Recent years have seen a rise in accidental exposure of children under the age of 5 to analgesic medications, antipsychotic and antidepressant drugs, and illicit substances resulting in intoxication-induced comas.

When carefully examining the substances involved—excluding paracetamol and ibuprofen, which are the most widely available and accessible medications at home—recent years have shown a notable increase in cannabis intoxication, as reported in the cases included in this work. Cannabis has become increasingly available in edible forms that often resemble appealing food items to children, such as candies, cookies, and baked goods, making them a common cause of accidental ingestion (38). Opioids, on the other hand, are now more accessible due to both a rise in therapeutic prescriptions and an increase in illicit use, especially of synthetic opioids such as fentanyl, with literature reports indicating a marked increase in hospitalizations attributed to opioid poisoning in the paediatric population (5, 39–41).

Most available paediatric protocols for the management of coma in the emergency department setting recommend urine toxicology screening as a second-line investigation, to be performed when the initial clinical assessment fails to identify a specific cause or when there is a well-founded suspicion of poisoning by exogenous substances (1–4).

Intoxication is a relatively more frequent cause of non-traumatic coma, particularly in children younger than 5 years of age, compared to other causes, such as metabolic diseases or diabetic ketoacidosis. Coma due to status epilepticus has also become less frequent than in the past, probably because of changes in pharmacological management and family education (1). On the other hand, it is important to emphasize that infectious causes represent the most frequent forms of coma in absolute terms. In such cases, the need to obtain a urine sample using a sterile technique makes catheterization a useful tool in the management of coma in the Emergency Department—not only for toxicological screening, but also for the assessment of potential urinary tract infections. In general, the literature does not report coma as an indication for performing urinary catheterization (42); however, we believe that the rapidity of execution and sample collection is sufficient to consider it as the method of choice (43).

Despite limitations, rapid urine screening test (RUS) can significantly contribute to a faster identification of neurotoxic agents, particularly in paediatric settings, where accidental ingestion of medications or substances of abuse often occurs unwitnessed or is not reported by caregivers. Urine screening can be completed within minutes and performed in the emergency department, whereas quantitative toxicological analysis requires a dedicated laboratory and may take several hours to days. Therefore, the qualitative toxicology assay can be considered as a point of care testing (POCT) modality, rapidly applicable in the emergency department setting. A high concordance was observed between qualitative and quantitative toxicological analysis in the 14 cases where both were performed, with no false-positive results identified. These findings suggest a reasonable level of reliability of this approach, for detecting the most common substance implicated in intoxication-induced coma. However, the limited number of cases and the lack of larger epidemiological studies may affect the robustness of these information.

In the context of diagnosing and managing coma in an emergency setting, having a quantitative analysis is not essential in initial steps. Moreover, the correlation between plasma and urinary levels and the clinical effect of the toxic substance is not always straightforward, particularly in paediatric patients, who may have different pharmacokinetics compared to adults.

Urine drug screening typically begins with immunoassays, which are widely used because they allow rapid, automated, large-scale testing and are even incorporated into point-of-care and home-testing kits. However, because immunoassays may yield false-positive results and cannot always distinguish between drugs within the same class, their findings are considered preliminary. Confirmatory testing is therefore performed using gas chromatography–mass spectrometry (GC-MS), which is regarded as the gold standard because of its ability to detect minimal quantities and accurately identify specific drugs. Despite its high accuracy and reliability, GC-MS is costly, time-consuming, and requires specialized expertise, so it is generally reserved for confirming positive immunoassay results (3, 44).

Most commercially available tests can identify the substances most frequently involved, including cannabinoids, opioids, benzodiazepines, barbiturates, cocaine, amphetamines, methamphetamines, buprenorphine, and tricyclic antidepressants (3). Therefore, a simple qualitative test may be sufficient to guide the initial decision-making process. Indeed, RUS has relevant limitations that must be carefully considered in clinical interpretation. False-negative results may occur and can reduce the diagnostic sensitivity of qualitative screening tests, particularly for substances that are not routinely included in standard immunoassay panels, such as fentanyl, other synthetic opioids or synthetic cannabinoids. False negatives may occur when the toxic substance is not included in the screening panel, when urine collection occurs outside the optimal detection window, or when urinary concentrations remain below the assay threshold and these characteristics may vary according to the substance involved. False-negative results represent one of the major limitations of rapid urine screening and may have relevant clinical consequences if misinterpreted. A negative screening result may create false reassurance and lead to premature exclusion of intoxication from the differential diagnosis, potentially delaying appropriate treatment. For this reason, RUS should not be used to rule out poisoning. Rather, it should be interpreted as an adjunctive diagnostic tool within the broader clinical context, and further toxicological investigations should be considered whenever clinical suspicion persists despite a negative result. In addition, immunoassay-based tests may be affected by cross-reactivity between structurally related compounds, potentially generating false-positive results (45).

For these reasons, confirmatory quantitative analysis (e.g., GC-MS or LC-MS/MS) remains essential whenever clinically indicated, particularly for positive screening results or when clinical suspicion remains high despite an initial negative result.

