Saudi Pharmaceutical Journal (2013) 21, 261–266
King Saud University
Saudi Pharmaceutical Journal www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
Adverse drug reactions in hospitalized pediatric patients of Saudi Arabian University Hospital and impact of pharmacovigilance in reporting ADR Lateef M. Khan a b
a,*
, Sameer E. Al-Harthi a, Omar I. Saadah
b
Department of Pharmacology, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia Department of Pediatrics, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Received 30 July 2012; accepted 11 September 2012 Available online 6 October 2012
KEYWORDS Adverse drug reactions; ADR monitoring; Hospitalized patients; Pharmacovigilance
Abstract Objectives: Children are more vulnerable to ADRs, and this susceptibility is compounded due to hospitalization. There is a lack of local data regarding the potential risk of ADRs in hospitalized pediatric patients. Therefore, this study is designed to identify the frequent nature, severity of adverse drug reactions, drugs implicated and factors influencing ADRs. Methods: Intensive monitoring study of ADRs was done in hospitalized pediatric patients of King Abdulaziz University Hospital, Jeddah from January to December 2011, with an analogous retrospective study for the preceding year to determine incidence rate, demographic aspects, causality appraisal, polypharmacy, body organs/systems involved and drugs implicated in ADR. Comparison of the two data was done to determine the impact of pharmacovigilance. Results: Incidence rate of ADRs in retrospective study was (4.50%) and (8.2%) in prospective study. ADR was more in patients who received 5–6 drugs, which was (15.5%) in retrospective study and (22.1%) in prospective study. Regarding age, it was the highest in patients of 0–1 year of age which was (40.7%) in retrospective study and (38.8%) in prospective study. Anti-infective agents were the most frequently involved in ADR (40.8%) in prospective study and (48.2%) and retrospective study. This study also demonstrated that, there was high susceptibility of the skin to the ADR which was (37%) in retrospective study and (42.9%) in prospective study. None of the ADRs proved to be fatal. Conclusion: Well premeditated intensive monitoring approach in pharmacovigilance amplifies the ADR detection, which can persuade healthcare providers into more drug safety. ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Address: Department of Pharmacology, College of Medicine, King Abdulaziz University, P.O. Box 80205, Jeddah 21589, Saudi Arabia. Tel.: +966 508267914; fax: +966 26408404. E-mail address:
[email protected] (L.M. Khan). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
1. Introduction Science of pharmacovigilance is accountable to identify, appraise, comprehend and avert ADRs with the eventual mean to develop secure and coherent utilization of medication (Montastruc et al., 2006; Arulmani et al., 2008; Avery et al., 2011; Mehta et al., 2008). Current methods of pharmacovigilance possess certain constraints reminiscent of under reporting,
1319-0164 ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jsps.2012.09.004
262 inability to find the incidence rate, size of the population exposed and bias in collection of drug exposure (Montastruc et al., 2006; Wasserfallen et al., 2001; Routledge et al., 2003; Smyth et al., 2012). Pharmacovigilance gives a vital measure of the burden of drug induced morbidity and approximately half of ADRs could be averted with better prescription care (Chien and Ho, 2011; Aagaard and Hansen, 2010; Napoleone, 2010). Most recent review of ADRs reported incidence of hospitalized ADRs in children in the range of 0.6–16.8% (Smyth et al., 2012). Children are at a higher risk of developing ADRs as they seldom express their own drug therapy experiences (Castro-Pastrana and Carleton, 2011). Consequently, medications in pediatrics have a risk of a variety of ADRs (CastroPastrana and Carleton, 2011; Impicciatore, 2003). This reality describes children as ‘‘therapeutic orphan’’ and they are at a precarious position of a high risk of therapeutic failure with additional vulnerabilities like lack of many appropriate pediatric formulations, exposure through maternal prenatal drug use and breast milk, major difference in pharmacokinetic, pharmacodynamics of drugs, ‘‘off-label use’’ and perhaps divergence of their illness from adult (Chien and Ho, 2011; Napoleone, 2010; Impicciatore, 2003; Leeder, 2003; Lindell-Osuagwu et al., 2009). There is an urgent need for evolving valuable methods for the early detection of ADRs in pediatrics hitherto their necessary stipulation of pharmacovigilance has not been tackled appropriately (Castro-Pastrana and Carleton, 2011) (Etwel et al., 2008). Few local studies correlated to community acquired ADR and clinical pharmacist intervention in intensive care unit that were reported (Al-Malaq et al., 2008; Al-Jazairi et al., 2008; Al-Olah and Al Thiab, 2008), and a study of attitude and behavior of hospital pharmacist toward reporting ADRs in Saudi Arabian hospital (AlSultan and Bawazir, 2009), whereas no study was found related to ADRs in hospitalized pediatric or adult patients. The intention of this paper is to study hospital acquired ADR by an intensive monitoring method and, to recognize and describe the pattern of ADRs due to frequently used drugs, this in turn may be useful to recognize and curtail preventable ADRs which may have an impact on pediatric drug safety. 