EpidEmiology in oral antidiabEtic poisoning in childrEn and adolEscEnts – a four-yEar study in a pEdiatric poison cEntrE

Oral antidiabetics have become a common etiology associated with acute poisoning in children. The study shall carry out an analysis of the demographic characteristics, circumstantial characteristics and clinical profile associated with oral antidiabetic poisoning. An observational, descriptive and retrospective study was carried out over a period of 4 years including children confirmed with the diagnosis of acute poisoning with oral antidiabetics. In the study group, there is a prevalence of voluntary acute poisoning in female patients in the 15 to 18 year age group. bIn the group study biguanides were the most frequent pharmaceutical dugs involved. The predominant clinical manifestations associated with oral antidiabetic intoxications were gastrointestinal.


INtrODUctION
Acute poisoning in children as reported by the World Health Organization are one of the main causes of mortality in this population group with more than 3,000 deaths per year (1). A national epidemiological study carried out over the period 2006-2010 analized 6,099 cases of acute intoxication in children and concluded that the predominant etiology involved was medication (2). Oral antidiabetics are a frequent etiology associated with acute poisoning in children as a result of the increased number of cases of type II diabetes and thus the increase in their use. The mechanisms of action of oral antiabetics are as follows: sulfonylureas and meglitinides stimulate the endogenous secretion of insulin, biguanides and glitazons increase tissue activity of insulin and α-glucosidase inhibitors decrease the intestinal absorption of carbohydrates (3). Newer classes of oral antidiabetics like dipeptide peptidase 4 inhibitors, amyline analogues, glucagon-like peptide-1 agonists, sodium-glucose cotransporter inhibitors act by slowing gastric emptying, reduction of postprandial glucagon production, reduction of dietary intake and blocking renal absorption of glucose (4). Oral antidiabetic agents have been classified according to their effect in hypoglycemic agents such as sulfonylureas and meglitinides and antihyperglycemic agents such as biguanide, glitazons, α-glucosidase inhibitors, dipeptide peptidase 4 inhibitors, amyline analogues, glucagon-like peptide-1 agonists, sodiumglucose cotransporter inhibitors (5).

ObJEctIVEs
We aimed to perform a demographic and circumstantial analysis of oral antidiabetic poisoning in children in order to identify the risk groups for toxic exposure and the clinical profile associated with oral antidiabetic poisoning.

MAtErIALs AND MEtHODs study design
A descriptive, observational and retrospective study was performed during a four year period (2014-2018) in the Toxicology-intensive Care Department of the Emergency clinical Hospital for children "Grigore Alexandrescu" in Bucharest. All pediatric patients (0-18 years old) with acute antidiabetic poisoning were included in the study.
Inclusion criteria were: • Age < 18 years old • Ingestion of oral antidiabetic intentional or accidental, associated with or whitout other medications • Occurence of the event during 2014-2018 • No other preexisting medical condition Exclusion criteria included: • Age > 18 years old • Other diagnsotic than mentioned before • Other medical conditions • Occurence of the event in other period than 2014-2018 Patients' specific data -age, gender, intention, number and type of drugs ingested, clinical signswere collected from medical charts.

statistical analysis
A database was created and analyzed using IBM SPSS to establish the statistical significance of associations between the various variable (gender, background, etiology, age). For the group study averages, percentages were calculated.

Medical ethics issues
The analysis of the medical chart was carried out in accordance with the applicable medical legislation. rEsULts 39 children were admitted with oral antidiabetic poisonig in the Toxicology Department of "Grigore Alexandrescu" Children Emergency Hospital in Bucharest in a four-year period (2014-2018).

Demographic analysis
The patients included in the study group are 2-18 years old, with an average age of 11.75 ± 5.65 years, with the youngest patient diagnosed with acute oral antidiabetic poisoning being 2 years old. Distribution of patients in the study group by age shows an incidence peak in the age group 15-18 years old (43.5%) (Fig. 1).
The distribution of patients in the study group according to their residence identifies that 13 (33.3%) patients come from rural areas and 26 (66.6%) from urban areas.
Intentional poisoning has been more common compared to accidental poisoning, with 29 cases of intentional poisoning (74.36%) and only 10 cases of accidental poisoning (25.64%).
In 9 (23.08%) cases we identified ingestion of only one toxicant and in 30 (63.33%) cases other pharmaceutical drugs than oral antidiabetic were ingested (table 2).
According with etiology the majority of cases 32(80%) the toxicant involved was biguanides, in 7 (17.5%) cases sulfonylureas poisoning was identified and only one case with meglitinides poisoning (figure 2).
In the study group for the 39 patients it is noted that: 30 patients (56%) showed gastrointestinal symptoms, 20 patients (37%) had neurological symptoms and only 4 (7%) patients had cardiac symptoms ( Figure 3).     The association of clinical manifestations and toxic exposure to biguanid and sulfonylureas was also analyzed and a predominance of gastrointestinal symptoms associated with these poisoning was observed (tables 3 and 4).

