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Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand? Hoi Y. Tong a, Nicolás Medrano a, Alberto M. Borobia a,b, Ana M. Martínez b, Julia Martín c, José A. Ruiz c, Santos García c, Manuel Quintana b, Antonio J. Carcas a, Jesús Frías a, Elena Ramírez a,⇑ a b c
Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPAZ, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain General Emergency Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain Paediatric Emergency Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 5 November 2014 Available online xxxx Keywords: Paracetamol Overdose Toxicity Poisoning Hepatotoxicity Acute liver failure Pharmacovigilance Safety pharmacology
a b s t r a c t Paracetamol (Acetaminophen) poisoning data can reveal the potential deficiencies of paracetamol poisoning management guidelines. We conducted a retrospective cohort study of patients >18 years who were attended in the emergency department (ED) of a Spanish tertiary hospital, from 2005 to 2010 for suspected paracetamol overdose and who had measurable paracetamol concentrations. 208 patients suspected of paracetamol poisoning were identified. The annual incidence in the ED increased from 2.0 (95%-CI: 0.2–7.2) cases per 10,000 patients in 2005 to 3.4 (95%-CI: 1.1–8.8) in 2010. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity signs, 4 (57.1%) of whom presented acute liver failure (ALF) criteria, while 8 of 10 patients (80%) with chronic paracetamol poisoning at toxic doses presented hepatotoxicity and 3 (37.5%) with ALF criteria. The time required to find medical care was 9.0 h for acute poisoning and 49.6 h for chronic poisoning (p < 0.001). We conclude that the incidence of suspected cases of paracetamol poisoning at our hospital is increasing. The majority of toxicity cases, including ALF, associated with the ingestion of paracetamol were due to chronic poisoning. This finding constitutes an important warning regarding paracetamol chronic poisoning, and clinicians should have a higher index of clinical suspicion for this entity. Ó 2015 Published by Elsevier Inc.
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1. Introduction
49
Paracetamol is the most widely used analgesic in the world. In most Western countries, including the UK (ÒGrady et al., 1989) and USA (Schiødt et al., 1999), it is the leading cause of acute liver failure (ALF). Accurately and rapidly predicting the risk of hepatotoxicity after a paracetamol overdose is essential because the clinical and biochemical signs of organ toxicity are not detectable until about 24 h after overdose, well past the optimum time for antidote therapy. Unintentional overdosing from self-medication for pain or fever that leads to daily doses exceeding 4 g is usually only recognized after the symptoms have developed. Delays in seeking medical attention and delays in initiating N-acetylcysteine (NAC) therapy are associated with a greater risk of morbidity and mortality (Dargan and Jones, 2002; Chun et al., 2009).
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⇑ Corresponding author at: Paseo de la Castellana, 261, Madrid 28046, Spain. Fax: +34 91 7277559. E-mail address: [email protected] (E. Ramírez).
Although the recommended doses of 4 gr/day is generally safe, Watkins et al. found that even with the ingestion of this dose for several days, it is possible to develop an asymptomatic ALT elevation in healthy volunteers (Watkins et al., 2006). In patients with impaired liver function there are no uniform criteria for recommending an appropriate dose of paracetamol. Along these lines, a meta-analysis concluded that among participants who consumed ethanol just prior to or during the trial and ingested 4 g/day of paracetamol, there was no evidence of elevation of ALT on day four (Rumack et al., 2012). Lewis et al. recommend that the dose of paracetamol for cirrhotic patients should be reduced to a maximum of 2–3 g/day (Lewis and Stine, 2013). Rossi et al. assessed healthcare providers´ recommendations on how over-the-counter analgesics should be used in patients with Chronic Liver Disease (CLD) and concluded that physicians recommend against the use of paracetamol more than NSAIDs in patients with CLD (Rossi et al., 2008). For nearly 20 years, it has been recognized that hepatotoxicity develops in about 6% of patients with a serum paracetamol concentrations above 200 lg/ml at 4 h from ingestion who are treated with NAC within 10 h of the overdose (Smilkstein et al., 1988).
http://dx.doi.org/10.1016/j.yrtph.2015.05.011 0273-2300/Ó 2015 Published by Elsevier Inc.
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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Patients with higher serum paracetamol concentrations, longer delays to NAC, and other risk factors (such as alcoholism) are at higher individual risk. Zyoud et al. (2011) also found that abdominal pain at presentation, the presence of psychiatric illness, and delays in NAC administration were associated with a prolonged hospital stay. In a substantial proportion of cases, the patient has concomitantly overdosed one or more drugs in addition to paracetamol; such drugs may affect the outcome of the paracetamol intoxication as a result of pharmacokinetic interaction or through independent toxic or hepato-protective properties. Suggested mechanisms of interaction include an increased or reduced rate of absorption of paracetamol, reduced conjugation of paracetamol, depletion of glutathione and inhibition of cytochrome P450-mediated metabolism (Bhattacharya et al., 2012) or an intrinsic inflammatory stimulus (Roth and Ganey, 2010). Schmidt and Dalhoff (2002) reported concomitant drug overdosing in 31%; (95% CI 27–34%) of patients (207/671) between 1994 and 2000. Benzodiazepines, opioid analgesics, acetylsalicylic acid (ASA), and nonsteroidal anti-inflammatory drugs (NSAIDs) predominated. The aim of this study was to analyze the incidence and outcome of acute paracetamol overdosing compared with chronic overdosing among adults in a tertiary hospital in Spain.