2. Methods This study was planned to appraise the incidence, frequent nature of ADRs with reference to their severity in hospitalized patients of pediatric wards of King Abdulaziz University Hospital and to corroborate the impact of pharmacovigilance in reporting ADR. Prospective observational study for monitoring ADR was conducted in hospitalized patients of pediatric department, King Abdulaziz University Hospital. This study was performed from January–December 2011. A parallel retrospective study was also taken on, by reviewing patient’s file for analysis of ADRs during the last one year. Each study was conducted by taking 600 patients. The sample size of 600 patients was planned to perceive an incidence rate of 6.7% found in an international systematic review (Wiffen et al., 2002). Study protocol was approved by institutional ethics committee. Discretion of information acquired was secured during the study. Suitable study design for monitoring ADR was
L.M. Khan et al. developed for data compilation and this was validated by accomplishing a pilot study in 25 patients. Exclusion criteria: duration of hospitalization less than 1 day, intake of drugs more or less than required (medication error or non compliance). Inclusion criteria: All patients of either sex between the ages 0–15 years admitted in pediatric wards were included in the study. No untoward episode was marked as ADR without the conformity of treating clinician. All relevant data of drugs, type of ADR, preliminary data of ADR suspected, drug causing ADR, body/system implicated in ADR, number of drugs administered to each patient and demographic information were scrutinized. Incidence rate was calculated in both studies and evaluation of proportion of total adverse drug reactions was done to ascertain significant differences in the incidence rate and impact of pharmacovigilance by intensive monitoring of ADR. Appraisal of the causality of ADR was done using Naranjo’s algorithm scale. This is the most common assessment tool of ADR, and verifies the chances of whether an ADR is essentially due to the drug or it is the result of other causes, the likelihood is consigned by the score, termed as definite, probable or possible (Naranjo et al., 1981). The severity of ADRs was assessed by Hartwig’s scale. Examples of ADRs assessed as severe are those that caused death, directly lifethreatening, lengthened hospitalization or shift to a higher level of clinical care (Hartwig et al., 1992). ADRs were also classified as either augmented or allergic/idiosyncratic (Rawlins and Thompson, 1991). 2.1. Statistical analysis Results are expressed in absolute number and percentages. The data were analyzed and comparisons between incidence of ADRs in both studies and in different age groups were executed with Chi-square test. P < 0.05 is considered significant. 2.2. Results In retrospective study (4.5%) patients developed ADR, compared to (8.2%) patients in prospective study (Table 1). The causality assessment in prospective study divulge that most of the ADRs belong to possible 23 (46.9%), followed by probable 22 (44.9%) and definite 4 (8.2%). However, in retrospective study ADR pattern was, possible 13 (48.2%), probable 12 (44.4%) and definite 2 (7.4%) (Table 1). Regarding type of ADRs, 33 out of 49 ADRs in prospective study, were type A reactions (augmented) and 16 were type B reactions (Bizarre), whereas in retrospective study they were 19 and 8 respectively (Table 1). All patients in both studies were divided in three groups according to the number of drugs consumed by them. The crest incidence of ADRs (15.5%) in retrospective study and (22.1%) in prospective study is observed in both groups receiving 5–6 drugs (Table 2). In both retrospective and prospective studies, all patients were divided into four age groups. The incidence of ADRs was the highest in patients of age 0–1 year in both prospective (40.7%) and retrospective studies (38.8%) and it was found to be statistically significant in both studies (Fig. 1). In prospective and retrospective studies within group analysis, comparing the frequency of ADRs between patients less
Adverse drug reactions in hospitalized pediatric patients of Saudi Arabian University Hospital Table 1
263
Causality, incidence, and type of adverse drug reactions in 600 patients of both retrospective and prospective studies.
Retrospective study Character
Prospective study
Male n (%)
Incidence Definiteª Probableª Possibleª ADR type A ADR type B
11(40.7) 01(50) 05(41.7) 07(53.8) 08(42.1) 3(37.5)
Female n (%) 16(59.3) 01(50) 07(58.3) 06(46.1) 11(57.9) 5(62.5)
Total n (%) **
27(4.5) 2(7.4) 12(44.4) 13(48.2) 19(70.3) 08(29.6)
P Value §
0.58 1.00§ 0.90§ 0.82§ 0.77§ 0.88§
Male n (%) 26(53.1) 01(33.3) 9(40.9) 14(60.9) 14(42.4) 05(31.3)
Female n (%) 23(46.9) 03(66.7) 13(59.1) 09(39.1) 19(57.6) 11(68.7)
Total n (%) **
49(8.2) 4(8.2) 22(44.9) 23(46.9) 33(67.3) 16(32.7)
P Value 0.86§ 0.83§ 0.66§ 0.55§ 0.61§ 0.35§
ª
Causality evaluation of ADR. No statistically significant influence of gender was observed on ADR. ** The difference of ADR incidence between two studies was significant (Chi-square 5.990, P < 0.05). §
Table 2 Correlation of drug consumption and adverse drug reaction in retrospective study and prospective studies.