However, despite these limitations, RUS may still provide a valuable early diagnostic clue and rapidly orient the diagnostic reasoning in emergency settings, where timely decisions are often required before confirmatory laboratory results become available. In this context, its role is not to establish a definitive diagnosis, but to support early clinical decision-making.

From a practical perspective, severe unexplained coma in children younger than 4 years represents a relatively uncommon but high-stakes clinical presentation. In this selected symptomatic population, where the pre-test probability of toxic ingestion is clinically enriched, the addition of a low-cost qualitative toxicology screen is unlikely to substantially increase overall diagnostic costs and may potentially reduce the use of more invasive or resource-intensive procedures such as lumbar puncture, neuroimaging, or prolonged diagnostic observation. At the same time a timely diagnosis may allow a prompt treatment with an antidote when available and required.

Although not all substances have an available antidote, an early diagnosis can help avoid invasive tests with potential risks of complications. In this review lumbar puncture was performed in 9 patients and was negative in all cases, cranial CT scan was performed in 12 patients and in 6 were unremarkable.

While some guidelines recommend performing urine toxicology screening (3, 4) only in the presence of a highly suggestive history of intoxication, clinical practice indicates that such history is often unreliable. Parents may sometimes withhold information out of fear, thereby compromising the accuracy of the anamnesis. For this reason, physicians should be aware of the importance of including urine toxicology testing as part of the initial evaluation of comatose patients, even in the absence of a witnessed or reported intoxication.

In the published cases included in this review, toxic substances were identified at the initial urine toxicological assessment in 85% of the patients tested. This finding should be interpreted as a descriptive measure of diagnostic yield within the selected published cases and not as an estimate of the diagnostic sensitivity or overall performance of rapid urine screening in the general paediatric emergency population.

Among the 35 positive cases, cannabinoids were the substances most frequently detected, followed by the opioid methadone. Interestingly, in one case methadone positivity was observed only after 36 h, and in another it was found in blood but not in urine, as the standard immunochemical urine screening failed to detect it (28).

Four further cases of urine test negativity were reported. In two cases of clozapine intoxication, initial urine and blood screenings were negative (37); in one of these, clozapine was later quantified in blood, possibly suggesting that the initial screening panel did not include this substance. In another case, the immunoassay was negative, but the authors specified that the assay used did not cover synthetic opioids, such as fentanyl (10). Similarly, in a case of baclofen intoxication, the drug was not included in the screening panel (8). In the case of tea tree oil intoxication, the substance was not identified, as it was not generally routinely screened for toxicologic purposes (12).

The method of collection was not specified in the 41 cases. While urine samples are commonly obtained using a collection bag or by urinary catheterization, in the emergency setting of a comatose child urinary catheterization was the likely method of choice. As a matter of fact, this procedure is associated with low procedural risk, vs. relevant clinical advantages in terms of efficiency and accuracy, and may represent a reasonable and justifiable approach in this context (42). Urine collection methods should be adapted to the clinical setting and the urgency of diagnostic assessment. Non-invasive approaches, such as urine collection bags or spontaneous voiding, may be considered when feasible, although they may be limited by delayed collection and a higher risk of sample contamination. In critically ill children presenting with unexplained coma, where rapid diagnostic orientation may be clinically important, intermittent urinary catheterization may provide a timely and reliable uncontaminated sample. Moreover, urinary catheterization is generally associated more with anxiety than with pain, so that it should be by far and large considered a non traumatic procedure in a comatous child. Specifically, regarding opioids, these substances can cause urinary retention by binding to mu and delta receptors. Therefore, urinary catheterization serves a dual purpose: it facilitates urine sampling for toxicological analysis and provides immediate relief of bladder distension (43).

However, this approach remains invasive, although it may offer clinical advantages in terms of efficiency and sample reliability. Importantly, the risk of urinary tract infection differs between single intermittent catheterization and prolonged indwelling catheterization, with the latter carrying a substantially higher infectious risk. When clinically indicated and performed under appropriate aseptic conditions, catheterization may represent a reasonable option, particularly when urine output monitoring or sterile urine sampling for infectious work-up is also required.

This review has limits. First, the main limitations of this review stem from the heterogeneity of the case reports included as clinical data and treatment details were not consistently or uniformly reported across all cases. Furthermore, the observed mortality rate in our sample (only 1 case) may not accurately reflect the true mortality associated with these intoxications, due to an inherent selection bias: patients who were declared dead on arrival at the emergency department were excluded. Nevertheless, it is important to note that the assessment of mortality falls outside the primary objectives of this review. It should be also remembered that the cases reported in the literature are highly likely to be a minority of all cases encountered in clinical practice due to a report bias and to the limited availability of large international epidemiological surveys. Moreover, the majority of the cases selected in this work showed a drug screening test result, suggesting a potential publication bias favouring studies with positive findings. These biases may have led to an overestimation of the diagnostic performance of RUS.

It should be reminded that reported cases in the literature are highly likely to be a minority of all cases encountered in clinical practice due to a report bias and to the limited availability of large international epidemiological surveys. Most cases were reported by authors based in the USA, Canada, and France; however, this likely reflects greater attention to publishing on this topic in these countries rather than a true geographic distribution of cases.

Finally, the results in these patients were consistent with larger studies conducted in adults (46, 47).