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BRIEF REPORTS/PEDIATRICS |
From the Immunology, Asthma and Allergy Research Institute, Children Medical Center, Tehran University of Medical Sciences, Tehran, Iran (Dr Fattahi, Dr Pourpak, Dr Moin); the Department of Biostatistics, School of Medicine, Tarbiat Modarres University, Tehran, Iran (Dr Kazemnejad); the Department of Infectious Diseases, Children Medical Center, Tehran University of Medical Sciences, Tehran, Iran (Dr Khotaei, Dr Mamishi, Dr Siadati, Dr Tabatabaei).
Address for reprints: Zahra Pourpak, MD, PhD, Associate Professor, Immunology, Asthma and Allergy Research Institute, Children Medical Center, Tehran University of Medical Sciences, No: 62, Dr. Gharib Street, Keshavarz Blvd., Tehran 14194, Iran.
Key Words: Adverse drug reactions • hospitalized children • infectious diseases • causality • frequency • Iran
A major problem of drug therapy, one that confronts primary care physicians on a daily basis, is the risk of adverse drug reactions (ADRs).1 The World Health Organization (WHO) definition of an ADR, which has been in use for about 30 years, is "a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function."2 Thus, this definition excludes adverse events caused by errors in drug administration or noncompliance (taking more or less of a drug than the prescribed amount). Using this conservative definition avoids overestimating the ADR rate.3
ADRs are a major and important health care problem.4-6 The percentage of patients experiencing an ADR during hospitalization has been reported to range from 1.5% to 35%.6 Also, the reported frequencies of hospital admissions attributed to ADRs vary from 0.1% to 16.8%.7 Several characteristics, such as a history of a previous ADR, duration of hospital stay, and liver or renal disease, have been suggested as risk factors for the development of ADRs.8 Although many ADRs are mild and disappear when the drug is stopped or the dose is reduced, others are serious, last longer, and are occasionally life threatening.5,9
It is usually stated that the frequency of ADRs is higher in adults than in children.10 A meta-analysis study reported ADR incidence among hospitalized children from 4.37% to 16.78%, with an estimated mean of 9.53%. This study also reported incidence of pediatric hospital admissions related to ADRs from 0.59% to 4.1%, with a weighted mean of 2.09%.11
Several risk factors, including differences in drug metabolism, which can produce increased susceptibility to certain drugs, may account for the severity and specificity of ADRs in children. In this case, some organs may be very sensitive to side effects. On the other hand, developmental processes in children may be susceptible to certain agents, and a number of drugs used in pediatric diseases can produce specific ADRs.12 Other risk factors for ADRs in children include multiple drug exposure, complex multisystem illness, age younger than 12 months, and increase in dose by parents or prescribers.13
Among the few studies in Iran, in a study on adult patients by Gholami and Shalviri14 in a department of infectious diseases, approximately 16.8% of hospitalized patients had at least 1 ADR.
The aim of this study was to investigate and determine the frequency, severity, and characteristics of ADRs in children (14 years and younger) as a cause of admission to a children's hospital or occurring during hospitalization in a pediatric diseases referral center in Iran.
METHODS
This study was conducted under the supervision of the Tehran University of Medical Sciences, and its ethics committee approved the study. Informed consent was obtained from the patients.
We prospectively studied all patients admitted to a department of pediatric infectious diseases during a 5-month period between February 14 and July 20, 2004. Patients with a hospitalization of less than 24 hours and those with repeated admissions were excluded from the study.
On each day of the study period, a specific questionnaire was completed for all children admitted. All children were evaluated daily for the presence of ADRs and were observed until discharge to ascertain the final diagnosis. If a suspected ADR was reported, data on that particular suspected drug and reaction were collected and documented in a suitably designed ADR Documentation Form. All relevant data, including all drugs the patient had received before the onset of the reaction, their respective dosages, the routes of administration with frequency, laboratory test results present in medical records, clinical details (system-organ class involvement), and the treatment (pharmacologic or nonpharmacologic) was noted. In addition, the patient's medication history was also taken, and comorbidity was identified to assess the causal relationship between the suspected drug and the reaction. The same documentation form was completed for the patients admitted to the hospital because of an ADR. Therefore, this study was done on 2 separate populations: those admitted to the hospital because of an ADR and those experiencing an ADR while in the hospital.
