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658
Pattaraporn Mekavuthikul, M.D.*, Sunsern Cheamanunkul, Ph.D.**, Pinsumon Chomchai,***, Jariya
Phuditshinnapatra, M.D.*
*Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Division of Science,
Mahidol University International College, Mahidol University, Nakhon Pathom, ailand, ***Shrewsbury International School Bangkok Riverside,
ailand.
Predicting the Need for Continuation of
N-acetylcysteine Treatment among Acute Paracetamol
Overdose Patients with Psi Parameter
ABSTRACT
Objective: AcetaCalc was used to evaluate Psi’s accuracy in predicting cases that required prolonged N-acetylcysteine
(NAC) therapy, as well as Psi’s optimal cut-o.
Materials and Methods: is is a retrospective study of patients with acute paracetamol overdose who were
treated with NAC at Siriraj Hospital between 2007 and 2016. e Psi parameter was calculated using the Acetacalc
aer entering paracetamol concentrations, blood sampling times, and NAC onset times. Indications for NAC
continuation is in accordance with the guidelines, which recommended that NAC treatment be continued if the
follow-up aminotransferase reached 50 U/L or higher.
Results: We enrolled 403 patients, the proportion of NAC prolongation was 50.4 %. Psi was shown to be a signicant
predictor of NAC prolongation (p < 0.001) with area under the receiver operational characteristics curve 0.766 (95%
condence interval (CI) 0.719-0.813). e Psi cuto with highest Youden index was 1.757 mM-hour. e sensitivities
and specicities of the cuto were 0.517 (95% CI 0.449-0.585) and 0.940 (95% CI 0.898-0.965), respectively.
Conclusion: Psi parameter calculated through AcetaCalc is a useful tool for the prediction of cases where extension
of NAC therapy beyond the standard regimen is indicated.
Keywords: Paracetamol; acute liver injury; N-acetylcysteine; prognosis; psi (Siriraj Med J 2022; 74: 658-665)
Corresponding author: Jariya Phuditshinnapatra
E-mail: jariya.ohu@mahidol.ac.th
Received 11 July 2022 Revised 14 August 2022 Accepted 20 August 2022
ORCID ID:http://orcid.org/0000-0002-6474-5613
http://dx.doi.org/10.33192/Smj.2022.77
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
INTRODUCTION
Hepatotoxicity from paracetamol overdose remains a
signicant healthcare burden in ailand and worldwide.
1
e most denitive treatment for the overdose is the
timely and sucient use of N-acetylcysteine (NAC),
administered as a 300 mg/kg intravenous infusion over
21 hours.
1
When NAC therapy is started early, usually
within 8 hours aer the overdose, hepatotoxicity can
eectively be minimized. Factors that can contribute to the
development of hepatotoxicity secondary to paracetamol
overdose are a high initial serum paracetamol concentration
and a delay in the initiation of NAC treatment. Studies
have shown that the risks of hepatotoxicity (dened by
aminotransferase concentration ≥ 1,000 U/L) when NAC
is initiated before 8 hours aer ingestion can range from
3.5-7.7%. at risk increases progressively to 10.3-22.2
% when NAC is given at 10-16 hours post ingestion.
Subsequently, it can be as high as 12.9-45.1% when NAC
is given later than 16 hours aer ingestion.
1,2
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In addition, even in instances where paracetamol-induced
hepatitis has already occurred, NAC therapy beyond the
initial 21-hour period has been shown to reduce the severity
of hepatotoxicity, as well as the rate of complications and
mortality.
3,4
e indication for prolonging NAC therapy is
an aminotransferase concentration of 50 U/L or higher.
5
It is recommended that the infusion be maintained until
aspartate aminotransferase concentration has decreased
to half of the peak level or lower.
6
On the other hand, the
assessment of hepatotoxicity risks has many interacting
clinical parameters such as the time of ingestion, the dose
of ingestion, the time to treatment initiation with NAC,
and the initial paracetamol level.
1,2
ese parameters
make up a risk prole which, with the right tool namely
the Psi parameter, can be individualized and extended
to predict the need for prolonged NAC treatment in
specic patients.
1,7
e Psi (Greek letter Ψ) parameter
is a composite calculation that accounts for both timed
serum paracetamol concentration and the time aer
ingestion until N-acetylcysteine therapy is initiated.
