Ten years’ experience of paediatrics acute drug poisoning in a tertiary center in Hong Kong

Introduction

Acute poisoning is defined as an acute exposure to a toxic substance within 24 hours (1). The pattern of acute poisoning varies over time among different localities and populations. This ranges from accidental ingestion of both pharmaceutical and non-pharmaceutical agents (e.g., household products or pesticides), to self-inflicted poisoning for suicide (2-6). Childhood poisoning is one of the leading causes of childhood morbidity and mortality worldwide.

In Hong Kong, hypnotics or analgesics were once the most common agents used in adult populations (7). However, there has been a change in the pattern of acute drug poisoning locally. As reported in the year 2016, up to 25% of the drug poisonings involved psychiatric-related medications (8). There has been a lack of up-to-date local data on pediatric acute drug poisoning for the past decade (9), which represents a constant challenge for Emergency Department (ED) physicians. The authors hypothesized that there would be a similar trend, as observed in the adult population, of increasing use of psychiatric-related medications in paediatric population. This is the first local study on the demographics and clinical outcome of acute drug poisoning with a focus in the paediatric population.

Deliberate drug poisoning is showing a rising trend over the past decades and constitutes a major public health concern, a significant percentage of drug poisoning cases necessitate admission to the Paediatric Intensive Care Unit (PICU) (10). Understanding the associated risk factors help identify preventive measures and refine drug regulation policies.

The primary objective of our study was to examine the 10-year trend of paediatric acute drug poisoning in Hong Kong. The secondary objective was to identify risk factors associated with PICU admission. We present this article in accordance with the STROBE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-23/rc).

Methods

Study population

This is a single center 10-year retrospective study. Children and adolescents aged 0–18 years old admitted for acute drug poisoning to Princess Margaret Hospital, a regional tertiary center in Hong Kong from 1^st January 2012 to 31^st December 2021 were reviewed.

Data collection

Patient list was generated by the Clinical Data Analysis and Reporting System (CDARS) with searching keywords of “accidental poisoning”, “suicidal and self-inflicted injury” & “acute poisoning” according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code. Patient data were retrieved from electronic patient record system.

Demographic data including age, gender, ethnicity, underlying psychiatric diagnosis and co-morbidities were collected. The time of ingestion and the drug source were obtained from the patient’s history. If the history was not available, the ingestion time was estimated by the time that the patient was last seen well. Outcome parameters included the length of stay (LOS) in PICU and the use of antidotes and decontamination therapy, the need for organ support, complications, patient disposal and death.

Inclusion and exclusion criteria

During the study period, there were 368 admission episodes for paediatric acute poisoning. A total of 61 episodes were excluded (Table S1) and 307 episodes were included in the statistical analysis.

• Children and adolescents aged 0–18 years old with acute drug poisoning presented to the Princess Margaret Hospital from 1^st January 2012 to 31^st December 2021 were included.
• Acute drug poisoning was defined as exposure to poisonous drugs within 24 hours (i.e., time elapsed before AED attendance). Only acute drug poisoning cases were included.
• Subjects excluded from the study are provided in Table S1, as there were more than one subject excluded from the study. Other non-drug poisoning including food, household products, animal bite, or venom poisoning were also excluded.

Definitions

Each study subject was defined as a patient-episode admitted for acute drug poisoning:

• Repeated admission was defined as two or more admissions related to acute drug poisoning for the same patient;
• Multiple drug overdose was defined as the use of two or more drugs within the same poisoning episode.

Mode of exposure was classified into three groups: suicidal, abusive or accidental poisoning:

• Suicidal poisoning was defined as an exposure due to the inappropriate use of drugs for self-destruction, by self-reporting or from psychiatric assessment;
• Abusive poisoning was defined as an exposure due to the inappropriate use of drugs, such as for symptoms or stress relief, recreation purpose, attention-seeking purpose, or as impulsive actions without concrete suicidal ideation or psychosis;
• Accidental exposure was defined as an exposure due to an unintentionally incorrect dosage, misuse of a drug prescribed for another condition, or taking a drug inadvertently due to a therapeutic error.