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2. Material and methods
108
This was an observational, longitudinal, retrospective cohort study conducted at La Paz University Hospital (LPUH) in Madrid, a tertiary teaching hospital with 1,365 beds that serves a population of 868,138 inhabitants. Using LabTrack (a database of an Integrated Laboratory System, development version; TrackHealth, Woolloomooloo, Australia), we identified all patients over 18 years of age whose paracetamol serum concentrations were measured by the Clinical Pharmacology Laboratory between 2005 and 2010. We then reviewed the patients’ medical records (electronic and paper) to document the study variables in a case report form (CRF) designed for this purpose. We conducted a causality analysis on those cases with impaired hepatic function with or without hepatic failure. The needed sample size was determined to be 198 patients (margin of error ±7%, 95% CI, 50% of distribution of response). The sample size for univariate logistic regression showed that accepting an alpha risk of 0.05 and a beta risk of 0.2, for a proportion of chronic overdose between 8 and 10%, between 196 and 179 subjects were needed to recognize a statistically significant odds ratio greater than or equal to 2. The study was approved by the Clinical Research Ethics Committee of LPUH, whose members are accredited by the Spanish Ministry of Health. The patients were classified according to the reason for requesting serum paracetamol serum concentrations: accidental ingestion, attempted suicide, and the study of impaired hepatic function for those with a history of paracetamol ingestion. Similarly, we classified the patients according to the type of ingestion: acute or chronic.
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136
2.1. Study population
137
The population consisted of all patients over 18 years of age for whom a determination of paracetamol serum concentration was requested from the Clinical Pharmacology Laboratory between 2005 and 2010. According to clinical protocols, paracetamol concentration tests are performed for all patients with suspected acute paracetamol poisoning (PAP) but not necessarily for chronic poisoning. In the latter case, the request was at the discretion of the
138 139 140 141 142 143
attending physician and was based on clinical and laboratory variables.
144
2.2. Definition of variables
146
The following information was recorded in the CRF: demographic and hospital variables, medical history, concomitant medication, reason for the request for paracetamol concentration test, laboratory findings, time elapsed since overdose and type of regimen (acute, chronic). Acute toxic doses of paracetamol were considered to be a single ingestion of paracetamol of more than 4 g, while chronic poisoning was defined as the repeated consumption of a dosage greater than 4 g/day for one or more days. Based on the Food and Drug Administration classification, we considered significant hepatotoxicity an increase in glutamic-pyruvic transaminase (GPT), also know alanine aminotransferase (ALT), concentrations >3 times the upper limit of normal (ULN) with or without >2 times the ULN in total bilirubin (FDA, Pre-marketing Guidance, 2009). Patients were considered to have ALF if they had an increased concentration of transaminases with acute onset of impaired coagulation (INR >1.5 or prothrombin activity 3 ULN due to paracetamol overdose (3.9% vs. 40%, p < 0.001) and in the percentage of ALF (2.2% vs. 15%, p = 0.021). The most relevant difference
Fig. 1.
3
between the acute and chronic cases of paracetamol toxicity was the frequency of hepatotoxicity. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity. With regard to chronic poisoning, 8 of the 10 patients (80%) with paracetamol poisoning at toxic doses presented hepatotoxicity, 3 (30%) of whom presented ALF criteria. Treatment with NAC was administered primarily to patients consulting for an acute poisoning by paracetamol compared with patients with the same but chronic consumption (p = 0.045). In addition, treatment with gastric lavage and activated charcoal was mainly performed on patients with acute paracetamol consumption (p = 0.002). The Odds Ratio for liver failure in the chronic poisoning group was 28.80 (95% CI 1.974–892.96, p = 0.007) with respect to acute poisoning.
256
4. Discussion
269
Despite changes in legislation that may have reduced the likelihood of intentional overdosing and increased the potential for effective treatment, a significant number of patients develop paracetamol hepatotoxicity (Brok et al., 2006; Hawkins et al., 2007; The Acetaminophen Hepatotoxicity Working Group, 2008). The incidence of paracetamol overdose during the study period was of 3.00 (95% Poisson CI: 0.61–8.77) cases per 10,000 patients. This incidence is higher than that found in the VEIA study (Caballero et al., 2008) (1.93 cases per 10,000 patients), which is an evolutional registry of acute poisonings attended in the Emergence Room of Doce de Octubre Hospital in Madrid (Spain) in 2004, and is also higher than the incidence found in the Emergence Department of Ramón y Cajal Hospital in Madrid in 2004 (1.37 cases per 10,000 patients attended) (Medina et al., 2008). Spain traditionally seems to have a lower incidence of accidental poisoning by paracetamol than other European countries. An epidemiological study conducted on 14 emergency departments in Spain concluded that the overall incidence of poisoning is slightly lower in Spain than in the rest of Europe (Burillo-Putze et al., 2003). However, the incidence of paracetamol poisoning increased from 2005 to 2010, and there is no current legislation controlling the sale of paracetamol in Spain. The reason for the discrepancy between countries may be due to the study methodology, as in the study all requests for paracetamol concentrations were included, as were studies on hepatitis or unknown causes. However, the annual incidence in the study increased from 2.00 (2005) to 3.35/10,000 per year (2010), with the highest rate (4.03/10,000) occurring in 2008. After 2008 a slight decline in cases was observed, probably due to transferring young individuals to a new hospital nearby. Paracetamol toxicity has become the most common cause of acute liver failure in both the United States and the United Kingdom (Bernal, 2003; Larson et al., 2005), whereas in other countries such Spain, acute liver failure is extremely rare (Escorsell et al., 2007). In this study, none of the 7 cases of paracetamol-induced ALF required liver transplantation, probably because the mean dose ingested was lower (5 g) than the dose described in other series on ALF (from 10 g to 50 g) (Gregory et al., 2010). A Danish study conducted between 1994 and 2000 concluded that 31% of the cases of paracetamol poisoning presented concomitant overdosing with at least one other drug, mainly benzodiazepines, opioid analgesics, salicylic acid and NSAIDs (Schmidt and Dalhoff, 2002). Similar results have been obtained in this study. The main concomitant drugs were those in the N group of ATC classification, highlighting benzodiazepines and secondly NSAIDs, although in our study the percentage of patients with an intake of other drugs was higher: 57.2% of the cases. Overdosing with paracetamol is more frequent in young women (Bravo et al., 2012; Kjartansdottir et al., 2012; Myers et al., 2008).