It was developed based on a toxicokinetic model as a
quasi-trapezoidal area-under–the-curve of paracetamol
concentration and the duration of hepatic glutathione
deciency.
8,9
(Fig 1) Its purpose is to individualize each
patient’s hepatotoxicity risk which can help clinicians
determine the disease prognosis with reasonable accuracy.
Overall, the Psi parameter reects exposure to N-acetyl-p-
benzoquinone imine (NAPQI), paracetamol’s hepatotoxic
metabolite, prior to starting NAC. Higher paracetamol
concentration and longer delay in NAC treatment results
in a higher calculated Psi parameter.
10,11
e details
about mathematical derivation of Psi can be found in
previously published works.
8,9
Consequently, the utility
and accuracy of the Psi parameter in predicting individual
risk of hepatotoxicity have been substantiated in various
publications.
9-12
In the ai population, high Psi (≥ 5.0
mM-hour) predicts hepatotoxicity with sensitivity of 96.9%
(95% condence interval (CI) 84.3-99.4) and specicity of
91.5% (95% CI 87.1-94.5).
10
However, despite such excellent
clinical data, its complex calculations severely limit its
usefulness in busy clinical settings.
9
In 2021, AcetaCalc,
a web-based application developed jointly by the Faculty
of Medicine Siriraj Hospital, Mahidol University and
Mahidol University International College, has made this
task much simpler. Users can simply input paracetamol
concentration, time aer ingestion when paracetamol
level was obtained, and the time to NAC initiation and
the application can calculate Psi parameter, as well as
other predictors of hepatotoxicity. is application can
be accessed at https://sunsern.github.io/aceta-calc/#/
tabs/info. In the present study, we evaluate the use of
Psi parameter, which is derived with AcetaCalc, as a
predictor of the need for prolonging NAC treatment
among patients with acute paracetamol overdose.
MATERIALS AND METHODS
is was a retrospective review of patients who
presented at Siriraj Hospital, Bangkok, ailand from
January 1, 2007 to December 31, 2016 with paracetamol
overdose. Inclusion criteria included age 12 years or older
and treatment with N-acetylcysteine. Patients were excluded
if they t one of the following criteria: mixed ingestion,
staggered ingestion (overdose process longer than 1 hour)
and abnormal initial aminotransferase concentrations.
A standard case record form was used to extract the
information from the medical records, including age,
gender, type and dose of the overdose, initial paracetamol
concentration, blood chemistry results, treatment, follow-
up blood chemistry results and clinical outcomes. e
study protocol was approved by the Siriraj Human
Research Protection Unit (MU-MOU CoA 472/2021).
e Psi parameter was calculated using the AcetaCalc
Application. Input data for Psi calculation included time of
blood sampling (hours aer overdose), measured paracetamol
Fig 1. Calculation of Psi parameter
Shaded area represents Psi parameter, tGD
= time of glutathione depletion (6 hours is
used as a default), tF = time of N-acetylcysteine
initiation, threshold = threshold paracetamol
concentration (45 mg/L is used)
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660
concentration (mg/L) and lag time from overdose to
NAC initiation (hours). Patients fullled the primary
outcome of the study if the follow-up aminotransferase
concentration was 50 U/L or higher, indicating the need
for prolonged NAC therapy. Hepatotoxicity was dened
as an aminotransferase concentration of 1,000 U/L or
above. For the purpose of comparison, extrapolated
paracetamol concentration at 4 hours post ingestion
([APAP]
4hour
) was calculated using the formula [APAP]
4hour
= C
t
/2e
>-(0.693/4)t
where C
t
represents measured paracetamol
concentrations and t indicated the time interval (hours)
from ingestion to blood sampling.
During the study period, intravenous NAC was
the mainstay treatment for acute paracetamol overdose.
e standard regimen for NAC administration was 150
mg/kg in one hour, 50 mg/kg in four hours and 100 mg/
kg in 16 hours, consecutively. Oral administration was
used only when the patients had a contraindication to
IV NAC or could not tolerate the intravenous regimen.