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 26. Data was expressed as a number (percentage) or mean ± standard deviation (SD) or median [interquartile range (IQR)]. For categorical data, analysis was performed by Chi-square test and the Fisher’s exact test. For numerical data, analysis was performed by Mann-Whitney U test. Factors with a P value less than 0.1 were entered into a logistic regression model for univariable and subsequently multivariable analysis to identify independent risk factors for PICU admission. The variance inflation factor (VIF) was used to measure the amount of collinearity, and factors included in regression model had a VIF of less than 3. A P value less than 0.05 was considered statistically significant.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Research ethics approval was granted by the Kowloon West Cluster Research Ethics Committee [No. KW/EX-22-083(177-03)] and individual consent for this retrospective analysis was waived.

Results

Age and sex distribution

The admission episodes displayed a bimodal distribution in age, with a higher rate of accidental poisoning in toddlers and suicidal or abusive (i.e., non-accidental) poisoning in teenagers (Figure 1). The mean age of accidental and non-accidental poisoning was 3.7±3.5 and 15.6±1.5 years respectively. Among the non-accidental poisoning group, there was a statistically significant gender difference with 198 (87.6%) girls and 28 (12.4%) boys (P<0.001). Accidental drug poisoning showed similar gender distribution. The overall female to male ratio is 3.8.

Figure 1 Age distribution.

Ten-year trends in paediatric drug poisoning from year 2012 to 2021

There has been an increasing trend in paediatric acute drug poisoning over the past 10 years (Figure 2). Comparing the years 2012–2016 and 2017–2021, the number of episodes increased from 80 to 227, contributed by a drastic increase in suicidal or abusive drug poisoning. Repeated admissions for drug poisoning increased from 3.8% to 16.7% and multiple drug poisoning increased from 18.8% to 34.8% (Table 1). The youngest age for suicidal or abusive poisoning decreased from 13.2 to 10.8 years old.

Figure 2 Total number of acute poisoning admission from 2012–2021.

Mode of poisoning (accidental vs. non-accidental poisoning)

The analysis revealed that a majority of the cases (73.6%, n=226) involved non-accidental drug poisoning, while a smaller portion (26.4%, n=81) was attributed to accidental drug poisoning. The demographic data, patient characteristics and clinical outcomes are shown in (Tables 2,3).

The former group had a higher incidence of underlying psychiatric diagnosis (79.2%), with depressive or anxiety disorders being the most common diagnoses. This group also had a larger proportion of patients who dropped out of school (14.2% vs. 0%), experienced family divorce (33.6% vs. 1.2%), and were the victims of child abuse (13.7% vs. 1.2%). For both groups, the major drug source was the patient’s own prescribed medications. Over-the-counter (OTC) medications and medications from household members represented other drug sources.

Time elapsed before attending Accidental and Emergency Department (AED) was longer in the non-accidental group when compared with the accidental group (5.3 vs. 3.8 hours), which may indicate their delayed healthcare-seeking behavior. Clinical symptoms were found more frequently in non-accidental group (78.8% vs. 48.1%). Complications, especially liver derangement (10.2% vs. 1.2%) and electrocardiographic (ECG) abnormalities (13.7% vs. 4.9%) also occured more frequently in non-accidental group, which was resulted from intentional paracetamol poisoning, anti-depressants and anti-histamine poisoning.

Poisoning drugs involved

The top five common drug categories for poisoning in descending order were paracetamol (33.8%), followed by anti-depressants/psychotropic medications (24.4%), anti-histamines/cold medications (22.1%), benzodiazepines (8.4%) and anti-hypertensives (6.5%) (Table 4). Among the analgesics drug group, paracetamol remained the single most common drug involved in poisoning, found in 104 admissions. It was far more common than other analgesics combined [non-steroidal anti-inflammatory drugs (NSAIDs) and opioid], with a total of 18 admissions. Co-ingestion (30.6%) was frequent. Concomitant alcohol use and illicit drug use was found in 5.5% and 2.9% respectively. Other medication entities included salbutamol and terbutaline use for asthma treatment; anti-emetics; calcium, vitamin or thyroxine supplements; and warfarin, furosemide or digoxin from household members.

