Clinical Toxicology

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Assessment of high-dose acetylcysteine in acute

high-risk paracetamol (acetaminophen) ingestion

Michael J. Moss, Brynne Hinchman, Joseph E. Lambson, Julie W. Scott, Paul

Hinckley, Sawyer J. Wylie & Alyrene Dorey

To cite this article: Michael J. Moss, Brynne Hinchman, Joseph E. Lambson, Julie W. Scott, Paul
Hinckley, Sawyer J. Wylie & Alyrene Dorey (2024) Assessment of high-dose acetylcysteine in
acute high-risk paracetamol (acetaminophen) ingestion, Clinical Toxicology, 62:8, 519-525, DOI:
10.1080/15563650.2024.2377268

To link to this article: https://doi.org/10.1080/15563650.2024.2377268

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CLINICAL TOXICOLOGY
2024, VOL. 62, NO. 8, 519–525
https://doi.org/10.1080/15563650.2024.2377268

POISON CENTRE RESEARCH

Assessment of high-dose acetylcysteine in acute high-risk paracetamol

(acetaminophen) ingestion
Michael J. Mossa,b , Brynne Hinchmana, Joseph E. Lambsonc , Julie W. Scotta, Paul Hinckleya,
Sawyer J. Wyliea, and Alyrene Doreya,b
a
UT Poison Control Center, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; bDepartment of Emergency Medicine,
University of Utah, Salt Lake City, UT, USA; cNM Poison and Drug Information Center, College of Pharmacy, University of New Mexico,
Albuquerque, NM, USA

ABSTRACT ARTICLE HISTORY

Background: Prompt acetylcysteine treatment with standard doses (300 mg/kg over 21 h in divided Received 15 January 2024
doses) is almost universally effective in preventing hepatotoxicity after paracetamol (acetaminophen) Revised 1 July 2024
overdose. However, hepatotoxicity is reported despite early treatment when paracetamol concentra­ Accepted 2 July 2024
tions exceed 300 mg/L (1,985 lmol/L) at 4 h. Prior studies evaluating high-dose acetylcysteine to treat
KEYWORDS
high-risk ingestions have shown mixed results. We compared outcomes in patients with high-risk Paracetamol; acetamino­
ingestions receiving standard or high-dose acetylcysteine. phen; acetylcysteine;
Methods: Records from a single poison center were reviewed from 1 January 2017 to 31 December toxicity; overdose;
2022. We included cases of acute paracetamol ingestion treated with intravenous acetylcysteine with hepatotoxicity
an initial paracetamol concentration above the “300 mg/L” (1,985 lmol/L) line on the Rumack-Matthew
nomogram. We compared standard and high-dose acetylcysteine groups by odds ratios and multivari­
able logistic regression. We defined hepatotoxicity as aminotransferase activity >1,000 U/L.
Results: We included 190 cases. Fifty-six percent received standard-dose acetylcysteine while 44%
received high-dose acetylcysteine. Treatment within 8 h yielded no difference in hepatotoxicity
between groups (odds ratio 1.67, 95% CI 0.067–42.3). Among patients treated after 8 h, hepatoxicity
was more common in the high-dose group (odds ratio 3.39, 95% CI 1.25–9.2) though odds of liver fail­
ure were similar (odds ratio 2.78, 95% CI 0.89–8.69). Eighty-eight percent of patients with hepatotox­
icity had elevated aminotransferase activity at presentation. No patient died or received a liver
transplant.
Discussion: Rates of hepatotoxicity were low in patients treated within 8 h regardless of acetylcysteine
dose. Unexpectedly, high-dose acetylcysteine treatment was associated with an increased odds of hep­
atoxicity in those treated after 8 h, but most had abnormal aminotransferase activities at presentation
and there was no difference in rates of liver failure. Limitations include the use of retrospective, volun­
tarily reported poison center data.
Conclusions: Prompt treatment with acetylcysteine, regardless of dose, prevented hepatotoxicity in
high-risk paracetamol ingestion.