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Table 1 Demographic, diagnostic and hospitalization, variables of patients with suspected paracetamol poisoning. Variables
Features
n
%
Median age (range) Sex
33 (18–92) Males Female
66 142
31.7 68.3
Total Spain Unknown Foreign
208 142 23 43
100 68.3 11.1 20.7
Total No Yes Not indicated
208 191 11 6
100 91 .8 5.3 2.9
Total No Yes Not indicated
208 180 22 6
100 86.5 10.6 2.9
Total No Yes Not indicated
208 200 2 6
100 96.2 1.0 2.9
Total None Dermatology Psychiatric Obstetric and gynecologic Digestive system Neurological Cardiovascular system Surgery Nephrology/urology Hematology Trauma Oncology Drugs consumer VIH Not indicated
208 85 1 81 3 2 13 6 1 3 2 3 4 10 2 6
100 38.3 0.5 36.5 1.4 0.9 5.9 2.7 0.5 1.4 0.9 1.4 1.8 4.5 0.9 2.7
Total No Yes Not indicated
222 81 119 8
100 38.9 57.2 3.8
Total Emergency Department Nephrology Psychiatric Intensive care Internal medicine Digestive Traumatology Oncology Neurosurgery Cardiology Pneumology
208 142 3 6 35 15 2 1 1 1 1 1
100 68.3 1.4 2.9 16.8 7.2 1 0.5 0.5 0.5 0.5 0.5
Total 2 (0–9) No Yes
208
100
125 83
60.1 39.9
Total Psychiatric Neurosurgery Cardiology Intensive care Digestive Internal medicine Nephrology Pneumology Oncology Traumatology
208 24 1 1 31 2 20 1 1 1 1
100 28.9 1.2 1.2 37.3 2.4 24.1 1.2 1.2 1.2 1.2
Total 8 (1–91) Discharge from ED Discharge from Ward
83
100
120 83
57.7 39.9
Origin
Liver disease
Alcoholism
Malnutrition
Other relevant medical history
Ingestion of other drugs
Service requesting
Median days in ED (range) hospitalization
Admission service
Hospital stay in days median (range) Outcome
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H.Y. Tong et al. / Regulatory Toxicology and Pharmacology xxx (2015) xxx–xxx Table 1 (continued) Variables
Reason for requested paracetamol serum level tests
Type of regimen
Treatment
Features
n
Death
5
% 2.4
Total Attempted suicide Accidental Liver enzyme disorder Unknown
208 173 4 18 13
100 83.2 1.9 8.7 6.3
Total Acute Chronic Unknown
208 180 20 8
100 86.5 9.6 3.8
Total N-acetyl cysteine Gastric lavage Activated carbon Haemodialysis
208 84 82 82 17
100 40.4 39.4 39.4 8.2
ED. emergency department; n. number; %. percentage
Fig. 2.