Clinical outcome

Among all cases, a significant proportion (29.3%) were identified as asymptomatic. The most commonly reported complaints across various drug groups were gastrointestinal disturbances (42%) including abdominal pain, vomiting and diarrhea. The symptoms can either be genuine drug side effects, for example, from caffeine (a common ingredient in cold medication), or can be subjected to reporting bias as an attention-seeking behavior in abusive drug use. Fever (5.5%) was an uncommon symptom, typically observed in cases of accidental poisoning resulting from erroneous administration of medication while a child is already experiencing a fever caused by an infection. Seizure (2%) was relatively uncommon. Glasgow Coma Scale (GCS) <9 was found in 2.9%. The most common ECG abnormality was sinus tachycardia. This was found in patients with serotonin or anti-cholinergic syndrome; in patients with reflex sinus tachycardia by calcium channel blocker (CCB) poisoning, and in patients using sympathomimetics (e.g., methylphenidate, methamphetamine, salbutamol). There were 11 cases of long QT interval (QTc) interval caused by anti-depressants/psychotropic medications poisoning, 2 cases of bradycardia caused by digoxin and zopiclone, and 1 case of ventricular ectopics in methamphetamine poisoning.

Overall complication rate was low. There were 9 cases (2.9%) presented with serotonin syndrome, while 3 cases (1.0%) presented with anti-cholinergic syndrome. Additionally, 24 cases had hepatic dysfunction with elevated liver enzymes; 4 cases had renal dysfunction with elevated creatinine; and 10 cases had deranged clotting profile related to paracetamol and warfarin overdose. There were 5 cases that exhibited raised creatine kinase levels, which were associated with serotonin syndrome, seizures and methamphetamine use.

A total of 41 cases (13.4%) required PICU admission, with a mean LOS of 3.2±1.4 days. There was no significant difference in PICU LOS between the accidental and non-accidental groups. Treatment was supportive in most cases. Antidotes were prescribed in 51 cases (Table 5) and GI decontamination was performed in 76 cases. Less than 1% of cases required invasive respiratory support or inotropic support. No patient required extracorporeal life support or renal replacement therapy. One patient died and the overall mortality rate was 0.3%. The mortality case was the first reported paediatric death case due to selective serotonin reuptake inhibitor (SSRI) poisoning in Hong Kong. Death was not analyzed as a dependent variable in the regression model because of its infrequent occurrence.

Risk factors associated with PICU admission

All patients who presented with a clinical toxidrome were admitted to PICU. The PICU cohort showed an overall higher complication rates (Table 6). Multiple drug poisoning [adjusted odds ratio (OR) 2.59, 95% confidence interval (CI): 1.17–5.70, P=0.02] and anti-hypertensive use (adjusted OR 10.84, 95% CI: 3.83–30.73, P<0.001) were identified as independent risk factors for PICU admission in multivariate regression (Table 7). The use of anti-depressants and psychotropic medications were associated with PICU admission (adjusted OR 1.86) but the result did not reach statistical significance (P=0.15). Suicidal or abusive drug poisoning was not found to be associated with a higher incidence of PICU admission.

Discussion

The 10-year trend

There has been an observed increase in paediatric acute drug poisoning involving the use of anti-depressants and psychotropic medications in Hong Kong over the past decade. This trend aligned with external studies conducted worldwide, particularly in developed countries (11,12), while agricultural pesticide and household products remained common sources of poisoning in developing countries (2,3,13).

Psychological disorders and family or school conflicts were identified as the most important triggering factors of voluntary poisoning in an epidemiological study (14). In our study, we also found a higher incidence of psychiatric diagnoses and socio-economic risk factors, such as family divorce, child abuse, and school dropout in non-accidental drug poisoning. The death of immediate relatives did not correlate with abusive drug use.

The bimodal distribution in age with female predominance in non-accidental drug poisoning was consistent with the finding in a local epidemiological study in the 2010s (10). Our results showed a trend towards a younger age of onset for non-accidental drug poisoning. Moreover, we observed an increase in the occurrence of multiple and recurrent drug poisonings. An increasing proportion of cases required inpatient psychiatric transferal, highlighting the growing burden of psychiatric diseases. These results emphasize the urgent need for promoting child mental health and drug safety at an earlier stage, particularly in primary schools.