Information regarding previous drug use was obtained by interviewing parents, relatives, home nurses, or others, as necessary. By visiting the ward daily, examining medical and nursing records, and attending clinical rounds, details on drug orders, excluding intravenous fluids, oxygen, and adverse clinical events that occurred during the hospitalization were recorded. ADRs were defined in accordance with the WHO definition of an ADR. We therefore excluded errors in drug administration, noncompliance, overdose, drug abuse, and therapeutic failures.2 All the pediatricians in the Department of Pediatric Infectious Diseases were asked to participate in the study and to record any suspected ADRs. A clinical pharmacist and a pediatrician acted as a final source of confirming any likely case of an ADR. The reactions (usually more than 1 per report) were classified according to the Adverse Reaction Terminology of the WHO ADR Monitoring Register in Uppsala into systemic organ classes.15 The suspected drugs were classified according to the WHO classification.16 The causality relationship between the ADR and the suspected drug therapy was assessed case by case using the WHO Probability Scale (Table I).17 A reaction's profile was made by calculating the number of reports of each system-organ class of reaction as a percentage of all the reports. Severity was classified into 4 categories according to the following scheme: fatal, severe (directly life-threatening and/or more than 1 month in duration, associated with organ-system dysfunction, reduced life expectancy), moderate (some but not all of the mild criteria and none of the severe criteria) and mild (uncomplicated primary disease, no treatment required, and drug discontinuation not necessary).12,18-20 All data from questionnaires and medical records were coded and statistical analysis of the results was performed.
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Continuous variables were analyzed with the t test, and comparisons between proportions were performed by using the chi-square test. A significance level of P < .05 was considered for all tests.
RESULTS
During February 14 through July 20, 2004, we had 437 admissions, of which only 404 admissions were included in the study. Thirty-three patients were excluded based on exclusion criteria. Among the studied population, 180 patients were younger than 1 year. The observational period comprised 2611 patient-days. The patients admitted had a wide variety of diseases. The main reason for admission was pneumonia (n = 124, 30.6%), followed by urinary tract infection (n = 37, 9.2%); 9 patients (2.2%) were admitted because of an ADR. Of the studied patients, 380 received drugs during hospitalization and 24 (5.94% of total patients) did not receive any drugs. The most commonly used drug was ceftriaxon (belonging to third-generation antibiotics), and the most common administration was intravenous route. The mean number of consumed drugs per patient per hospitalization was 3.44 (SD, 2.95; range, 0-20).
The prevalence of ADRs at admission was 2.2% (9 admissions of 404 admissions); the prevalence during hospitalization was 9.9% (40 cases of 404 patients). Overall, in 49 of 404 patients (12.1%), at least 1 ADR was detected. Of the 380 admitted patients who received drugs, 40 (10.52%) had a suspected ADR to at least 1 drug during their hospital stay. Among the patients with ADRs, 34.7% (17 cases) had a previous history of ADRs. Because some patients had several reactions (eg, maculopapular rashes and diarrhea after ceftriaxon intake), the total number of reactions is higher than the total number of patients having the reactions; thus, 94 reactions were detected among 49 patients (1.9 reactions per patient). The suspected ADRs were considered to be definite in 15 cases (16%), probable in 47 cases (50%), possible in 29 cases (30.9%), conditional in 2 cases (2.1%), and improbable in 1 case (1.1%).
A total of 57.1% (28 cases) of the reports involved males, whereas 42.9% (21 cases) involved females. The mean age for pediatric patients was 38.9 ± 6.35 (SEM) months. Only 1 of the patients admitted because of an ADR had another ADR while in the hospital.
The frequency of ADRs according to age is as follows: 20% in patients 10 to 14 years, 14.3% in patients 5 to 9 years, and approximately 11% in patients 1 to 4 years and younger than 1 year.
There were no statistical differences between children older and younger than 1 year regarding the number of ADRs suffered (relative risk [RR], 1.28; 95% confidence interval [CI], 0.83-1.99 and RR, 1.05; 95% CI, 0.65-1.69, respectively). The gender ratio (male/female) was the same in both the group with ADR and the group without ADR (1.2 vs 1.3, respectively; P = .85).