320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340
In this study, 83.2% of the cases were suicide attempts, a figure that is in accordance with countries with over-the-counter (OTC) paracetamol (Kjartansdottir et al., 2012; Manthripragada et al., 2011; Myers et al., 2008) but is higher than those reported in countries where paracetamol is still sold by prescription (Bravo et al., 2012). An important finding of this study is the incidence of a maximum ALT of over 3 times the ULN in patients with chronic overdosing of paracetamol compared with acute overdosing: 8 (40%) cases vs. 7 (3.9%) cases, p < 0.001. It is expected that patients with acute poisoning would have higher ALT values on arrival at the hospital than patients with chronic intoxication (Craig et al., 2012). This discrepancy in our findings could be due, among other factors, to the delay in arrival at the hospital, which is greater in chronic overdosing than in acute (49.55 vs. 9.04 h; p < 0.001), leading to a delay in starting treatment. In addition, treatment with NAC was administered primarily to patients with acute poisoning compared to patients with chronic poisoning (p = 0.045). Likewise, treatment with gastric lavage and activated charcoal were mainly performed on patients with acute overdose of paracetamol (p < 0.002). However, in the study by Craig et al., patients with chronic poisoning by paracetamol, despite having lower ALT values on arrival at
the hospital, were more likely to show hepatic encephalopathy (Craig et al., 2012). We therefore found more cases of ALF in chronic poisoning than in acute poisoning: 3 (15%) cases vs. 4 (2.2%) cases, p < 0.001. These cases had longer hospital stays and the accompanying increased morbidity and financial costs. Causality was evaluated using two algorithms: the RUCAM (CDER-PHRMA-AASLD Conference, 2000) and the SPVS (Capellá and Laporte, 1993). Both provide equal sensitivity to rule out the cases that are unrelated to paracetamol poisoning. While the RUCAM algorithm reported more paracetamol causality than SPVS, there was no difference in the assessment of causality between acute or chronic intoxication. Acute poisoning of paracetamol might be easier to recognize, and its management is widely known, but chronic poisoning is more difficult to diagnose and its management is more uncertain. A number of factors may contribute to this problem. First, the symptoms of paracetamol-induced liver injury include nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of liver injury may not be apparent until 48 to 72 h post-ingestion. NAC can prevent liver injury if given within 12 h after a single ingestion (Alsalim and Fadel, 2003); however, unintentional chronic overdosing is usually only recognized
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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Table 2 Variables according to reason for requested paracetamol serum level test. N (%)
Accidental 4 (1.9%)
Suicide attempt 173 (83.2%)
Unknown 13 (6.3%)
Liver enzyme disorder 18 (8.7%)
Age (years)
38.5 (23–76)
31 (18–87)
42 (25–87)
49.5 (32–92)
Sex Female n (%) Male n (%) Total
2 (50%) 2 (50%) 4 (100%)
127 (73.4%) 46 (26.6%) 173 (100%)
5 (38.5%) 8 (61.5%) 13 (100%)
8 (44.4%) 10 (55.6%) 18 (100%)
3 (75%) 1 (25%) 4 (100%) 2 (1–3)
113 (65.3%) 40 (23.1%) 20 (11.6%) 173 (100%) 2 (1–9)
10 (76.9%) 1 (7.7%) 2 (15.4%) 13 (100%) 2 (0–5)
16 (88.9%) 1 (5.6%) 1 (5.6%) 18 (100%) 2 (1–2)
1 (25%) 3 (75%) 4 (100%) 31
59 (34.1%) 114 (65.9%) 173 (100%) 7 (2–67)
7 (53.8%) 6 (46.2%) 13 (100%) 12 (5–89)
16 (88.9%) 2 (11.1%) 18 (100%) 9 (2–91)
10 (17.0%) 24 (40.7%) 24 (40.7%) 1 (1.7%)
2 (25.6%) 2 (28.6%)
8 (50%) 5 (31.3%)
Origin Spain Abroad Unknown Total hours of ED care Days in ED Admission Yes No Total Days in ward Admission service Internal ICU Psychiatry Neurosurgery Gastroenterology Traumatology Nephrology Pneumology Cardiology Oncology Total
1 (100%) 1 (100%)
59 (100%)
7 (100%)
16 (100%)
Transaminase impairment due to paracetamol No Yes Total
4 (100%) 4(100%)
5 (2.9%) 168 (97.1%) 173 (100%)
13 (100%) 13 (100%)
10 (55.6%) 8 (44.4%) 18 (100%)
3 (75%) 1 (25%)
110 (63.6%) 63 (36.4%)
4 (100%)
173 (100%)
5 (38.5%) 6 (46.2%) 2 (15.4%) 13 (100%)
2 (11.1%) 12 (66.7%) 4 (22.2%) 18 (100%)
4 (100%)
169 (97.7%) 4 (2.3%)
5 (27.8%) 13 (72.2%)
4 (100%)
173 (100%)
2 (15.4%) 3 (23.1%) 8 (61.5%) 13 (100%)
(n = 4) 8.25 (6–13)
(n = 107) 8 (1–80) (n = 4) 7 (4–11)
(n = 2) 3.75 (1–6.5) (n = 3) 3 (2–3)
(n = 4) 2.97 (1–5) (n = 12) 3.5 (2–32)
1 (25%) 3 (75%) 4 (100%) 3.01 (1–83.8) 12.5 (1–24) (n = 94) (n = 4) 2/2 (50%/50%) 1/3 (25%/75%) 0/4 (0%/100%) 0/4 (0%/100%)
112 (64.7%) 55 (31.8%) 173 (100%) 3.68 (0–371.4) 6 (1–48) (n = 2) (n = 154) 77/77 (44.5%/44.5%) 80/74 (46.2%/42.8%) 82/72 (47.4%/41.6%) 15/139 (8.7%/80.3%)
2 (15.4%) 9 (69.2%) 2 (15.4%) 13 (100%) 1.98 (0–71.38) 10 (6–24) (n = 3) (n = 12) 1/11 (7.7%/84.6%) 1/11 (7.7%/84.6%) 0/12 (0%/100%) 1/11 (7.7%/84.6%)
4 (22.2%) 14 (77.8%) 18 (100%) 2.89 (0.5–10.3) 48 (24–72) (n = 7) (n = 18) 4/14 (22.2%/77.8%) 0/18 (0%/100%) 0/18 (0%/100%) 1/17 (5.6%/94.4%)
Outcome Discharge from ED Discharge from WARD Death Total Type of regimen Acute Chronic Unknown Total Ingested dose Acute (gr) Median (range) Chronic (gr) Median (range) Ingestion of other drugs Yes No unknown Total Paracetamol level on admission lg/ml Time from ingestion to level test request (hours) Treatment (Yes/No) N-acetyl cysteine Gastric lavage Activated carbon Haemodialysis
2 (12.5%) 1 (6.3%) 1 (14.3%) 1 (14.3%) 1 (14.3%)
18 (100%)
ED, emergence department.
