Adverse drug events in hospitalized patients in Brazil: Integrative literature review

Objective: Analyzing studies related to Adverse Drug Events (ADE) in hospitalized patients in Brazil. Method: integrative review, for which the National Library of Medicine (PubMed), Biblioteca Virtual de Saúde (BVS), Repository of the Fundação Oswaldo Cruz (FIOCRUZ) and Capes Journals databases were selected for searching the studies primary, with the descriptors: Patient Safety, Drug-related side effects and adverse reactions, Patient harm, Hospitalization, Inpatients. Results: Twenty articles were identified, 50% (10) were from the southeast region of Brazil. Regarding the methodology adopted to identify the ADEs, 70% (14) used the retrospective data review. The trackers were used in 5 (25%) articles, 3 of which used the triggers proposed by the Institute for Healthcare Improvement, and the other 2 the trackers used were proposed by the researchers themselves. The number of adverse drug reactions ranged from 12 to 96, while the occurrence of AE ranged from 4 to 122. In one study 50% (41) of participants had at least one adverse drug event. Conclusion: There is great variability in scientific production in Brazil, and in the occurrence of Adverse Drug Events as well. There is a need for strategies to identify these events and create strategies to promote patient safety.


underreporting.
In the active search, AE is identified through a retrospective and / or prospective review of the patient's medical record based on criteria previously defined by the institution. This method is more effective in identifying AE, but it requires time, human and financial resources to be well employed. In addition, the effectiveness of the method, when performed retrospectively, depends on the quality of the professionals' records, which also becomes a limiting factor (WHO, 2002;Griffin & Resar, 2009;Classen et al, 2011).
Therefore, identifying and knowing the occurrence of ADRs and ADEs are requirements to make health services more secure and financially healthy. Therefore, this review aims to analyze studies related to Adverse Drug Events (AME) in hospitalized patients in Brazil.

Methods
Also based on studies by Haukland, Plessen, Nieder and Vonen (2017). This work is an integrative review based on the research question: "How is the identification of ADRs made and what is the profile of AS in hospitalized patients in Brazil?". This was delimited by the PICO strategy (acronym for Patient, Intervention, Comparison, Results). The steps taken in preparing the study were: elaboration of the research question, sampling or search in the literature of primary studies, data extraction, evaluation of primary studies, interpretation of results, presentation of the review.
The primary studies were searched from July to August 2019, in the following databases: National Library of Medicine of the National Institutes of Health (PubMed), Virtual Health Library (VLH / BVS), Repositório da Fundação Oswaldo Cruz (FIOCRUZ) and Capes Journals.
The controlled descriptors selected in the Health Sciences Descriptors (HSD) of the Virtual Health Library (VLH / BVS) and HSD in PubMed were "Patient Safety, Side Effects and Adverse Reactions Related to Medicines, Patient Damage, Hospitalization, Inpatients " (in English). The descriptors were combined using the Boolean operators, which obtained the following searches: "patient safety AND side effects and adverse reactions related to drugs and damage to the patient and hospital and inpatients", "patient safety AND related side effects and adverse reactions to medicines ". OR damage to the patient AND Hospitalization OR Inpatients ".
The inclusion criteria were articles whose main and / or secondary objective was to identify ADRs and / or ADEs in hospitalized patients. Regarding the period, we selected the articles published in the last five years (2014 to 2019). The search was conducted in Portuguese, Spanish and English. The exclusion criteria were: studies carried out in emergency rooms and outpatient services in hospitals, case reports and studies that did not differentiate the types of adverse events.
The choice of articles was divided into three stages: 1) Search for articles using descriptors in the databases, filtering the period of 5 years.
2) Reading of titles and abstracts by two independent reviewers who decided to include or exclude the article. In case of disagreement, a third reviewer was invited.
3) Reading of the articles in full by the reviewers, in order to identify whether the article answered the proposed question.
Were identified 194 articles in the four databases. After applying the criteria, 174 articles were excluded, for the following reasons: Duplicates (17), Secondary Studies and / or Case Report (8), Other Countries (6), Does not Answer the Proposed Question (116) and Studies in Outpatients (27). Thus, 20 articles were qualified for this review.

Results
The information extracted from the primary studies included in the review is shown in Table 1. Research, Society and Development, v. 10, n. 4, e3410413818, 2021 (CC BY 4. Use of 13 or more medications; Research, Society and Development, v. 10, n. 4, e3410413818, 2021 (CC BY 4.