Introduction ingestion [1,8,9]. The emergence of this literature has

prompted the designation of “massive” or “high-risk” inges­
Paracetamol (acetaminophen) is one of the commonest drug
tions. Patients falling into this category are those with a
overdoses reported to United States (US) poison centers
paracetamol ingestion >30 g and/or a serum paracetamol
each year [1]. In addition, paracetamol overdose is consist­
ently one of the top causes of death reported by America’s concentration plotting above the 300 mg/L (1,985 lmol/L)
Poison Centers [2–5]. The standard treatment for patients line on the Rumack-Matthew nomogram [1,10].
with paracetamol overdose is acetylcysteine, which has his­ The recognition of this higher-risk subset of paracetamol-
torically been highly effective at preventing hepatotoxicity overdosed patients has prompted new thinking regarding
and liver failure if administered within 8 h of paracetamol appropriate management strategies for these patients. It has
ingestion [6,7]. been hypothesized that larger ingestions of paracetamol
Some patients with paracetamol overdose are at a higher result in increased production of the toxic metabolite N-
risk of hepatotoxicity and liver failure in spite of treatment acetyl-p-benzoquinoneimine (NAPQI) in excess of the detoxi­
with acetylcysteine, namely those patients with greater fying ability of glutathione and standard acetylcysteine
serum paracetamol concentrations at presentation and those doses. To resolve this deficit, one treatment strategy for
receiving acetylcysteine more than 8 h after paracetamol patients with “massive” paracetamol ingestions is the use of

CONTACT Michael J. Moss [email protected] Utah Poison Control Center, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
Supplemental data for this article is available online at https://doi.org/10.1080/15563650.2024.2377268
� 2024 Informa UK Limited, trading as Taylor & Francis Group
520 M. J. MOSS ET AL.