362 363 364 365 366 367 368
after symptoms have developed. Second, currently approximately 400 OTC medicines or prescription medicines containing some form of paracetamol, as single ingredient products or multiple ingredient (combination) products, are marketed in Spain. Patients may attempt to treat different symptoms at the same time with more than one product containing paracetamol and without knowing that they are at risk of a paracetamol overdose. Third, many consumers
do not know that paracetamol overdose can cause serious liver injury. In June 2009, an FDA advisory committee recommended that the maximum dosage at any given time should be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited (FDA, April 28, 2009a; FDA, June 29-30, 2009b). In January 2011, the FDA asked
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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H.Y. Tong et al. / Regulatory Toxicology and Pharmacology xxx (2015) xxx–xxx Table 3 Comparison of acute poisoning and chronic poisoning. Variables
Acute n = 180
n
Chronic n = 20
n
p
Age mean (SD) Males n (%)
35.1 (15.8) 50 (27.8%)
180 50
54.6 (19.8) 11 (55%)
20 11
3 ULN secondary to acetaminophen Yes n (%) No n (%) Total n (%)
7 (3.9%) 173 (96.1%) 180 (100%)
7 173 180
8 (40%) 12 (60%) 20 (100%)
8 12 20
3 ULN cases)
4 (2.2%) 176 (97.8%) 180 (100%)
4 176 18 0
3 (15%) 17 (85%) 20 (100%)
3 17 20
0.003
Rucam Improbable Possible Probable
3 (30%) 1 (10%) 6 (60%)
3 1 6
3 (27.3%) 1 (9.1%) 7 (63.6%)
3 1 7
Capella and LaPorte System Improbable Possible Probable
3 (30%) 3 (30%) 4 (40%)
3 3 4
3 (27.3%) 2 (18.2%) 6 (54.5%)
3 2 6
Treatment (Yes/No) N-acetyl cysteine Gastric lavage Activated carbon Unknown
78/82 (43.3/45.6%) 79/81 (43.9/45%) 80/80 (44.4/44.4%) 20 (11.1%)
160 160 160 20
5/15 (25/75%) 2/18 (10/90%) 2/18 (10/90%) 0 (0%)
20 20 20 0
0.045 0.001 0.001 0.239
Liver function Maximum ALT UI/L, median (range) Maximum AST UI/L, median (range) Maximum GGT UI/L, median (range) Maximum total bilirubin, mean (SD)
36 (15–5260) 27.5 (9–3785) 22 (3–4445) 0.6 (0.1–12.6)
106 106 99 95
858 (34–4800) 464 (43–12798) 273 (33–2182) 2.6 (0.5–19.9)
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Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand? Hoi Y. Tong a, Nicolás Medrano a, Alberto M. Borobia a,b, Ana M. Martínez b, Julia Martín c, José A. Ruiz c, Santos García c, Manuel Quintana b, Antonio J. Carcas a, Jesús Frías a, Elena Ramírez a,⇑ a b c
Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPAZ, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain General Emergency Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain Paediatric Emergency Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 5 November 2014 Available online xxxx Keywords: Paracetamol Overdose Toxicity Poisoning Hepatotoxicity Acute liver failure Pharmacovigilance Safety pharmacology
a b s t r a c t Paracetamol (Acetaminophen) poisoning data can reveal the potential deficiencies of paracetamol poisoning management guidelines. We conducted a retrospective cohort study of patients >18 years who were attended in the emergency department (ED) of a Spanish tertiary hospital, from 2005 to 2010 for suspected paracetamol overdose and who had measurable paracetamol concentrations. 208 patients suspected of paracetamol poisoning were identified. The annual incidence in the ED increased from 2.0 (95%-CI: 0.2–7.2) cases per 10,000 patients in 2005 to 3.4 (95%-CI: 1.1–8.8) in 2010. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity signs, 4 (57.1%) of whom presented acute liver failure (ALF) criteria, while 8 of 10 patients (80%) with chronic paracetamol poisoning at toxic doses presented hepatotoxicity and 3 (37.5%) with ALF criteria. The time required to find medical care was 9.0 h for acute poisoning and 49.6 h for chronic poisoning (p < 0.001). We conclude that the incidence of suspected cases of paracetamol poisoning at our hospital is increasing. The majority of toxicity cases, including ALF, associated with the ingestion of paracetamol were due to chronic poisoning. This finding constitutes an important warning regarding paracetamol chronic poisoning, and clinicians should have a higher index of clinical suspicion for this entity. Ó 2015 Published by Elsevier Inc.
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1. Introduction
49
Paracetamol is the most widely used analgesic in the world. In most Western countries, including the UK (ÒGrady et al., 1989) and USA (Schiødt et al., 1999), it is the leading cause of acute liver failure (ALF). Accurately and rapidly predicting the risk of hepatotoxicity after a paracetamol overdose is essential because the clinical and biochemical signs of organ toxicity are not detectable until about 24 h after overdose, well past the optimum time for antidote therapy. Unintentional overdosing from self-medication for pain or fever that leads to daily doses exceeding 4 g is usually only recognized after the symptoms have developed. Delays in seeking medical attention and delays in initiating N-acetylcysteine (NAC) therapy are associated with a greater risk of morbidity and mortality (Dargan and Jones, 2002; Chun et al., 2009).
