3.1 Time Trend, Demographics and Exposure Characteristics

Between January 2017 and June 2023 there was a total of 24,648 exposures identified as dosing errors with paracetamol as a recorded substance. After restricting exposure calls to those aged ≥ 12 years, 14,384 exposures were identified; however, four records were excluded due to products which did not contain paracetamol. Therefore, a total of 14,380 paracetamol exposure calls were identified (with a combined total of 15,597 calls, Fig. 1). The majority of exposures involved adults (78.2%, n = 11,239). Where recorded, the median age was 43 years (exact age reported in 47.1% of exposures), and 8996 (62.6%) were female (Table 1). A summary of the patient demographics and details relating to their exposure can be found in Table 1.

Table 1 Basic characteristics, entire cohort (2017–2023) compared to 2021 cohort

There was an average of 42.4 (range 18–76) exposure calls per week (Fig. 2) and 6.1 (range 4.5–8.3) exposure calls per day for dosing errors with paracetamol. The yearly rate of exposures increased from 16.5 per 100,000 population in 2017 to 19.3 in 2022, showing a yearly 2.5% increase (95% CI 1.6–3.8%; p < 0.0001) on average (Fig. 3). Between 2017 and 2023 there was an average of 4.7 (range 4.1–5.0) exposures per 100,000 population per year that were either in hospital or referred to hospital (Fig. 3, note: 2023 rate has been estimated based on data from January to June only). The rate of exposures with a hospital-related disposition showed no increase (95% CI −0.2–3.3% per year; p = 0.07) while the rate of exposures with a community-related disposition increased by 2.9% (95% CI 1.4–4.4%; p < 0.0001) per year. The greatest frequency of exposure calls occurred on Sundays and Thursdays (Supplementary Fig. 1). The majority of all calls (62.6%, n = 9764) came from the community followed by 17.9% (n = 2794) from hospital doctors (Supplementary Table 1).

Fig. 2

Weekly count of exposure calls to the NSWPIC about dosing errors with paracetamol, 2017–2023. Exposure calls were calculated as counts per week, consisting of 7-day intervals. The vertical dotted line represents codeine rescheduling to Prescription Only in February 2018. The dot-dash line represents the release of the updated Australian paracetamol poisoning guidelines in December 2019. The dashed line represents the COVID-19 pandemic declaration by the World Health Organisation in March 2020. The double-dot-dash line represents modified-release paracetamol rescheduling to Pharmacist Only in June 2020. The solid line represents the initial stages of international border reopening for Australia in November 2021, which was followed by a surge in COVID-19 cases. COVID-19 coronavirus disease 2019, NSWPIC New South Wales Poisons Information Centre

Fig. 3

Exposures per 100,000 population per year split by disposition. Black bars represent exposures that had a hospital-related handling/disposition code. Grey bars represent exposures that had a community-related handling/disposition code. The 2023 rate has been doubled to provide an estimated yearly rate

The most common forms of paracetamol involved included immediate-release (51.8%, consisting of tablets, capsules, liquid and suppository formulations) and modified-release paracetamol (25.6%, consisting of controlled-release tablets only), both of which are single ingredient formulations. This was closely followed by combinations with opioids (primarily consisting of paracetamol and codeine with just 0.7% paracetamol and tramadol) and cold and flu preparations (which often include other ingredients including decongestants and sedating antihistamines). Multiple paracetamol-containing products (which may include more than one brand of the same category) were taken in 2816 (19.6%) exposures with spikes observed in 2019, 2021 and 2022, the greatest of which occurred in 2022 (Supplementary Fig. 2). Most exposures were advised to stay at home and were asymptomatic (Table 1).

3.2 Characteristics of 2021 Dosing Errors, Stratified by Need for Hospital Referral

Prior to in-depth screening, there were 2259 exposures recorded for the year 2021, which was reduced to 1899 exposures meeting inclusion criteria after screening. Basic exposure characteristics were similar to that recorded for the entire cohort (Table 1). Of these exposures 1204 (63.4%) were females and the median age was 46 years. Immediate- and modified-release paracetamol were again highly implicated and almost one-quarter (22.0%, n = 418) of exposures involved multiple paracetamol-containing products. Similar to the entire cohort, most exposures were advised to stay at home and were asymptomatic (Table 1); however, nearly one-third (30.5%, n = 580) were referred to or had the initial exposure call originate from the hospital.

The 2021 exposures were subject to in-depth screening, and it was determined that over one-quarter of exposure calls (26.8%, n = 509) required hospital management with paracetamol as the primary presenting problem (the remaining 71 hospital presentations were deemed not primarily due to paracetamol, despite a paracetamol error occurring). We compared characteristics of the community group versus the hospital group, to identify possible drivers of more severe cases. Immediate-release and modified-release were the most common formulations used in the community group whilst immediate-release and combinations with opioids were the two most common formulations for those in the hospital group (Table 2). The use of multiple paracetamol-containing products was consistent across both the community and hospital groups. Products classified as Schedule 2/Unscheduled were primarily involved across both groups; however, Schedule 2/Unscheduled products accounted for a higher proportion within the hospital group (Table 2).