Discussion
In this review 50% (10) of the studies came from the southeast region, from these, 20% (4) concentrated in SP. These data corroborate the reports of The Royal Society (2011) which verified spatial heterogeneity in scientific production, with a large concentration of studies in the southeast region, and listed São Paulo as the region responsible for about 20% of scientific production in Brazil.
In the methodology adopted, there was a prevalence 70% (14)of studies with retrospective review of data. According to some authors in the identification of ADEs, retrospective review of medical records is one of the most widely used methods, as well as spontaneous reporting, but they point out the retrospective methodology usually has limitations in identifying associated risk factors and determining the causality chain [38, 39.40] . In addition, Franklin's study at a surgical center in 2010 found the lack of complete data in patient records was a factor that hinder the ADEs identification, from the 207 records analyzed, 25% (51 / 207) did not have complete data and 17% (35) did not have accessible laboratory data (Franklin, Birch, Sachter & Barber, 2010).
In literature, there are variations in the identification rates of AE found through trackers (IHI or other triggers), some studies show rates of only 2%, while in others the identification rates are approximately 24% (Classen, Pestotnik, Evans, Burke & Battles, 1991;Davies, Green, Mottram & Pirmohamed, 2006). In addition to the lack of information in medical records, other factors that may interfere are the number of trackers used to identify events and the rate of change that trackers undergo when adapted to the reality of each health service (Seddon et al, 2013). There is a correlation between the event occurrence and variables such as length of stay, gender, age and presence of comorbidities. Thus, the characteristics of the studied population also directly influence the number of adverse events found (Seddon et al, 2013;Robb, Loe, Maharaj, Hamblin & Seddon, 2017;Varallo et al, 2017).
There is great variability in the occurrence rates of ADES and/or ADRs within hospital services, this may be related to the fact that there is no gold standard to calculate the rate of AE, as well as the safety measures already implemented by health services where the studies were performed (Griffin & Resar, 2009).
From the 16 articles, which characterized the patients'gender, 11 (69%), had a prevalence of male hospitalization.
This data is consistent with some studies in which men present characteristics that potentiate the disease, due to greater neglect of health and low use of primary and secondary care, being at greater risk of clinical decompensation (Camarano, 2002;Almeida, Mafra, Silva & Kanso, 2015).
Fifty per cent (7) of the 14 articles which identify the patients age had a mean age greater than 60 years. Among the factors that predispose the patient to ADEs, the following stand out: extremes of age, severity of the clinical condition, comorbidities and polytherapy, which would characterize geriatric patients as a risk group. The geriatric population is possibly the most medicalized group in society due to the high incidence of chronic degenerative diseases among them, and the progressive decrease in functional capacity and self-medication. In addition, during the aging process there are physiological changes interfering in pharmacokinetic (drug absorption, metabolism and excretion) and pharmacodynamic processes, which predispose this group to toxicity-related interactions, drug interactions, and adverse reactions (Silva, Ribeiro, Klein & Acurcio, 2012;Carvalho et al., 2012).
Regarding the drugs that caused ADEs, we highlight the antimicrobial and central nervous system drugs. In the study by Almeida, Castro and Caldas (2011) anti-infectious drugs were also the main drugs related to ADEs. These drug classes were related to severe skin reactions such as Steven-Johnson Syndrome and Toxic Epidermal Necrolysis (Grando et al., 2014;Emerick et al., 2014).
The risk factors associated with the occurrence of myocardial infarction were the length of stay, polytherapies and previous history of myocardial infarction. Regarding length of stay, two studies showed differences of 5 (Toffoletto et al., 2016) and 15 (Roque et al., 2016) days, respectively, when comparing patients with and without ADE. These findings corroborate the results found by Briant, Ali, Lay-yee, and Davis (2004) and Rozenfeld, Giordani and Coelho (2013), where the first author identified patients that were affected by drug-related damage had their length of stay increased by 6 days, and the second author showed the time difference between the two groups. These variables seem to be interdependent, since as events increase length of stay, prolonged hospitalization is closely related to the increased risk of suffering care events and increased cost to health services.
Obviously, there are several methods for searching and identifying adverse events, despite the active search, such as the use of trackers. This kind of study had identified the largest number of adverse winds, and spontaneous reporting was biased to underreport events, it should not be replaced by another active search methodology. For while active search usually mobilizes only a few authors involved in event screening, spontaneous reporting spreads the culture of harm reduction and promotion of patient safety among all participants in the care process (Sari et al., 2007). Thus, health services should structure both forms of event identification (Rutberg et al., 2014).
The drug-related events are the third leading cause of adverse events within health services usually due to medication errors. In the structure of services the pharmacist represents one of the best professionals to identify, correct or reduce potential risks associated with therapy (Pepe & Osório-de-Castro, 2000), but in this review only 2 studies used the pharmacist to identify ADEs. Due to his vast knowledge of medicines and therapeutics, the pharmacist is trained to act directly in the identification, detection, prevention and management of medication errors, drug interactions, and adverse reactions within the multiprofessional team (Sriram et al., 2011). There are even studies that have already shown a reduction in the number of medication errors in institutions where pharmacists performed interventions with the clinical staff (Planas, 2004). In this sense, the pharmaceutical intervention, by reducing the number of adverse events, should be used to increase the quality of care and decreases hospital costs.

Conclusion
In Brazil, there is variability in the occurrence of ADEs in hospitalized patients, and because these events are associated with increased length of stay, patient damage, and increased hospital costs, health services should implement strategies for their identification. Performing analysis of each event individually in order to identify possible weaknesses in the processes within hospitals and propose corrective measures that promote patient safety are urgent. Therefore, it is essential that new studies are carried out focused on the identification and risk factors, but mainly prevention factors.