NAC prolongation was carried out by the administration
of 150 mg/kg/24 hours of NAC intravenously. In actual
clinical settings, the decision to start and then discontinue
the prolonged NAC therapy was based on each clinician’s
perception of whether a signicant elevation and subsequent
decline of aminotransferase had occurred.
Statistical analysis
Descriptive data were displayed as frequencies with
percentages and means with 95% condence intervals
(CI). However, medians with interquartile ranges (IQR)
were used for variables with non-normal distributions.
Dierences were tested with Student’s t-test or Mann-
Whitney U test. Proportions were tested with a chi-
squared test or Fisher’s exact test. Factors or co-variates
with p ≥ 0.05 were further tested with multiple logistic
regression in order to predict cases that required NAC
prolongation. Multiple logistic models were assessed using
backward stepwise multiple logistic regression. Receiver
operating characteristics (ROC) curve and area under
the curve (AUC) with 95% CI were used to assess the
accuracy of Psi in predicting the outcome. e optimal
cuto was selected using the highest Youden index.
13
Validities of the predictions were evaluated by sensitivity,
specicity, positive likelihood ratio (LR+) and negative
likelihood ratio (LR-) with 95% CIs. Statistical analyses
were performed using PASW 18 (Release version18.0.0)
statistical program.
e sample size estimation for this study was performed
based on the “rule of 10 for logistic regression”.
14
Since we
expected no more than four factors or co-variates in the
predicting model, the minimal number of events in this
study was estimated to be 40. erefore, we required at least
40 cases that fulll the indication for NAC prolongation
to achieve a desirable statistical power.
RESULTS
During the study period, 1,286 patients presented to
Siriraj Hospital due to paracetamol overdose. Among these,
883 cases were excluded. erefore, we enrolled 403 into
the analyses. (Fig 2) e subjects consisted of 332 females
(82.4%) with a median age of 23 years (IQR 20 28, range
13-62). Compared with the group receiving standard NAC
duration, the NAC prolongation group had signicantly
higher extrapolated four-hour paracetamol concentrations,
Fig 2. Subject enrollment ow
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Psi values, peak aminotransferase concentrations and
proportion of hepatotoxicity and longer time-to-NAC-
therapy, while having a signicantly lower proportion of
patients who received decontamination with activated
charcoal. (Table 1) None of the patients experienced
liver failure and no mortality occurred in this study.
Both the Psi parameter and the decontamination
with activated charcoal were entered into the multiple
logistic regression analysis. However, activated charcoal
yielded no statistical signicance (p-value 0.401) in the
multiple logistic regression model (Model 1). Activated
charcoal was removed since the resultant Nagelkerke R
2
of Model 2 with Psi parameter alone was higher than
Model 1 (a higher score meant better t of the model).
(Table 2) When using the equation Logit P = -0.918
+ (0.824 * Psi), Psi was a signicant predictor of the
need to prolong NAC treatment (p-value <0.001). Fig 3
demonstrates the scatter plots of [APAP]
4hour
and onset
of NAC therapy, as classied by cases with and without
the need for NAC prolongation. ere is a clear pattern
of the need for NAC prolongation in cases with high
[APAP]
4hour
or delayed NAC onset.
e ROC curve for Psi in predicting NAC prolongation
has an AUC of 0.766 (95%CI 0.721-0.806) and is shown
in Fig 4. e highest Youden index was found at the Psi
concentration of 1.757 mM-hour. e 1.757 mM-hour
cuto yielded a sensitivity 51.7% and a specicity 94.0%.
When the cuto was increased to 2.948 mM-hour, the
specicity achieved a maximal value of 99.5%. (Table 3)
TABLE 1. Demographic and clinical characteristics of the overall subjects, groups with and without N-acetylcysteine
(NAC) prolongation.