Table 2 Characteristics of dosing errors in people aged ≥12 y with paracetamol, based on 2021 data (n = 1899)

A variety of indications were listed for the use of paracetamol with some individuals citing more than one indication. The majority did not have an indication documented in the PIC call record/medical record (Table 2); however, within each individual group the top 5 indications differed. Where known, the top 5 indications for those in the community group included cold/flu symptoms/COVID-19, migraine/headache, none (medicines given to the wrong patient), dental pain/dental work and unspecified pain. A full list of indications recorded in the community and hospital groups is available in Supplementary Tables 2 and 3, respectively. For the hospital group, the top indications were dental pain/dental work, migraine/headache, unspecified pain, back pain and cold/flu symptoms/COVID-19. Proportions were significantly different across all top indications besides migraine/headache, with the biggest difference for dental pain/dental work (21% of the hospital group vs 4% of the community group) (Table 2). Of the 166 unique exposures who were treating dental pain/dental work, approximately 60.8% used only immediate-release and/or modified-release paracetamol. The remaining 39.2% used formulations of paracetamol in combination with other ingredients such as opioids or anti-inflammatories (± single ingredient paracetamol).

The community group had a greater proportion of once-off errors (Table 2) with the greatest sources of error being an acute incorrect dose (35.3%) or an acute interval error (39.3%). In the hospital group, over half of the exposures were complex RSTIs and as expected a much greater proportion had doses associated with risk of acute liver injury based on the Australian and New Zealand guidelines [21] (Table 2). There were only 5 exposures that had no apparent error but developed symptoms of toxicity, all of which were in the hospital group. Only 11 exposures were reported to be due to an individual receiving a therapeutic dose despite needing a dose reduction for their weight.

The dose of paracetamol and duration of error was significantly higher in the hospital group compared to the community group (Table 2). The median dose per 24-h period for the hospital group was 8.0 g with a median duration of error of 2.0 days. This was more than double the median dose of the community group and double their median duration of error (Table 2).

Overall, exposures with an acute dose and/or interval error had lower median doses per 24-h period compared to exposures with a repeated dose and/or interval error or complex RSTIs (Fig. 4). The highest median daily dose was 12.0 g (IQR 9.0–20.0 g) for exposures with a repeated dose and interval error.

Fig. 4

Violin plot showing frequency distribution of dose taken per 24 h by error type. The dashed lines represent the median dose and dotted lines represent quartiles 1 and 3. RSTI repeated supratherapeutic ingestion

3.3 Treatment and Outcomes of Exposures Requiring Hospital Referral/Management, All 2021 Cases

There were 215 (42.2%) exposures that required treatment with NAC of which a small subset required an extended regimen (Table 3). For an explanation of the NAC treatment regimen see Supplementary Methods. It was unknown whether NAC was administered in 194 (38.1%) exposures (as eMR information was only accessible for a subset of cases, see below). Thus, the proportion who received NAC was likely higher. The median recorded peak paracetamol level was 20 mg/L. The median recorded peak ALT level was 51.0 U/L. Approximately one-half of exposures had elevated ALT (>50 U/L), while 26 (8.4%) had a peak ALT >1000 U/L and 2 had an ALT >10,000 U/L. The median recorded peak INR level was 1.1. Only 14 exposures (10.8%) had a peak INR ≥2. No deaths or occurrence of a liver transplantation were recorded for this group.

Table 3 Outcomes of hospital group dosing errors in people ≥12 y of age with paracetamol, based on 2021 data for all states (n = 509)3.4 Further Detail on 2021 Cases Where Complete Outcome Information was Obtained

The NSWPIC had access to complete medical records for a subset of hospitals in the state of NSW only (comprising 12 out of 15 Local Health Districts and 39 out of 64 hospitals). In 2021 in NSW, there were 193 exposures reported to the NSWPIC that were managed in hospital. Of these exposures 73 had an eMR that was not accessible due to either missing patient identifying details in the PIC database, or lack of access to the hospital files at that Local Health District. Therefore 120 exposures were included that allowed for complete follow-up data (Table 4). The median age was 41.5 years and 59 (49.2%) were female. Immediate-release paracetamol, combinations with opioids and modified-release paracetamol were highly implicated (Table 4) with multiple paracetamol-containing products used in 27 (22.5%) exposures.

Table 4 Clinical features and outcomes of NSW hospitalised patients in 2021 where complete outcome data were available (n = 120)

The median time between the last dose of paracetamol and presentation to hospital was 3.0 h (IQR 1.4–7.1, maximum 70 h, reported in 75.8% of exposures). In 12 (10.0%) exposures, either before the paracetamol dosing error was identified by clinicians or before the patient had been medically cleared, an additional therapeutic dose of paracetamol was given to the patient in hospital (Table 4). There were 2 (1.7%) exposures who had been given the dosing error whilst in hospital (iatrogenic errors).

A total of 62 (51.7%) exposures received NAC with five (4.2%) receiving double-dose NAC and 11 (9.2%) receiving an extended regimen. Symptoms of toxicity were reported for over half of the exposures (Table 4).

The majority of exposures had a detectable paracetamol concentration on presentation (Table 4). Almost half had an abnormal ALT (> 50 U/L), while 7 exposures (5.9% of those with complete outcome data) had an ALT > 1000 U/L. There were no deaths or liver unit transfers in the 120 exposures with complete outcome information and there were 8 patients admitted to the intensive care unit (ICU). The majority (57.5%) were admitted to hospital for paracetamol overdose; however, the overall median length of stay was short, at 12.9 h (Table 4).