Figure 1 summarizes the suspected ADRs detected during the period of hospitalization according to the organ-system affected. It should be noted that a single report can contain several clinical or paraclinical manifestations. During the study period, the total number of clinical or paraclinical manifestations because of ADRs was 94. The most commonly affected organ systems involved in an ADR were skin and appendages (28.4%), gastrointestinal system (21.6%,) and the body as a whole, or general (18.18%). Involvement of other organ systems was less common (Figure 1). The most common clinical manifestation of an ADR during the study period was rash, with 23 cases, followed by nausea with or without vomiting, and fever (14 cases each). Pruritus and diarrhea were present in 12 and 9 cases, respectively; application site reaction was observed in 5 cases.
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In total, 58 drugs alone or in combination were incriminated in the occurrence of 94 ADRs (a mean of 1.7 reactions per offending drug). The ADRs were most frequently caused by the following drugs: anti-infective agents (65.8%); immunological medicines, which include BCG vaccine and intravenous immunoglobulin (15.5%); and other medicines, such as antineoplastics and gastrointestinal medicines (3.4% each) (Figure 2 can be accessed from http://jcp.sagepub.com/cgi/content/full/45/11/1313/DC1/). The most common ADR-related pharmaceutical formulations were ceftriaxon and rifampin, observed in 7 and 6 cases, respectively, followed by amphotricin-B (related to 4 cases of suspected ADRs), ampicillin, cotrimoxazol, metoclopramide, keflin, and vancomycin (3 cases each). We also recorded 1 case of suspected ADR (generalized maculopapular rashes) related to amoxicillin in a patient with infectious mononucleosis.
Suspected ADRs reported in hospitalized patients were mild in 47.9% (45 cases), moderate in 44.68% (42 cases), and severe in 7.4% (7 cases). All patients recovered without long-term sequelae.
The mean number of pharmaceutical formulations consumed during the study period for suspected ADRs was 5.4 ± 3.9 per patient, significantly different from the number consumed by patients who did not have an ADR (3.1 ± 2.6). A consistent relationship was noted between the number of drugs administered and the frequency of ADRs. (P < .0001)
DISCUSSION
ADRs contribute significantly to a patient's morbidity and mortality and are a significant public health concern.9,21
Although there have been many studies regarding ADRs among pediatric patients in other countries,10-13,18,19 in Iran there have been few. This study estimated the percentage of children who were admitted because of a drug-related diagnosis (2.2%) or who had a significant ADR in the hospital (9.9%). This result showed that ADRs are very common (
10%).22
Some studies have focused on adverse drug events, which include errors in administration.23 Although our study excluded medication errors, it showed that there is a large number of ADRs, even when the drugs are properly prescribed and administered. Furthermore, one of the advances of the present study is its case-finding process of intensively monitoring admissions to the Department of Infectious Diseases and not relying on the spontaneous reporting of ADRs. The prevalence of ADRs during hospital stays found in this survey is similar to the result obtained by Vargas et al20 (9.2% of 401 patients) and higher than the reports of Jonville-Bera et al10 (2.64% ADRs among 260 children) and Vazquez de la Villa et al24 (4.4% ADRs of 597 patients). In the assessment of ADRs as a cause of admission in other studies, the frequency of ADRs was estimated as 0.2% to 4%.11 Mitchell et al showed that 2% of admissions to pediatric beds at 2 teaching hospitals and 3 community hospitals were prompted by ADRs.25 These findings are in agreement with our study. Jonville-Bera et al reported that 1.53% of pediatric patients were admitted for ADRs.10
In these studies, which are similar to our study, ADRs were evaluated according to the WHO definition. The difference in frequency of ADRs could be related to the difference of methodology used to detect ADRs, sample size, patient age, and classes of drugs used; in addition, this difference may be explained by the different causality assessment definition. In our study, the WHO definition for the classification of causality assessment was applied.