increased doses of acetylcysteine [11]. Hendrickson [9] pro­ Oral acetylcysteine is very infrequently utilized in our region
posed a graduated schema for acetylcysteine dosing which and these cases were not included. An acute ingestion was
anticipates the amount of acetylcysteine needed to detoxify defined as occurring within a 60 min time period to select a
various subsets of high-risk paracetamol ingestion. group with a well-defined high-risk ingestion, rather than uti­
Previous work has shown conflicting results when treating lizing more broad definitions (e.g., ingestion within a 24 h
high-risk paracetamol-overdosed patients with increased period) that could overestimate the risk stratification of a
doses of acetylcysteine. A prospective observational study by paracetamol concentration. We screened and included all
Chiew et al. showed the benefit of increased doses of acetyl­ cases with a paracetamol concentration obtained at least 4 h
cysteine administered to 43 patients presenting with massive after ingestion plotting above the 300 mg/L line.
overdose [9]. In contrast, two retrospective analyses of state- Cases were excluded for unknown time of ingestion, more
wide poison center data (117 and 24 patients) found no stat­ than 2 h interruption in acetylcysteine treatment, inconsistent
istically significant benefit when high-dose acetylcysteine acetylcysteine dosing (e.g., received multiple different acetyl­
was administered to high-risk paracetamol overdose patients cysteine infusion rates after the loading dose), miscoded
[12,13]. With conflicting data, it remains unclear whether chronicity (e.g., actually acute-on-chronic or chronic based
patients presenting with high-risk paracetamol ingestion may on case narrative review), incomplete data, or elevation of
benefit from increased doses of acetylcysteine [14]. The pur­ activities of either aspartate aminotransferase or alanine ami­
pose of our study is to evaluate patient outcomes after the notransferase confounded by an alternative cause (e.g.,
administration of high-dose acetylcysteine following high-risk rhabdomyolysis, ischemic liver injury, other non-paracetamol
paracetamol overdose. drug-induced liver injury). We did not exclude cases solely
due to ingestion of substances other than paracetamol.
Chart reviewers were pharmacists with certification for
Methods
specialists in poison information or faculty medical toxicolo­
We conducted a retrospective review of patient records from gists. All reviewers received specific training on chart abstrac­
a single poison center from 1 January 2017 to 31 December tion from the lead author using a standardized data
2022. The poison center established guidelines for recom­ collection instrument with the review of 10 cases by the lead
mending high-dose acetylcysteine for patients with a para­ author for accuracy before completing the chart review. Data
cetamol concentration above the 300 mg/L line on the abstracted from charts included patient demographics, para­
Rumack-Matthew nomogram without requiring toxicologist cetamol formulation, ingested dose (only obtained if exact
consultation beginning in January 2020. Before the institution dose known), co-ingestion of alcohol/opioids/anticholinergic
of the guideline, the poison center occasionally recom­ agents, reason for exposure, laboratory values (including ser­
mended high-dose acetylcysteine in consultation with the on- ial paracetamol concentrations, aspartate aminotransferase
call toxicologist but there was no standard practice. This activity, alanine aminotransferase activity, and whether the
allowed a review of approximately 3 years of data before and international normalized ratio [INR] was >2), acetylcysteine
after the change in practice. We adapted acetylcysteine dose received after loading dose as either standard (FDA
dosing outlined by Hendrickson [10] and recommended a protocol: 150 mg/kg over 1 h, 50 mg/kg over 4 h, 100 mg/kg
standard 150 mg/kg intravenous (IV) loading dose followed by over 16 h) or any high-dose regimen (e.g., 12.5, 18.75, or
a 20 h infusion of either 12.5, 18.75, or 25 mg/kg/h for para­ 25 mg/kg/h for 20 h after a 150 mg/kg loading dose), total
cetamol concentrations above the 300 mg/L (1,985 lmol/L), duration of acetylcysteine therapy, gastrointestinal decon­
450 mg/L (2,977 lmol/L), or 600 mg/L (3,969 lmol/L) nomo­ tamination, administration of fomepizole, need for hemodi­
gram lines, respectively. The poison center utilizes the alysis, adverse effects of acetylcysteine therapy, and medical
standard US Food and Drug Administration (FDA) approved outcome. Paracetamol ratio was defined as the first paraceta­
3-bag acetylcysteine protocol of a 150 mg/kg loading dose mol concentration divided by the corresponding concentra­
over 1 h, a second infusion of 50 mg/kg over 4 h, followed by tion on the 150 mg/L line (e.g., a concentration of 450 mg/L
100 mg/kg over 16 h. The increased dose regimens were [2,977 lmol/L)] at 4 h yields a paracetamol ratio of 3).
administered by increasing the dose in both the second and/ Hepatotoxicity was defined as a peak aspartate aminotrans­
or third infusions. Whether this was consolidated to a single ferase or alanine aminotransferase activity >1,000 U/L. Liver
20 h infusion or left as separate 4 and 16 h infusions with an failure was defined as hepatotoxicity with an INR > 2.0.
increased dose was left to the discretion of treating providers. Demographic and case information were summarized
The poison center utilizes toxiCALLV (Aurora, CO, USA) for
R
with descriptive statistics using Microsoft Excel. Groups were
electronic health record keeping. Poison center staff routinely compared by chi-squared analysis for categorical variables
collect information on each case including documentation of and Mann–Whitney U test for nonparametric continuous vari­
prespecified and hard coded data on the agents ingested, ables. Odds ratios with 95% CI were calculated for outcomes
therapies administered, clinical effects, and medical out­ of hepatotoxicity and liver failure between standard and
comes with multiple follow-up calls to providers. We high-dose acetylcysteine groups. Groups were assigned
searched the database for all patients with acute paraceta­ based on the actual treatment received. We did not assess
mol exposures (using all America’s Poison Centers generic whether the dose recommendation was made appropriately
codes for single ingredient and combination paracetamol or whether providers followed the recommendation.
products) that also received intravenous (IV) acetylcysteine. Univariable logistic regression analysis was performed for all
 CLINICAL TOXICOLOGY 521