Characteristics Overall NAC prolongation No NAC prolongation P-value
(403 case) (203 cases) (200 cases)
Female (frequency (%) 332 (82.4) 167 (82.3) 165 (82.5) 0.951
Age (median (IQR) (years) 23 (20-28) 24 (21-27) 23 (19-31) 0.387
Paracetamol 281.7 294.1 256.4 0.250
dose (mg/kg) (200.0-400.0) (202.0-408.2) (200.0-378.8)
[APAP]
4hour
237.3 356.0 195.5 <0.001
(mg/L) (181.4-355.5) (289.3-474.1) (170.6-222.8)
NAC onset (hours) 7 (5-9) 8 (6-10) 5 (4-7) <0.001
Psi (mM-hour) 0.476 1.873 0.001 <0.001
(0.001-2.250) (0.001-4.995) (0.001-0.639)
Initial AST (U/L) 13 (10-18) 16 (11-31) 14 (10-30) 0.742
Initial ALT (U/L) 11 (8-17) 15 (8-31) 14 (9-30) 0.861
Peak AST (U/L) 37 (22-79) 76 (54-457) 24 (19-30) <0.001
Peak ALT (U/L) 41 (19-86) 86 (60-572) 26 (15-37) <0.001
Peak INR 1.1 (1.0-1.2) 1.1 (1.0-1.2) 1.1 (1.0-1.2) 0.048
Activated Charcoal 87 (21.6) 22 (10.8) 64 (32.5) <0.001
Hepatotoxicity 45 (11.2) 45 (22.2) 0 (0) <0.001
Abbreviations: NAC, N-acetylcysteine; IQR, interquartile range; [APAP]
4hour
, Extrapolated 4-hour paracetamol
concentration; AST, aspartate aminotransferase; ALT, alanine aminotransferase
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662
TABLE 2. Logistic regression models of Psi and activated charcoal administration as predictors of N-acetylcysteine
prolongation.
Models Factorsorco-variates Regressioncoefcients P-value -2loglikelihood NagelkerkeR
2
1 Psi 0.786 <0.001 423.678 0.285
Activated charcoal -0.253 0.401
2 Psi 0.824 <0.001 424.394 0.378
Fig 3. Scatter plots of extrapolated paracetamol
concentration at 4 hours and onset of
N-acetylcysteine (NAC) treatment (cases are
classied as cases with (1) and without (0)
NAC prolongation)
Fig 4. Receiver operating characteristics curve
of Psi for predicting prolongation of
N-acetylcysteine therapy
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TABLE 3. Diagnostic validities of Psi for predicting N-acetylcysteine prolongation at various cuto concentrations
(* remarks cuto psi concentration with highest Youden index).
Psicutoff Sensitivity Specicity LR+ LR-
(mM-hour) (95% CI) (95% CI) (95% CI) (95% CI)
2.948 39.9 (33.4-46.8) 99.5 (97.2-99.9) 79.80 0.60
(11.22-567.87) (0.54-0.68)
1.757* 51.7 (44.9-58.5) 94.0 (89.8-96.5) 8.62 0.51
(4.90-15.16) (0.44-0.60)
0.257 70.9 (64.3-76.7) 67.0 (60.2-73.1) 2.15 0.43
(1.73-2.67) (0.34-0.55)
0.001 100.0 (98.1-100.0) 0.0 (0.0-0.019) 100.0 (100.0-100.0) -
Abbreviations: CI, condence interval; LR+, positive likelihood ratio; LR-, negative likelihood ratio
DISCUSSION
NAC therapy for paracetamol overdose is one of
the most studied antidotal treatments, as apparent by
the numerous guidelines for its administration. When
given early, its ecacy in preventing hepatotoxicity is
well-established. Currently, it is most oen given in
either a two-bag (200 mg in four hours and 100 mg in
16 hours) or a three-bag (150 mg/kg in one hour, 50 mg
in 4 hours and 100 mg/kg in 16 hours) regimen over a
period of 21 hours.
1,2
Serum paracetamol concentration
and time-to-NAC therapy are two regularly assessed
clinical parameters for clinicians when prognosticating the
outcome of patients with paracetamol overdose.
2,8,10
e
availability of these information makes the derivation of
Psi parameter possible. Because the treatment regimens are
so well adopted by clinicians, the associated demands for
healthcare resources such as the frequency of laboratory
monitoring eorts, the amount of antidote needed, as
well as the patient’s length of stay can oen be reasonably
predicted. However, in a subset of patients, paracetamol-
induced hepatotoxicity can occur despite the completion
of a standard NAC administration. In these cases, the
continuation of NAC has been shown to signicantly
reduce mortality and complications. Postulated mechanisms
of the action include NAC acting as an inammatory
modulator, increasing oxygen delivery and utilization
and improving blood ow in the microvasculature.