Table 3 Frequency of systems implicated in ADR in retrospective and prospective studies.
Group of Number of ADR n (%) ADR n (%) patients drugs in retrospective study. in prospective study
Systems involved in ADR
Number of ADRs (%) in retrospective study
Number of ADRs (%) in prospective study
Gastrointestinal Skin and appendages Central nervous system Metabolic Liver Hematological Multi-system
9(33.3) 10(37) 2(7.4) 2(7.4) 1(3.8) 2(7.4) 1(3.7)
12(24.5) 21(42.9) 7(14.3) 1(2.0) 1(2.0) 4(8.2) 3(6.1)
A B C
1–2 3–4 5–6
3(1.8) 9(2.6) 15(15.5)*
7(4.0) 19 (5.9) 23(22.1)§
§
Whereas in prospective study P value was > 0.0001. In retrospective study within group analysis of less than 5–6 drugs and more than 5–6 drugs P value was < 0.05. *
Table 4 Drugs most frequently implicated in ADR in retrospective and prospective studies.
Figure 1 Relationship of ADR to age in retrospective and prospective studies.
than 0–1 year and patients of more than 0–1 years of age, P value was > 0.001 and < 0.05 respectively (See Table 2). Skin associated ADRs were most frequent in both retrospective and prospective studies 37% and 42.9% followed by gastrointestinal tract 33.3% and 24.5% respectively (Table 3). Concerning patient medications, anti-infective drugs were the more commonly implicated 40.9% in prospective study and 48.2% in retrospective study followed by antiepileptic drugs 16.3% in prospective study and 14.8% in retrospective study (Table 4).. 3. Discussion In this study the incidence rate of adverse drug reaction in retrospective study was 4.5% and in prospective study it was 8.2%. There was a significant difference between these two
Drug class involved in ADRs
Number of ADRs (%) in retrospective study
Number of ADRs (%)in prospective study
Anti-infective drugs Anticancer Drugs Anti-epileptic drugs NSAIDs Immunomodulators Hormonal preparations Diuretics Total
13(48.2) 3(11.1) 4(14.8) 2(7.4) 0(00) 2(7.4) 3(11.1) 27(100)
20(40.9) 3(6.1) 8(16.3) 6(12.2) 5(10.2) 6(12.2) 1(2.1) 49(100)
studies (Chi-square = 5.990 and P < 0.05). In comparison, our results are in the lower range of the most recent extensively studied review of ADRs in pediatrics with a coverage span of 45 years and consist of 51 studies of hospitalized ADRs (Smyth et al., 2012). The variation in incidence of ADRs across the globe includes ethnic, genetic and dietary factors. Other attributes could be difference in disease pattern, national financial class, healthcare infrastructure, local pharmaceutical company promotion and most importantly the detection methods employed (Eliasson, 2006; Camargo et al., 2006; Demoly and Bousquet, 2001). Yet, it could be due to the use of computerized physician order entry (CPOE) system practiced in our hospital which can probably reduce the medication error rates; such practice had shown reduction of medication error
264 by 55% and preventable ADR rate by 17% (Kaushal et al., 2003). The present study is done on a small number of patients and short duration could be the additional grounds. Polypharmacy is an additive risk of drug–drug interaction and important predictor of ADR (Smyth et al., 2012; Impicciatore, 2003; (Priyadharsini et al., 2011). It is reported that 30% of neonates receiving more than 10 drugs get no less than one ADR (Priyadharsini et al., 2011), exponential rise of ADRs in neonates was seen when exposed to four or more medications, newborn and infants are at a higher risk due to immature metabolizing system (Kaushal et al., 2001). This is reflected in our study by the significant increase of ADRs with the use of 5–6 drugs (P value was > 0.001 and < 0.05 respectively in prospective and retrospective studies). It is recommended to circumvent polypharmacy if it is not essential and to report the drug intake by each child to discover potential sources of heterogeneity between studies (Smyth et al., 2012; Jua´rez-Olguı´ n et al., 2007). The characteristics which facilitate the development of ADR in children are comparable to those of adults, nevertheless this vulnerability is potentiated due to age related divergence in physiological function, dissimilarity in disease pattern and smaller size and body weight (Impicciatore et al., 2001). In our study incidence of ADRs was observed to be the highest in 0–1 year of age and it was found to be statistically significant in both groups. Further, there are documented evidences that both the incidence below the age of 1 year and the susceptibility to death in 0–2 years of age are significantly more due to ADRs (Moore et al., 2002; Aagaard et al., 2010a,b). Assessment of ADR comes to pass all the time more and more crucial with ever increasing perception of its consequences in pediatrics, and the development of a customary authenticated ADR assessment tool for this age group is