included cases for age, gender, paracetamol ratio, whether hepatotoxicity analyses. We included these patients in the
aminotransferase activity was elevated at presentation, ace­ liver failure analyses as neither had an INR >2 at
tylcysteine treatment within 8 h, and treatment with high- presentation.
dose acetylcysteine. Similar to Lewis and colleagues [12], The median age was 18 years (interquartile range 15–27)
multivariable logistic regression was performed using varia­ and 138 (72.6%) were female. Groups were largely similar at
bles of clinical interest including paracetamol ratio, whether baseline, with more patients in the high-dose acetylcysteine
aminotransferase activity was elevated at presentation, ace­ group receiving activated charcoal and having acetylcysteine
tylcysteine treatment <8 h after ingestion, and whether the initiated within 8 h of ingestion (Table 1). All but three cases
patient was treated with high-dose acetylcysteine. JASP soft­ were suspected suicide attempts. Two patients received
ware (JASP Team, version 0.17.3) was used for chi-squared fomepizole, both in the high-dose acetylcysteine group (see
analysis, odds ratios, and logistic regression analysis. Supplementary Information). No patient received hemodialy­
The study was approved by the University of Utah sis or kidney replacement therapy. Most patients (81%) in
Institutional Review Board and did not receive any funding. the increased dose acetylcysteine group received a 12.5 mg/
kg/h infusion for 20 h following the loading dose. Due to the
lower number of patients receiving 18.75 or 25 mg/kg/h infu­
Results sions, we combined all increased dose acetylcysteine patients
into a single group for analysis. Other than a single patient
A total of 345 cases met inclusion criteria with 155 cases with a paracetamol concentration of 1,096 mg/L (7,250 lmol/
excluded, leaving 190 cases for analysis. Reasons for exclu­ L), the highest paracetamol concentration in the rest of the
sion were: >24 h to acetylcysteine treatment (25), incomplete entire cohort was 625 mg/L (4,135 lmol/L). A comparison of
data (six), miscoded (one), acetylcysteine interruption (21), patients treated before and after the high-dose acetylcys­
inconsistent acetylcysteine dosing (31), and unknown time of teine guideline implementation is shown in Table 2.
ingestion (71). Though not part of our initial exclusion crite­ Among patients treated with acetylcysteine within 8 h of
ria, two patients in the high-dose acetylcysteine group ingestion, one developed hepatotoxicity which progressed to
already had hepatotoxicity at presentation (18 and 19 h after liver failure in the high-dose acetylcysteine group (see
ingestion, respectively) and were excluded from all Supplementary Information).

Table 1. Comparison of baseline characteristics of standard-dose and high-dose acetylcysteine patients.