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⇑ Corresponding author at: Paseo de la Castellana, 261, Madrid 28046, Spain. Fax: +34 91 7277559. E-mail address: [email protected] (E. Ramírez).
Although the recommended doses of 4 gr/day is generally safe, Watkins et al. found that even with the ingestion of this dose for several days, it is possible to develop an asymptomatic ALT elevation in healthy volunteers (Watkins et al., 2006). In patients with impaired liver function there are no uniform criteria for recommending an appropriate dose of paracetamol. Along these lines, a meta-analysis concluded that among participants who consumed ethanol just prior to or during the trial and ingested 4 g/day of paracetamol, there was no evidence of elevation of ALT on day four (Rumack et al., 2012). Lewis et al. recommend that the dose of paracetamol for cirrhotic patients should be reduced to a maximum of 2–3 g/day (Lewis and Stine, 2013). Rossi et al. assessed healthcare providers´ recommendations on how over-the-counter analgesics should be used in patients with Chronic Liver Disease (CLD) and concluded that physicians recommend against the use of paracetamol more than NSAIDs in patients with CLD (Rossi et al., 2008). For nearly 20 years, it has been recognized that hepatotoxicity develops in about 6% of patients with a serum paracetamol concentrations above 200 lg/ml at 4 h from ingestion who are treated with NAC within 10 h of the overdose (Smilkstein et al., 1988).
http://dx.doi.org/10.1016/j.yrtph.2015.05.011 0273-2300/Ó 2015 Published by Elsevier Inc.
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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Patients with higher serum paracetamol concentrations, longer delays to NAC, and other risk factors (such as alcoholism) are at higher individual risk. Zyoud et al. (2011) also found that abdominal pain at presentation, the presence of psychiatric illness, and delays in NAC administration were associated with a prolonged hospital stay. In a substantial proportion of cases, the patient has concomitantly overdosed one or more drugs in addition to paracetamol; such drugs may affect the outcome of the paracetamol intoxication as a result of pharmacokinetic interaction or through independent toxic or hepato-protective properties. Suggested mechanisms of interaction include an increased or reduced rate of absorption of paracetamol, reduced conjugation of paracetamol, depletion of glutathione and inhibition of cytochrome P450-mediated metabolism (Bhattacharya et al., 2012) or an intrinsic inflammatory stimulus (Roth and Ganey, 2010). Schmidt and Dalhoff (2002) reported concomitant drug overdosing in 31%; (95% CI 27–34%) of patients (207/671) between 1994 and 2000. Benzodiazepines, opioid analgesics, acetylsalicylic acid (ASA), and nonsteroidal anti-inflammatory drugs (NSAIDs) predominated. The aim of this study was to analyze the incidence and outcome of acute paracetamol overdosing compared with chronic overdosing among adults in a tertiary hospital in Spain.
107
2. Material and methods
108
This was an observational, longitudinal, retrospective cohort study conducted at La Paz University Hospital (LPUH) in Madrid, a tertiary teaching hospital with 1,365 beds that serves a population of 868,138 inhabitants. Using LabTrack (a database of an Integrated Laboratory System, development version; TrackHealth, Woolloomooloo, Australia), we identified all patients over 18 years of age whose paracetamol serum concentrations were measured by the Clinical Pharmacology Laboratory between 2005 and 2010. We then reviewed the patients’ medical records (electronic and paper) to document the study variables in a case report form (CRF) designed for this purpose. We conducted a causality analysis on those cases with impaired hepatic function with or without hepatic failure. The needed sample size was determined to be 198 patients (margin of error ±7%, 95% CI, 50% of distribution of response). The sample size for univariate logistic regression showed that accepting an alpha risk of 0.05 and a beta risk of 0.2, for a proportion of chronic overdose between 8 and 10%, between 196 and 179 subjects were needed to recognize a statistically significant odds ratio greater than or equal to 2. The study was approved by the Clinical Research Ethics Committee of LPUH, whose members are accredited by the Spanish Ministry of Health. The patients were classified according to the reason for requesting serum paracetamol serum concentrations: accidental ingestion, attempted suicide, and the study of impaired hepatic function for those with a history of paracetamol ingestion. Similarly, we classified the patients according to the type of ingestion: acute or chronic.
109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
136
2.1. Study population
137
The population consisted of all patients over 18 years of age for whom a determination of paracetamol serum concentration was requested from the Clinical Pharmacology Laboratory between 2005 and 2010. According to clinical protocols, paracetamol concentration tests are performed for all patients with suspected acute paracetamol poisoning (PAP) but not necessarily for chronic poisoning. In the latter case, the request was at the discretion of the
138 139 140 141 142 143
attending physician and was based on clinical and laboratory variables.
144
2.2. Definition of variables
146
The following information was recorded in the CRF: demographic and hospital variables, medical history, concomitant medication, reason for the request for paracetamol concentration test, laboratory findings, time elapsed since overdose and type of regimen (acute, chronic). Acute toxic doses of paracetamol were considered to be a single ingestion of paracetamol of more than 4 g, while chronic poisoning was defined as the repeated consumption of a dosage greater than 4 g/day for one or more days. Based on the Food and Drug Administration classification, we considered significant hepatotoxicity an increase in glutamic-pyruvic transaminase (GPT), also know alanine aminotransferase (ALT), concentrations >3 times the upper limit of normal (ULN) with or without >2 times the ULN in total bilirubin (FDA, Pre-marketing Guidance, 2009). Patients were considered to have ALF if they had an increased concentration of transaminases with acute onset of impaired coagulation (INR >1.5 or prothrombin activity 3 ULN due to paracetamol overdose (3.9% vs. 40%, p < 0.001) and in the percentage of ALF (2.2% vs. 15%, p = 0.021). The most relevant difference
Fig. 1.