an indispensible prerequisite for safe and effective pharmacotherapy (Du et al., 2012; Aagaard et al., 2010a,b; Carleton et al., 2009; Vassilev et al., 2009). Du et al., 2012 introduced an ADR assessment algorithm most suitable for pediatric age. However, most of the pediatric studies frequently use Naranjo’s algorithm for ADR assessment (Smyth et al., 2012). It is simple and brief, its validity and reliability have been demonstrated in adults but not in children (Lamabadusuriya and Sathiadas, 2003; Weiss et al., 2002). We also used the same scale in our study for causality assessment and it was revealed that most of the ADRs belonged to ‘‘possible’’ followed by ‘‘probable’’ category, and ‘‘definite’’ category, this is similar to that reported in other recent studies (Napoleone, 2010). Classification and evaluation of ADRs in terms of severity can recognize the root cause of ADRs and appropriate steps by healthcare providers can improve pediatric pharmacovigilance (Smyth et al., 2012). It was notable that in our study, none of the cases was recognized as severe type, and it is worthwhile to state that there was no mortality due to ADR. Most of the preventable adverse drug events take place in the prescribing stage of medication, improper prescribing judgment and inadequate patient monitoring are the most frequent causes identified for preventability of adverse drug events. The median preventability of ADRs in hospitals was reported as 35.2% (18.7–73.2%) (Kanjanarat et al., 2003). Proportions of augmented ADR 70.3% in retrospective study and 67.3% in prospective study were observed in our study, which was in accordance with this study. The type A or augmented
L.M. Khan et al. ADR is predictable and therefore can be prevented by careful therapeutic selection of drugs, precedence of this should be taken by the healthcare providers in order to improve the cost effectiveness and safety for these illnesses (Lundkvist and Jo¨nsson, 2004). The most common class of drugs implicated in our study was anti infective agents with most common symptoms of vomiting, diarrhea and skin eruptions, this finding correlates with 24 hospitalized studies showing incidence rate of ADRs within a range of 8.6–100% (Smyth et al., 2012; Clavenna and Bonati, 2009; dos Santos and Coelho, 2006). The second most common class of drugs involved was anti epileptic drugs, producing frequent symptoms like ataxia and drowsiness, this was consistent with 14 ADR studies of hospitalized pediatric patients, with incidence rate of 3.9–46.6% reported in a review study (Smyth et al., 2012). Moreover, the most frequently affected system by ADRs in our study was the skin and the symptoms were mild rash, urticaria. This was followed by gastrointestinal system and the symptoms were diarrhea, nausea and vomiting, this was similar to recent reports (Napoleone, 2010; Priyadharsini et al., 2011; Aagaard et al., 2010a,b; Clavenna and Bonati, 2009; dos Santos and Coelho, 2006). Incidence of skin and gastrointestinal system ADRs in our both retrospective and prospective studies were comparable with the range shown by (Aagaard et al., 2010a,b). The endeavor of this study is to determine the impact of intensive monitoring on finding the improvement of incidence rate of ADRs. The difference between our two studies was noteworthy, this highlights the significance of intensive prospective collection of ADRs over spontaneous reporting, usual reminders fails to improve detection, and this is amply evident from our results. It is highly imperative that more patients can be brought to record, if we explore for the incidence of ADRs with a well premeditated approach. Healthcare providers must be aware of the value of ADR surveillance, scrupulous recording and informing the immediate responsible authority. Cognizance and application of this fact will amplify the coherence of drug therapy and improve drug safety as well. Despite the shortcomings of diminutive study interval, petite sample dimension, limited to a solitary institute and single department, this study was able to recognize the potential of active monitoring of ADRs in pharmacovigilance. Specific comprehensible causality tool for ADR assessment explicitly for pediatrics, and reporting of ADR by the patient, in addition to evidence based treatment approach are crucial for reducing the incidence of hospitalized ADRs and improve the pediatric drug safety. 4. Conclusion Although this study provides preface information, it highlights the necessity to amplify active monitoring system and encourages more drug safety initiative by healthcare providers to facilitate safe and effective medication in children. 5. Disclosure There is no conflict of interest in this study.
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