Standard-dose acetylcysteine (n ¼ 84) High-dose acetylcysteine (n ¼ 106) P-value
Gender
Female, n (%) 63 (75) 75 (71) 0.515
Male, n (%) 21 (25) 31 (29)
Age (median, IQR) 18 (15–27) 18 (15–27) 0.817
Reason for exposure
Misuse, n (%) – 1 (1) 0.663
Suspected suicide, n (%) 83 (99) 104 (98)
Unintentional, n (%) 1 (1) 1 (1)
Co-ingestion
Opioids, n (%) 4/84 (5) 3/106 (3) 0.483
Anticholinergics, n (%) 16/84 (19) 15/106 (14) 0.364
Alcohol, n (%) 2/84 (2) 6/106 (6) 0.264
Acetylcysteine started <8 h 31/84 (37) 57/106 (54) 0.021
Time to acetylcysteine
<8 h, n (%) 31 (37) 57 (54) 0.029
>8–�12 h, n (%) 16 (19) 24 (23)
>12–�16 h, n (%) 20 (24) 16 (15)
>16–�20 h, n (%) 13 (16) 5 (5)
>20–<24 h, n (%) 4 (5) 4 (4)
Aspartate aminotransferase or alanine 17/84 (20) 20/106 (19) 0.813
aminotransferase activity >50 IU/L
at presentation, n (%)
Aspartate aminotransferase activity at 26 (21–48) 25 (20–35) 0.34
presentation (median, IQR)
Alanine aminotransferase activity at 25 (19–41) 23 (15–36) 0.40
presentation (median, IQR)
Received activated charcoal, n (%) 4/84 (5) 14/106 (13) 0.048
Acetylcysteine dose
Standard, n (%) 84 (100%)
12.5 mg/kg/h, n (%) 81 (76)
18.75 mg/kg/h, n (%) 13 (12)
25 mg/kg/h, n (%) 12 (11)
Paracetamol ratio
�2 and <3, n (%) 58/84 (69) 69/106 (65) 0.751
�3 and <4, n (%) 11/84 (13) 18/106 (17)
� 4, n (%) 15/84 (18) 19/106 (18)
IQR: interquartile range.
Bold values indicate P < 0.05 by chi-squared testing.
522 M. J. MOSS ET AL.

Table 2. Proportion of patients treated with high-dose acetylcysteine stratified by paracetamol ratio pre and post implementation of a high-dose acetylcysteine
guideline with baseline characteristics and outcomes.
Pre-guideline (n ¼ 92) Post-guideline (n ¼ 98)
Patients receiving high-dose acetylcysteine by paracetamol ratio
>2–3, n (%) 17/62 (27) 52/65 (80)
>3–4, n (%) 6/13 (46) 13/16 (81)
>4, n (%) 3/17 (18) 15/17 (88)
Total, n (%) 26/92 (28) 80/98 (82)
Acetylcysteine started <8 h, n (%) 45/92 (49) 43/98 (44)
Aspartate or alanine aminotransferase activity elevated at presentation, n (%) 16/92 (17) 21/98 (21)
Outcomes
Aspartate or alanine aminotransferase activity >1,000 IU/L, n (%) 8/92 (9) 16/96 (17)
International normalized ratio >2, n (%) 6/92 (7) 11/98 (11)
Two patients in the post-guideline group were excluded from the hepatotoxicity analysis as they presented with hepatotoxicity.

