This prospective multicenter observational cohort study was prospectively registered in an Open Science Framework (OSF) (OSF registration ID: osf.io/7e5uy). The accredited Medical Research Ethics Committee of the University Medical Centre Utrecht (UMCU) did not consider the Dutch Medical Research Involving Human Subjects Act to be applicable to this study (ethics reference number: 20-495/C). The original name was the "TOXIC-Europe study", but the name was changed to the INTOXICATE-study in October 2021 at the request of researchers involved in the Toxicology Investigators Consortium (ToxIC) run by the American College of Medical Toxicology, to avoid confusion.

ICU physicians in Europe and other continents were invited to participate in the INTOXICATE study through the European Association of Poison Centres and Clinical Toxicologists (EAPCCT) [10] and the European Society of Intensive Care Medicine (ESICM) [11]. The eligibility criteria for ICUs were that they were university affiliated-, community teaching-, and community non-teaching hospitals in Europe or other continents. The ICU could be medical, surgical, specialized in toxicology or any other specialty, or mixed. An ICU was defined as a unit where a patient can be endotracheally intubated and mechanically ventilated. Therefore, high-dependency units (HDUs) or high-care units (HCUs) that can mechanically ventilate patients, were considered an ICU in this study. Ethics approval and signing a data sharing contract were mandatory.

Data were collected between 1st November 2020 and 30th June 2023. A list of collaborators is provided in the Acknowledgments section. The study was managed by a central coordinating team supervising the national coordinators. All participating units provided either local research ethics committee approval or a waiver of consent. A data-sharing contract had to be signed between the participating unit and the coordinating center.

The patient inclusion criteria were adult patients (aged 18 years or older); patients admitted to the ICU from an emergency department, ambulance, or ward; intoxication (due to poisoning) as the main reason for ICU admission; and patients who stayed in the ICU for four hours or more. Patients were excluded if they were younger than 18 years; admitted to the ICU because of another serious comorbidity (e.g., trauma from a car accident while intoxicated as the management, outcome and duration of admission were likely to be dictated by the comorbidity rather than the intoxication); and an ICU stay of less than four hours. Toxicity was defined as the occurrence of any toxic effect to humans following a single or repeated exposure to a mixture of natural or synthetic substances available on the market or present in the environment. Pure ethanol intoxication was covered by the exposure definition. Informed consent of the participating patients was either required or not, depending on the country and/or the unit.

The primary outcome, ‘eventful ICU admission’, was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital.

Exposure variables were the exposure exact name, category, dose, and route. Human medications were categorized according to the underlying pharmacological group based on [4]: alcohol (ethanol, other alcohols); analgesics; antidepressants (cyclic antidepressants, lithium); street drugs (opiates, cocaine, amphetamine); sedatives (hypnotics, antipsychotic, benzodiazepines); ‘other poisons’ (carbon monoxide, arsenic, cyanides); other toxins; and mixed intoxications (combination of two or more sub-types of intoxication).

Data were collected on potential predictors (type of units, unit size, country, patient’s age, sex, comorbidities, possible second reason for ICU admission, vital signs, investigations (including ECG).

The data entered by local investigators included only information that would have been collected as part of routine clinical care. Local investigators reported only pseudoanonymized data. The data were entered into two study-specific databases (one for units and one for patients) developed in Castor EDC (Electronic Data Capture) [12]. Local investigators could access Castor through an account that required two-factor authentication (2FA). Local investigators entered their data into the database for patients identified as eligible, usually after hospital discharge. Data from Denmark were imported into Castor EDC in a single block (all patients from all Danish units at the same time) because Danish investigators collected patient data using the Redcap system; this made it easier for the Danish investigators to obtain the necessary institutional approval.

Standard definitions of the variables were provided on the study website. To ensure complete case ascertainment, any missing or inconsistent data were identified at the end of the overall study data collection period and the local investigator was contacted to update/provide the data. We predicted that there would be enough eligible patients in one year. However, the COVID-19 pandemic hit almost immediately after the start of the study, forcing us to extend the study by a further year and eight months.

Before the study began, we calculated the sample size, based on the hypothesized proportion of outcome in the population of interest, using the following formula:

$$n = \left( \right)} }}} \right)^ DE$$

Taking the values p = 6.5% (based on [4]); z = 1.96 for a 95% level of confidence; d = 0.065/2 (the allowable error); a correction factor DE = 7.65 for 20 clusters (the 20 countries where the study would be conducted, we get n = 1691. We applied a non-response rate of 10%, which resulted in n = 1691/0.9 = 1879 patients.

Quantitative variables concerning the ICUs were the number of ICU beds, the total number of ICU admissions in the last year, and the number of ICU admissions related to poisoning in the last year. All were grouped in categories.

Patient’s age, Body Mass Index (BMI), time elapsed between exposure and hospital admission, number of exposures, systolic blood pressure, heart rate, body temperature, SaO2, arterial pH, potassium, lactate, leucocytes, serum creatinine were considered as quantitative variables. None of them were categorized. The Glasgow Coma Score was categorized in four categories (GCS ≥ 14; GCS > 9 and < 14; GCS > 6 and ≤ 9; GCS < 6).

Quantitative variables related to ICUs are expressed as numbers and percentages by category. Continuous patient data are expressed as median ± interquartile range. Patient categorical data are expressed as numbers (percentages). Rates were calculated as the number of outcomes divided by the total number of included patients, with the corresponding 95% confidence interval (CI). Rates were calculated before and after exclusion of patients who received mechanical ventilation, vasopressors or cardiopulmonary resuscitation before ICU admission.

Patients with missing data were identified. Percentages were calculated for those with available data, and the denominator with missing data removed is reported throughout. When patients were transferred to another ICU, this second ICU was contacted by the local investigator to obtain the patient data.

In a post-hoc analysis, we used two alternative definitions of ‘eventful ICU admission’ in order to compare our findings with previous studies [4, 13]. The alternative definitions of “eventful ICU admission” included fewer ICU treatments. In alternative definition 1, according to [13], an eventful ICU admission was defined as having received mechanical ventilation and/or vasopressors and/or renal replacement therapy (RRT) and/or cardiopulmonary resuscitation in the first 24 h in ICU or who died in-hospital. In alternative definition 2, according to [4], eventful ICU admission was defined as having received mechanical ventilation and/or vasopressors and/or cardiopulmonary resuscitation in the first 24 h in the ICU, or having died in hospital (similar to alternative definition 1 except that RRT was not considered).

We hypothesized that the rate of eventful admission (with alternative definition 1 and definition 2) was greater than previously reported in the two studies [4, 13]. A one-sample z test was used to test the difference in outcome in this study compared with the rate reported in each study (15.4% in [13] and 6.5% in [4]).

We also performed two sensitivity analyses. First, to mitigate the potential influence of the heterogeneity in enrollment rates between ICUS, we repeated the main analysis after including only units that included at least 80% of the patients admitted to their unit in the study. Second, to minimize the potential influence of a mandatory informed consent, we repeated the main analysis to units where an informed consent was not mandatory.

Statistical analyses were carried out in SPSS Statistics 29.0 and/or R studio version 2023.06.2 for Windows (R version 4.2.2.). The STROBE checklist was used in the preparation of this manuscript following the EQUATOR guidelines.