1972 6 Aranda JV, Cohen S, Neims AH: Drug utilization in a newborn intensive care unit. J Pediatr 89:315-317, 1976 7. Patz A: Oxygen studies in retrolental fibroplasia: Clinical and experimental observations. Am J Ophth 38:291-301, 1954 8 Collins GE, Clay MM, Falletta JM: A prospective study of the epidemiology of adverse drug reactions in pediatric hematology and oncology patients. Am J Hosp Pharm 31:968-975, 1974