3
between the acute and chronic cases of paracetamol toxicity was the frequency of hepatotoxicity. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity. With regard to chronic poisoning, 8 of the 10 patients (80%) with paracetamol poisoning at toxic doses presented hepatotoxicity, 3 (30%) of whom presented ALF criteria. Treatment with NAC was administered primarily to patients consulting for an acute poisoning by paracetamol compared with patients with the same but chronic consumption (p = 0.045). In addition, treatment with gastric lavage and activated charcoal was mainly performed on patients with acute paracetamol consumption (p = 0.002). The Odds Ratio for liver failure in the chronic poisoning group was 28.80 (95% CI 1.974–892.96, p = 0.007) with respect to acute poisoning.
256
4. Discussion
269
Despite changes in legislation that may have reduced the likelihood of intentional overdosing and increased the potential for effective treatment, a significant number of patients develop paracetamol hepatotoxicity (Brok et al., 2006; Hawkins et al., 2007; The Acetaminophen Hepatotoxicity Working Group, 2008). The incidence of paracetamol overdose during the study period was of 3.00 (95% Poisson CI: 0.61–8.77) cases per 10,000 patients. This incidence is higher than that found in the VEIA study (Caballero et al., 2008) (1.93 cases per 10,000 patients), which is an evolutional registry of acute poisonings attended in the Emergence Room of Doce de Octubre Hospital in Madrid (Spain) in 2004, and is also higher than the incidence found in the Emergence Department of Ramón y Cajal Hospital in Madrid in 2004 (1.37 cases per 10,000 patients attended) (Medina et al., 2008). Spain traditionally seems to have a lower incidence of accidental poisoning by paracetamol than other European countries. An epidemiological study conducted on 14 emergency departments in Spain concluded that the overall incidence of poisoning is slightly lower in Spain than in the rest of Europe (Burillo-Putze et al., 2003). However, the incidence of paracetamol poisoning increased from 2005 to 2010, and there is no current legislation controlling the sale of paracetamol in Spain. The reason for the discrepancy between countries may be due to the study methodology, as in the study all requests for paracetamol concentrations were included, as were studies on hepatitis or unknown causes. However, the annual incidence in the study increased from 2.00 (2005) to 3.35/10,000 per year (2010), with the highest rate (4.03/10,000) occurring in 2008. After 2008 a slight decline in cases was observed, probably due to transferring young individuals to a new hospital nearby. Paracetamol toxicity has become the most common cause of acute liver failure in both the United States and the United Kingdom (Bernal, 2003; Larson et al., 2005), whereas in other countries such Spain, acute liver failure is extremely rare (Escorsell et al., 2007). In this study, none of the 7 cases of paracetamol-induced ALF required liver transplantation, probably because the mean dose ingested was lower (5 g) than the dose described in other series on ALF (from 10 g to 50 g) (Gregory et al., 2010). A Danish study conducted between 1994 and 2000 concluded that 31% of the cases of paracetamol poisoning presented concomitant overdosing with at least one other drug, mainly benzodiazepines, opioid analgesics, salicylic acid and NSAIDs (Schmidt and Dalhoff, 2002). Similar results have been obtained in this study. The main concomitant drugs were those in the N group of ATC classification, highlighting benzodiazepines and secondly NSAIDs, although in our study the percentage of patients with an intake of other drugs was higher: 57.2% of the cases. Overdosing with paracetamol is more frequent in young women (Bravo et al., 2012; Kjartansdottir et al., 2012; Myers et al., 2008).
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Table 1 Demographic, diagnostic and hospitalization, variables of patients with suspected paracetamol poisoning. Variables
Features
n
%
Median age (range) Sex
33 (18–92) Males Female
66 142
31.7 68.3
Total Spain Unknown Foreign
208 142 23 43
100 68.3 11.1 20.7
Total No Yes Not indicated
208 191 11 6
100 91 .8 5.3 2.9
Total No Yes Not indicated
208 180 22 6
100 86.5 10.6 2.9
Total No Yes Not indicated
208 200 2 6
100 96.2 1.0 2.9
Total None Dermatology Psychiatric Obstetric and gynecologic Digestive system Neurological Cardiovascular system Surgery Nephrology/urology Hematology Trauma Oncology Drugs consumer VIH Not indicated
208 85 1 81 3 2 13 6 1 3 2 3 4 10 2 6
100 38.3 0.5 36.5 1.4 0.9 5.9 2.7 0.5 1.4 0.9 1.4 1.8 4.5 0.9 2.7
Total No Yes Not indicated
222 81 119 8
100 38.9 57.2 3.8
Total Emergency Department Nephrology Psychiatric Intensive care Internal medicine Digestive Traumatology Oncology Neurosurgery Cardiology Pneumology
208 142 3 6 35 15 2 1 1 1 1 1
100 68.3 1.4 2.9 16.8 7.2 1 0.5 0.5 0.5 0.5 0.5
Total 2 (0–9) No Yes
208
100
125 83
60.1 39.9
Total Psychiatric Neurosurgery Cardiology Intensive care Digestive Internal medicine Nephrology Pneumology Oncology Traumatology
208 24 1 1 31 2 20 1 1 1 1
100 28.9 1.2 1.2 37.3 2.4 24.1 1.2 1.2 1.2 1.2
Total 8 (1–91) Discharge from ED Discharge from Ward
83
100
120 83
57.7 39.9
Origin
Liver disease
Alcoholism
Malnutrition
Other relevant medical history
Ingestion of other drugs
Service requesting
Median days in ED (range) hospitalization
Admission service
Hospital stay in days median (range) Outcome
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H.Y. Tong et al. / Regulatory Toxicology and Pharmacology xxx (2015) xxx–xxx Table 1 (continued) Variables
Reason for requested paracetamol serum level tests
Type of regimen
Treatment
Features
n
Death
5
% 2.4
Total Attempted suicide Accidental Liver enzyme disorder Unknown
208 173 4 18 13
100 83.2 1.9 8.7 6.3
Total Acute Chronic Unknown
208 180 20 8
100 86.5 9.6 3.8
Total N-acetyl cysteine Gastric lavage Activated carbon Haemodialysis
208 84 82 82 17
100 40.4 39.4 39.4 8.2
ED. emergency department; n. number; %. percentage
Fig. 2.