DIscUssION
Acute poisoning with oral antidiabetics have increased in frequency in the pediatric population as a result of increased accessibility to these pharmaceuti-cal drugs. Analyzing the acute poisoning cases admitted in the Toxicology Department of the Emergency Clinical Hospital for children "Grigore Alexandrescu" in Bucharest, we have seen a 0.8% increase in the prevalence of acute poisoning by oral antidiabetic poisoning in the period 2014-2018 compared to the 2010-2014. This phenomenon is explained by the large number of adults diagnosed with type 2 diabetes mellitus who benefit from oral antidiabetes treatment and easy access of children to these types of medication. In literature are few studies in regard oral antidiabetic poisoning in children.
When analyzing the distribution of patients with oral antidiabetic poisoning by age group, the age group 15-18-year-olds is best represented (n = 17, 43.58%) and an equal percentage distribution for the 11-14-year and 0-5-year-olds is obeserved.This findings are in accordance with the literature data. According to literature data there is a predominance of poisoning cases in adolescents particulary through toxic exposure to pharmaceutical drugs. Data collected from United States of America antitoxic centers reveals that acute poisoning are more frequent in adolescents and the mortality associated with toxic exposures is at a maximum in the age group 13-19 years. The 2019 Annual Report of the American Association of Poison Control Centers reported a number of 86 fatalities associated with toxic exposures an 8% increase compared to 2018 report, of which 71 cases were associated with drug poisoning (12). 29 (25.64%) cases of intentional oral antidiabetic poisoning was identified in the group study. Correlating the instances of drug exposure, age, gender, residence we observed that the events in children under 5 years old occured accidental and those in children over 15 years old were intetional. An epidemiological study carried out in Romania during the period 1997-2000 on 11,890 patients admitted in the antitoxic center of the Emergency clinical Hospital for children "Grigore Alexandrescu" in Bucharest revealed a predominance of cases of accidental toxic exposure to the patient age group 1-4 years (65 %) and male (13).
According with the data collected from United States of America antitoxic centers regarding the instances of drug exposure accidental toxic exposure were more frequent in children under 5 years old meanwhile intentional toxic exposure was predominat in children over 13 years old (12).
In 30 (76.9%) cases data showed ingestion of more than one drug. Correlating the number and type of drugs ingested, gender, age and instances of drug exposure we identified a predominance of acute intentional multidrug poisoning in teenagers girls. This finding is supported by a an epidemiological study carried out during the period 2006-2010 on 6099 patients admitted in four pediatric antitoxic centers in Romania who revealed a predominance of cases of intentional toxic exposure (82%) in females (2).
Analyzing the etiology of poisoning in the group study we identified that in 32 (80%) cases the drug involved was a biguanide, phenomen explained by the extensive use of biguanides-metformin in monotherapy or in association with other oral antidiabetic in treating type II diabetes mellitus. In 2018 metformin was the fourth most prescribed drug with almost 83 million prescriptions, being the most widely used medication for diabetes (14).
The clinical manifestations associated with oral antidiabetic poisoning were predominantly gastrointestinal (n = 30, 56%). An analysis of clinical symptoms in correlation with the etiology of toxic exposure has identified in the group study that in both biguanid and sulfonylureic poisoning gastrointestinal symptoms are dominant. Sulfonylurea poisoning leads to hypoglycaemia which can be clinically expressed as: nausea vomiting, abdominal pain. The expert reviews identified an increased incidence of the use of metformin and the appearance of digestive symptoms (15). Metformin poisoning according with the data collected by the United States regional antitoxic centers have shown that for 55 patients with acute metformine poisoning the primary clinical findings were gastrointestinal as follows: nausea (2 patients), diarrhea (2 patients) (16).

cONcLUsIONs
Acute oral antidiabetic poisoning has the potential to evolve to severe forms with high lethality, especially if they evolve with acute renal failure or refractory lactic acidosis.
Increasing prevalence of the use oral antidiabetic agents implies a high exposure tare of this type of medication as toxicant in children and adolescents. Information campaigns need to be launched with regard to the toxic potential of such medication and regulatory measures to limit access for pediatric patients to oral antidiabetic agents are required.