Among patients treated with acetylcysteine more than 8 h similar between patients receiving standard-dose and high-
after ingestion, the high-dose acetylcysteine group had dose acetylcysteine. Hepatotoxicity occurred most frequently
greater odds of developing hepatotoxicity. Rates of liver fail­ in patients with elevated aminotransferase activity at presen­
ure and duration of acetylcysteine treatment were similar tation and in those treated more than 8 h post ingestion.
between groups (Table 3). To investigate whether the Our findings support the importance of prompt treatment
increased odds of hepatotoxicity in those treated after 8 h with acetylcysteine and increased odds of hepatotoxicity
was related to a higher paracetamol ratio or the presence of associated with delayed treatment [6,7].
elevated aminotransferase activity at presentation, we further Chiew and colleagues [9] described 79 patients with a
analyzed these subgroups. There was no association with paracetamol ratio >2 who received high-dose acetylcysteine
paracetamol ratio. An increased odds of hepatotoxicity within 8 h of ingestion and had a 73% decreased risk of
among those with an abnormal aminotransferase activity at hepatotoxicity, suggesting benefit from high-dose acetylcys­
presentation persisted in those treated with high-dose teine. Other studies have since reported contradictory find­
acetylcysteine. ings. Lewis and colleagues [12] reported that of patients
Of all patients with elevated aminotransferase activity at with a paracetamol ratio >2, there was no difference in
presentation, excluding the two previously mentioned rates of hepatotoxicity between patients treated with high-
patients with hepatotoxicity at presentation, 21 of 35 (69%) dose IV acetylcysteine, standard-dose IV acetylcysteine or
went on to develop hepatotoxicity. These 21 patients oral acetylcysteine. Abnormal aminotransferase activity at
accounted for 88% of those that would ultimately develop presentation conferred higher odds of developing hepatox­
hepatotoxicity. All three patients who developed hepatotox­ icity [12]. An abstract by McElroy and colleagues [13]
icity but had normal aminotransferase activity at presenta­ reported that 24 patients with a paracetamol ratio >2 who
tion had acetylcysteine treatment initiated at least 10 h from received high-dose acetylcysteine showed no difference in
ingestion. Of these three, one received standard dose acetyl­ the incidence of hepatotoxicity when compared with
cysteine and two received high-dose acetylcysteine. patients receiving standard acetylcysteine dosing. Finally, a
No patient developed an anaphylactoid reaction to acetyl­ study by Downs and colleagues [15] evaluated patients with
cysteine. There were no deaths or liver transplants in the a high-risk paracetamol ingestion treated only with standard
entire study population. Figure 1 shows initial paracetamol dose acetylcysteine. They found that a delay in presentation
concentrations (but not time to acetylcysteine treatment) and treatment was associated with hepatotoxicity.
and outcomes for each case. Interestingly, our study found increased odds of hepatotox­
Univariable and multivariable logistic regression analysis icity in late-presenting patients treated with high-dose acetyl­
of variables potentially associated with hepatotoxicity are cysteine. We stratified these outcomes by paracetamol ratio
shown in Table 4. Patients treated with acetylcysteine within and the presence of elevated aminotransferase activity at
8 h of ingestion had decreased odds of developing hepato­ admission to evaluate whether the high-dose acetylcysteine
toxicity (odds ratio 0.039 95% CI 0.003–0.38). The presence group contained a higher-risk subgroup. There was an
of abnormal aminotransferase activity at presentation was increased odds of hepatotoxicity in the high-dose acetylcys­
the most predictive of hepatotoxicity (odds ratio 117.9 95% teine group for those with abnormal aminotransferase activity
CI 21.29–684.66). High-dose acetylcysteine was associated at presentation. This increased risk of hepatotoxicity with
with increased odds of hepatotoxicity (odds ratio 8.64 95% high-dose acetylcysteine is of questionable clinical significance
CI 1.56–47.95). as there was no increase in liver failure or duration of acetyl­
cysteine treatment. It is possible that this finding reflects an
increased risk of hepatotoxicity in patients who have elevated
Discussion
aminotransferase activity at presentation [12]. Even so, the use
Our study was unable to demonstrate a benefit from high- of high-dose acetylcysteine was still associated with hepato­
dose acetylcysteine in high-risk paracetamol overdose toxicity after multivariable regression analysis.
patients and, surprisingly, showed increased odds of hepato­ With the addition of our findings, several studies now
toxicity in patients treated with high-dose acetylcysteine show no benefit of high-dose acetylcysteine for paracetamol
more than 8 h post-ingestion. Rates of liver failure were ingestions with a paracetamol ratio >2, suggesting that
 CLINICAL TOXICOLOGY 523

Table 3. Comparison of outcomes between standard-dose and high-dose acetylcysteine groups.