In paediatric population, overall complication rate is low and the low mortality rate is consistent with other external studies (3-6,9,10). This can be attributed to improvements in medical care access, supportive treatment and clinical toxicology training. Locally, the Hong Kong Poison Information Center (HKPIC) was established in 2005, providing 24-hour telephone consultation for up-to-date poison information and management advice for all health care professionals.

Poisoning drugs involved

Analgesics remained the most common agents involved in drug poisoning due to their widespread prescription and easy availability for self-purchased from pharmacies. Firstly, paracetamol is almost a universal active ingredient in the preparation of analgesics or cold medications. Secondly, the use of aspirin has declined since its association with Reye syndrome in 1980s (15). Thirdly, opioid analgesics such as morphine is listed in the dangerous drug ordinance in Hong Kong, which adds barrier to its accessibility. Fourthly, the purchase of antibiotics from OTC pharmacy requires prescription from registered practitioners. All of these factors stress the importance of drug regulation and help explain why paracetamol poisoning is far more common than poisoning from other analgesics or antibiotics.

Anti-depressants and psychotropic medications have emerged as the second most common agents involved in drug poisoning. Overdosing on these substances can lead to life-threatening conditions such as serotonin syndrome or anti-cholinergic syndrome, as illustrated by our death case. Serotonin syndrome is caused by drugs that increase serotonin levels in central nervous system (CNS) which classically presents with a triad of altered mental state, autonomic hyperactivity and neuromuscular abnormalities. On the other hand, anti-cholinergic syndrome is caused by drugs that inhibit the muscarinic acetylcholine receptors. Classical signs include mydriasis, tachycardia, flushed skin, anhidrotic hyperthermia, urinary retention and decreased bowel sounds. Severe CNS toxicity may result in confusion, coma and seizures.

In our patient’s case, death resulted from a massive overdose of fluoxetine and promethazine. We believe that the prolonged QT interval and malignant arrhythmias were the primary cause of death. This prolonged QT effect was aggravated by simultaneous anti-cholinergic intoxication. In 2011, the U.S. Food and Drug Administration (FDA) has issued warnings on QT prolongation associated with high dose citalopram use (16). Although subsequent studies have suggested that other SSRIs (including fluoxetine) appear to have low risk of QT prolongation at standard dosage (17), a meta-analysis in 2014 showed a dose-dependent increase in QTc interval associated with SSRIs (18). As cardiac abnormalities can be potentially dangerous, electrocardiogram should be obtained in every case with suspected poisoning. Limiting a patient’s drug supply through regular medication review is an important protective measure against massive overdose. Drug take-back events can be encouraged for safe disposal of unused medications. Additionally, frontline healthcare workers should be familiarized with clinical toxidromes for prompt patient management.

Anti-histamines (e.g., chlorphenamine, loratadine, diphenhydramine, promethazine, hydroxyzine hydrochloride) are commonly found in OTC cold medications. It is not uncommon for multiple anti-histamines to be prescribed as symptomatic relief medications within the same consultation. Moreover, promethazine is commonly prescribed by psychiatrists as a sleeping aid due to its sedating side effects. However, these practices can be potentially dangerous and shall be discouraged, particularly in patients prone to risk-taking behaviors. Our study revealed a significant number of cases of abusive anti-histamine poisoning involved prescription from psychiatrists. This included 16 cases of promethazine poisoning, of which 3 patients obtained multiple anti-histamines including additional chlorpheniramine from psychiatrists. Overdosed patients can develop life-threatening anti-cholinergic syndrome and delayed gastric emptying can enhance co-ingested drug intoxication. Melatonin appears to be a safer alternative with a more favourable side effect profile.

Exposure to anti-hypertensives in accidental drug poisoning was relatively common and can be potentially dangerous. For example, Nifedipine retard was commonly prescribed for adult hypertension and the drug had an attractive appearance to toddlers. Of note, CCBs (esp. nifedipine, diltiazem and verapamil) were listed in the “one pill can kill” list in paediatric poisoning by Dr. Gideon Koren (19). Among all beta-blockers, propranolol is the most lethal in cases of acute poisoning (20). Surprisingly, our study identified a new trend of abusing anti-hypertensive agents for suicidal attempt. Four cases involved the use of propranolol, obtained either from household members or prescribed by psychiatrists for anxiety relief. Another four cases involved the use of OTC amlodipine for a suicidal attempt. Fortunately, no mortality has been resulted. Extended-release preparations can result in delayed onset of symptoms which requires prolonged intensive blood pressure monitoring for potential cardiovascular compromise. Strict legislation is needed to prevent OTC CCB overdose. Paediatricians or psychiatrists should exercise extra caution when prescribing propranolol for migraine prophylaxis or anxiety disorder.