The analysis of the sample showed no difference between genders in developing an ADR. These results coincide with those obtained by Mjorndal et al26 and Morales-Olivas et al,12 although they studied only spontaneous reports of ADRs. In contrast, some of the studies found that the female gender was associated with a slightly increased risk of developing an ADR.18,19,27
It has been hypothesized that patients 1 year of age or younger are at greater risk of developing ADRs.13 In our study, the age distribution among patients with an ADR was similar to patients without an ADR, and no particular age predisposition existed, which is in agreement with the findings of Martinez-Mir et al,18,19 Cirko-Begovic et al28 (in infants and preschool outpatients), and Mjorndal et al.26 In contrast, our results differed from those obtained by Kramer et al,29 who found that patients under the age of 1 year developed ADRs more commonly than older patients. In a systematic review and meta-analysis of reported ADRs by Impicciatore et al, it was shown that there was no difference between age groups in developing an ADR; only one study specified an age group difference for ADRs.11 It should be mentioned that this study involved general pediatric outpatients and a different methodology.
We found that skin and appendage system disorders and gastrointestinal disorders accounted for 50% of all ADR reports. This pattern is in line with previous reports.12,28,30 The most frequently reported reaction was an objective clinical manifestation (rash), similar to the findings of other studies.12,28,29 Generally, like other studies,28-30 ADRs were associated mostly with anti-infective agents in the form of rash and gastrointestinal complications (nausea and vomiting). However, these therapeutic agents are the agents most commonly used in pediatric patients, especially in our study that involved hospitalized children in the Department of Infectious Diseases. The high prevalence of ADRs related to anti-infective drugs can be explained by the high prevalence of their use, so the most commonly prescribed drugs are those most often implicated in ADRs in pediatric patients. ADRs associated with ceftriaxon were more frequently reported in the study. Almost 50% of the ADRs were moderate or severe, thus requiring treatment (drug discontinuation, a change in drug therapy, or both). This finding is consistent with the results of Martinez-Mir et al.18
The data analysis of the present study suggest a significant association between the number of medications received by children and the risk of an ADR. It was noted that patients with an ADR were taking significantly more medications than were patients without an ADR, which is consistent with findings of other authors.17,24 Moreover, recently published investigations conducted in pediatric inpatients and outpatients show polypharmacy to be an important factor that predisposes patients to ADRs.11 The same results have been found in adult patients.27 This hypothesis is reinforced by the observation of a clear relationship between the number of drugs consumed and the prevalence of ADRs.
However, some limitations may have influenced the results of our study. First, because our study was performed in a pediatric infectious ward, where there was a high consumption of anti-infective agents, bias exists because of this specific ward type. (Anti-infective drugs were more likely to be associated with an ADR report.) Second, the frequency of reactions during hospitalization is calculated as the number of patients with a reaction divided by the total number of patients who received drugs (10.52%). However, we also considered ADRs among total hospitalized children, regardless of whether they received drugs (9.9%). Third, laboratory tests were not performed for some of the patients because of a lack of parental permission; therefore, the actual number of ADR cases may be more than what we found. Fourth, because data were collected in spring and part of winter but not for a 1-year period, it is possible that seasonal variations may have influenced the frequency of ADRs reported. Fifth, the actual number of ADRs in our patients might be higher than the number of ADRs detected during hospitalization because some ADRs triggered by the medical treatment during hospitalization may have occurred after discharge.
Despite these biases, we should be aware that these kinds of ADRs are likely to have a great impact on the parents, and therefore, they might be very sensitive to selective reporting.
However, ADRs in this article were estimated to be very common.22 Therefore, these results suggest that ADRs in pediatric patients are a significant public health issue. Although most of the ADRs were mild or moderate, in a few cases, they were severe and life threatening. In addition, the number of drugs administered was found to be a risk factor for ADRs in our patients. Therefore, attention to appropriate prescription of drugs (especially antibiotics) with more careful clinical and laboratory monitoring of patients seems necessary.
ACKNOWLEDGEMENTS
We thank Dr K. Bidad, Dr L. Sedighipour, Dr Kh Gholami, Dr G Shalviri, Dr M. Yeganeh, Dr R. Tajeddin, Dr H. Mozaffari, Ms F. Hamed, Mrs S. Davarian and all fellowships, residents and nurses of ward 1 in Children Medical Center of Tehran University of Medical Sciences for their cooperation.
The study was performed in the Department of Infectious Diseases of the Children Medical Center, Tehran University of Medical Sciences, Tehran, Iran; the College of Pharmacy, Department of Clinical Pharmacy, University of Medical Sciences, Tehran, Iran, approved the study protocol. Online figure can be accessed from http://jcp.sagepub.com/cgi/content/full/45/11/1313/DC1/.
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