Standard-dose acetylcysteine, n (%) High-dose acetylcysteine, n (%) Odds ratio (95% confidence interval)
Hepatotoxicity
Acetylcysteine started <8 h 0/31 1/57 (1.8%) 1.67 (0.07–42.3)
Acetylcysteine started >8 h 7/53 (13.2%) 16/47 (34%) 3.39 (1.25–9.2)
Paracetamol ratio
>2–3 3/30 (10) 5/21 (24) 2.81 (0.59–13.37)
>3–4 0/9 5/12 (42) 13.93 (0.66–293.97)
>4 4/14 (29) 6/14 (42.9) 1.88 (0.39–9.01)
Aspartate or alanine aminotransferase activity elevated at presentation
Yes 6/12 (50) 14/15 (93.3) 14.0 (1.37–142.9)
No 1/41 (2.4) 2/32 (6.3) 2.67 (0.23–30.8)
Liver failure
Acetylcysteine <8 h 0/31 1/57 (1.8) 1.67 (0.067–42.3)
Acetylcysteine >8 h 5/53 (9.4%) 11/49 (22.5) 2.78 (0.89–8.69)
Paracetamol ratio
>2–3 1/30 (3%) 1/21 (5) 1.45 (0.09–24.57)
>3–4 0/9 3/12 (25) 7.0 (0.32–154.865)
>4 4/14 (29) 7/16 (44) 1.94 (0.42–8.92)
Aspartate or alanine
aminotransferase activity elevated
at presentation
Yes 5/12 (42) 10/17 (58.8) 2.00 (0.45–8.96)
No 0/41 1/32 (3) 3.95 (0.156–100.31)
Mean duration of acetylcysteine 30.4 29.1 P ¼ 0.297
therapy (h)

Figure 1. Initial paracetamol concentrations plotted with hepatotoxicity outcomes in patients treated with (a) standard-dose acetylcysteine and (b) high-dose ace­
tylcysteine. Patients with abnormal aminotransferase activity at presentation are highlighted. Seven patients developed hepatotoxicity in the standard dose group
and 17 in the high-dose group.

Table 4. Unadjusted and adjusted odds ratios by logistic regression for development of hepatotoxicity (aminotransferase activity
>1,000 U/L).
Odds ratio P-values
Unadjusted odds ratio
Paracetamol ratio 1.40 0.002
Aspartate or alanine aminotransferase activity elevated at presentation 75.0 <0.001
Acetylcysteine started <8 h 0.038 0.002
High-dose acetylcysteine 2.15 0.11
Age 1.0 0.73
Gender 1.41 0.466
Adjusted odds ratio 95% Confidence interval
Paracetamol ratio 1.1 0.86–1.38
Aspartate or alanine aminotransferase activity elevated at presentation 117.9 20.29–684.66
Acetylcysteine started <8 h 0.039 0.003–0.38
High-dose acetylcysteine 8.64 1.56–47.95

increased acetylcysteine does not provide benefit beyond all these studies, it is not possible to assess whether that
prompt standard-dose acetylcysteine. Given the relatively subgroup of high-risk ingestions may benefit from high-dose
small number of patients with a paracetamol ratio >3 across acetylcysteine.
524 M. J. MOSS ET AL.