In paediatric populations, the co-ingestion of alcohol and illicit drugs is less common compared to the adult population. Ethanol was the second most common type of poison exposure in adult population in Hong Kong (21). In our study, illicit drug use was only incidentally discovered by urine toxicology analysis. The identified drugs included cocaine, methamphetamine, ketamine, cannabis and lysergic acid diethylamide (LSD). It is important to note that the true incidence may be under-reported as alcohol or drug abusers are less likely to seek medical attention. Furthermore, abusive alcohol or illicit drug use result in various adverse long-term health consequences beyond acute poisoning. These cases cannot be captured by current study’s scope.

Risk factors associated with PICU admission

The second objective of our study was to identify risk factors for severe drug poisoning that necessitated admission to the PICU. In our study, the proportion of cases required PICU admission was slightly higher compared to the figures reported in external studies (4-6). This higher rate can be attributed to the overall increase in prevalence of intentional multiple or massive drug poisoning, as well as the increased awareness of the potential lethality associated with certain drug groups, commonly referred to as the "one pill can kill" concept. It is important to note that admission criteria also varied across different institutions. In some other units, patients can be safely triaged to an observation ward or high dependency unit (HDU) for close monitoring without admitting to the PICU.

Certain drug groups are more toxic than others, meaning that they have more severe side effects or side effects occur at lower drug doses or in a narrow therapeutic window. Maxime Maignan et al. demonstrated that specific drug classes (meprobamate, neuroleptics, cardiac drugs), a low GCS, a short interval between drug ingestion and ED admission as well as the amount of the intake are independent predictive factors for transfer to the ICU (22). In our study, we found that multiple drug poisoning and anti-hypertensives poisoning were both independent risk factors for PICU admission. Anti-depressants and psychotropic medications poisoning may also be associated with PICU admission, and overdose can result in death. Surprisingly, our study did not find a higher frequency of PICU admission in cases of suicidal or abusive drug poisoning. This suggests that accidental drug poisoning can be equally severe if the amount of ingestion is massive or if certain dangerous drug groups are involved.

Limitations

Our research has several limitations. Firstly, the effect of acute poisoning follows a dose-response relationship. However, the effect of dosage cannot be studied as heterogeneous groups of pharmaceutical agents were involved. Secondly, this is a local single center study. Patient demographics and the pattern of acute poisoning may vary across different territories within Hong Kong (Hong Kong Island, Kowloon and New Territories) and abroad. Thirdly, the lack of standardized criteria for PICU admission may reflect the need of invasive monitoring rather than the actual disease severity. A multi-center study with a larger sample size would be beneficial to demonstrate the differences in clinical outcomes among patients. Fourthly, age can be a potential confounding factor in the comparison of accidental and non-accidental poisoning group, which may be corrected with a larger sample size of age-matched control.

Conclusions

Our study revealed a concerning upward trend in suicidal or abusive poisoning involving anti-depressants and psychotropic medications among paediatric patients over the past ten years. Multiple drug poisoning and anti-hypertensives poisoning were identified as independent risk factors for PICU admission. Knowledge of the latest trend can assist in prompt diagnosis and treatment. It is important to prioritize child mental health from an earlier stage and to collaborate with schools and social workers to address the contributing socio-economic factors. Legislation, drug regulations, drug safety education, and safer prescription practices are ways to prevent both accidental and non-accidental drug poisoning.

Acknowledgments

The authors would like to thank Dr. Chan Chi Keung from Hong Kong Poison Information Centre and Princess Margaret Hospital Secretaries.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-23/rc

Data Sharing Statement: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-23/dss

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-23/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-23/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Research ethics approval was granted by the Kowloon West Cluster Research Ethics Committee [No. KW/EX-22-083(177-03)] and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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