1,3,4
According to the current guideline on the treatment
of acute paracetamol poisoning, NAC continuation is
recommended when the aminotransferase is elevated, as
determined by AST or ALT of 50 U/L or higher.
1,5
Despite
the seemingly low value, we believe that this cuto oers
maximal safety for patients with paracetamol induced
hepatotoxicity. erefore, we used this value to select
cases for the primary outcome of this research. NAC
continuation means intravenous infusion of NAC at the
rate 150 mg/kg/24hours aer completing the standard
21-hours NAC regimen.
In this study, the Psi parameter is shown to be an
accurate predictor of NAC prolongation. e ROC’s AUC
of 0.766 implies that Psi has an acceptable accuracy in
discriminating cases with and without the need for NAC
prolongation. Although decontamination with activated
charcoal is also signicantly associated with the need
for NAC prolongation, we postulate the mechanism to
be the reduction of serum paracetamol due to activated
charcoal’s eects which, in turn, aects the calculation
of the Psi value. Subsequently, when activated charcoal
is eliminated from the logistic regression model, the Psi
parameter remains as a sole and adequate predictor of
the need for NAC prolongation. Our study illustrates the
tendency for increasing need of prolonging NAC therapy
as a function of higher paracetamol concentration and
greater delay in NAC administration (Fig 3). Similarly,
Cairney et al, reported a phenomenon whereby incidences
of acute liver injury, as dened by aminotransferase
> 150 U/L, gradually increased as a function of paracetamol
nomogram groups. e incidence was 6% in the 0-100
mg/L nomogram group and progressed to as high as 27%
in the > 500 mg/L nomogram group. e rates of acute
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liver injury were lower in patients who were treated with
NAC within 8 hours.
15
Of note, the term ‘nomogram group’
in this study is similar to the [APAP]
4hour
concentration
groups in our study.
We proposed that the Psi cuto of 1.757 mM-hour
be used as the criterion to predict the need for NAC
prolongation, since it yielded good specicity, although
the sensitivity was mediocre. (Table 3) On the other hand,
the 2.948 mM-hour cuto had very high specicity, but
the sensitivity became unacceptably low. e cuto of
0.257 is shown in Table 3 because it is the second lowest
concentration cuto, next to 0.001 mM-hour. e cuto
value of 0.001 mM-hour is also signicant because it has
100% sensitivity for the need for NAC prolongation, in
concordance with previous ndings that Psi of 0.001
mM-hour has a very high sensitivity for hepatotoxicity
(aminotransferase > 1,000 U/L).
12
e ndings in our study have relevant clinical
implications. Firstly, when Psi is calculated at the onset of
treatment, physicians can expect to have to continue NAC
therapy beyond the standard regimen if its value is 1.757
mM-hours or higher. is has signicant ramication on
the expected length of stay in the hospital and suggests
that, in these cases, the reimbursement scheme may
need to be adjusted. Secondly, when Psi is at its lowest
possible value of 0.001 mM hour the probability of
requiring NAC beyond the routine protocol should be
very low since the value signies early NAC treatment
and low paracetamol concentration. Furthermore, the
omission of a follow-up aminotransferase level aer
completion of the standard NAC therapy can also be
justied based on such reasoning. irdly, our study
shows that decontamination with activated charcoal
can signicantly reduce the need for NAC continuation
beyond the routine protocol. is recapitulates the ndings
of previous studies and reiterates the importance of
adequate gastric decontamination.
16-18
e limitations of this study are in its retrospective
nature. e data in medical records are intended for clinical
services, and some errors in information obtained from
the medical records may exist. e most important piece
of information that can aect the result of this study is
the time of paracetamol overdose, since it is a reference
point from which the time of blood sampling and NAC
initiation are calculated. In this study, a large number of
subjects were excluded because they did not fulll the
requirement for Psi application. However, we do not
expect them to result in any distortion of the results.
For the future, we suggest that the study question is
re-evaluated in a prospective observational study.
CONCLUSION
Psi parameter, a composite value of paracetamol
concentration, time of blood sampling and onset of
N-acetylcysteine treatment, is a useful tool to help clinicians
predict the need for the continuation of NAC treatment
beyond the standard regimen. e Psi parameter can
be derived conveniently with the use of a computer
application.
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