Though it seems logical that higher doses of paracetamol variables. Patients with a paracetamol ratio >3–4 are likely at
would produce more NAPQI and thus require higher doses much higher risk of hepatotoxicity compared to those just
of acetylcysteine to prevent hepatotoxicity, no benefit to above a paracetamol ratio of 2. However, all patients regard­
high-dose acetylcysteine has been demonstrated across mul­ less of paracetamol ratio fared well if treated within 8 h, and
tiple studies with the exception of the study by Chiew and paracetamol ratio was not associated with development of
colleagues [9]. There are several possible explanations for hepatotoxicity in the multivariable model. Patients present­
these observations. The most common regimen of high-dose ing after 8 h may have already developed hepatotoxicity, and
acetylcysteine in our study was to increase the dose of the elevated paracetamol concentrations could be more consist­
16 h acetylcysteine infusion from 6.25 to 12.5 mg/kg/h. With ent with a hepatotoxicity related increase in paracetamol
this dosing, a patient receives no additional acetylcysteine half-life rather than reflecting a true high-risk ingestion [18].
beyond the standard protocol for at least 5 h after treatment It is possible that by chance or selection bias, these high-risk
initiation. It is possible that increased doses of acetylcysteine patients were more likely to receive high-dose acetylcysteine,
are needed earlier during toxicity. Other dosing regimens uti­ and that the outcome of increased hepatotoxicity in that
lizing 18.75 or 25 mg/kg/h starting with the second infusion group simply reflects reverse causation and a tendency to
could provide more acetylcysteine earlier in the treatment
treat higher risk patients more aggressively, rather than the
course, but very few patients received these doses.
high-dose acetylcysteine causing hepatotoxicity.
Anecdotal experience from our poison center staff revealed
Future studies should focus on including patients at the
poor adherence to recommendations for 18.75 or 25 mg/kg/h
highest risk for hepatotoxicity despite prompt treatment
dosing. Glutathione stores may be depleted more rapidly in
within 8 h: those with a paracetamol ratio >3 [1]. Multicenter
high-risk ingestions making acetylcysteine treatment necessary
studies are likely required to achieve a sufficient sample size.
even sooner than the typical 6–8 h timeframe. However, our
Meta-analysis of published studies could also be undertaken.
results showed excellent efficacy of acetylcysteine initiated
Other adjunctive treatments beyond acetylcysteine for these
within 8 h of ingestion. Other mechanisms of toxicity may be
at play in high-risk ingestions [16]. Our cohort also fared very high-risk patients remain under investigation [16].
well compared to prior studies with a low rate of hepatotox­
icity in the group treated within 8 h of ingestion. This could
be due to the young age of our study group, the predomin­ Conclusions
ance of paracetamol ratios between 2 and 3, or other uniden­ High-dose acetylcysteine therapy did not appear to decrease
tified patient factors. hepatotoxicity or liver failure in patients with high-risk para­
There are several limitations in this study. We relied on cetamol ingestions compared to standard therapy. Elevated
voluntarily reported retrospective data from a single poison aminotransferase activity at presentation was most associ­
center. Patients were not randomized to treatment or ated with hepatotoxicity. Prompt treatment with acetylcys­
studied prospectively. The utilization of a pre/post practice
teine had the lowest odds of hepatotoxicity. Only one
guideline implementation design may help mitigate some
patient treated within 8 h of ingestion developed hepatotox­
confounders as there was an increase from 28% of patients
icity. Further research or meta-analysis of existing studies
receiving high-dose acetylcysteine to 82% following the prac­
specifically evaluating patients with a paracetamol ratio >3
tice change. Poison center staff or treating providers may
and utilizing higher doses of acetylcysteine are needed.
have elected to utilize high-dose acetylcysteine in patients
perceived to be at higher risk for hepatotoxicity, such as
those with elevated aminotransferase activity at presentation
or an elevated acetaminophen/aminotransferase multiplica­ Disclosure statement
tion product [17]. However, groups were similar with regard No potential conflict of interest was reported by the authors.
to paracetamol ratio and the presence of abnormal amino­
transferase activity at presentation. It is possible providers
did not initiate high-dose acetylcysteine until liver injury
Funding
became apparent. However, if a patient received varying ace­ The authors reported there is no funding associated with the work fea­
tylcysteine infusion rates (e.g., started with a regular 16 h tured in this article.
infusion of 6.25 mg/kg/h and then switched to 12.5 mg/kg/h)
the case would have been excluded from analysis. The time
ORCID
of ingestion is based on provided history which may lead to
misclassification of risk. The number of patients who received Michael J. Moss http://orcid.org/0000-0001-8596-8122
18.75 or 25 mg/kg/h acetylcysteine infusions or had paraceta­ Joseph E. Lambson http://orcid.org/0009-0009-2671-6668

mol ratios >3 was small so the power to detect a difference,

if any, in these higher risk or higher dose scenarios was low.
We did not perform a formal power analysis. Similarly, the Data availability statement
small number of patients developing hepatotoxicity in the The data that support the findings of this study are available from the
study lead to wide confidence intervals around predictor corresponding author, MM, upon reasonable request.
 CLINICAL TOXICOLOGY 525

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