320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340
In this study, 83.2% of the cases were suicide attempts, a figure that is in accordance with countries with over-the-counter (OTC) paracetamol (Kjartansdottir et al., 2012; Manthripragada et al., 2011; Myers et al., 2008) but is higher than those reported in countries where paracetamol is still sold by prescription (Bravo et al., 2012). An important finding of this study is the incidence of a maximum ALT of over 3 times the ULN in patients with chronic overdosing of paracetamol compared with acute overdosing: 8 (40%) cases vs. 7 (3.9%) cases, p < 0.001. It is expected that patients with acute poisoning would have higher ALT values on arrival at the hospital than patients with chronic intoxication (Craig et al., 2012). This discrepancy in our findings could be due, among other factors, to the delay in arrival at the hospital, which is greater in chronic overdosing than in acute (49.55 vs. 9.04 h; p < 0.001), leading to a delay in starting treatment. In addition, treatment with NAC was administered primarily to patients with acute poisoning compared to patients with chronic poisoning (p = 0.045). Likewise, treatment with gastric lavage and activated charcoal were mainly performed on patients with acute overdose of paracetamol (p < 0.002). However, in the study by Craig et al., patients with chronic poisoning by paracetamol, despite having lower ALT values on arrival at
the hospital, were more likely to show hepatic encephalopathy (Craig et al., 2012). We therefore found more cases of ALF in chronic poisoning than in acute poisoning: 3 (15%) cases vs. 4 (2.2%) cases, p < 0.001. These cases had longer hospital stays and the accompanying increased morbidity and financial costs. Causality was evaluated using two algorithms: the RUCAM (CDER-PHRMA-AASLD Conference, 2000) and the SPVS (Capellá and Laporte, 1993). Both provide equal sensitivity to rule out the cases that are unrelated to paracetamol poisoning. While the RUCAM algorithm reported more paracetamol causality than SPVS, there was no difference in the assessment of causality between acute or chronic intoxication. Acute poisoning of paracetamol might be easier to recognize, and its management is widely known, but chronic poisoning is more difficult to diagnose and its management is more uncertain. A number of factors may contribute to this problem. First, the symptoms of paracetamol-induced liver injury include nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of liver injury may not be apparent until 48 to 72 h post-ingestion. NAC can prevent liver injury if given within 12 h after a single ingestion (Alsalim and Fadel, 2003); however, unintentional chronic overdosing is usually only recognized
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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Table 2 Variables according to reason for requested paracetamol serum level test. N (%)
Accidental 4 (1.9%)
Suicide attempt 173 (83.2%)
Unknown 13 (6.3%)
Liver enzyme disorder 18 (8.7%)
Age (years)
38.5 (23–76)
31 (18–87)
42 (25–87)
49.5 (32–92)
Sex Female n (%) Male n (%) Total
2 (50%) 2 (50%) 4 (100%)
127 (73.4%) 46 (26.6%) 173 (100%)
5 (38.5%) 8 (61.5%) 13 (100%)
8 (44.4%) 10 (55.6%) 18 (100%)
3 (75%) 1 (25%) 4 (100%) 2 (1–3)
113 (65.3%) 40 (23.1%) 20 (11.6%) 173 (100%) 2 (1–9)
10 (76.9%) 1 (7.7%) 2 (15.4%) 13 (100%) 2 (0–5)
16 (88.9%) 1 (5.6%) 1 (5.6%) 18 (100%) 2 (1–2)
1 (25%) 3 (75%) 4 (100%) 31
59 (34.1%) 114 (65.9%) 173 (100%) 7 (2–67)
7 (53.8%) 6 (46.2%) 13 (100%) 12 (5–89)
16 (88.9%) 2 (11.1%) 18 (100%) 9 (2–91)
10 (17.0%) 24 (40.7%) 24 (40.7%) 1 (1.7%)
2 (25.6%) 2 (28.6%)
8 (50%) 5 (31.3%)
Origin Spain Abroad Unknown Total hours of ED care Days in ED Admission Yes No Total Days in ward Admission service Internal ICU Psychiatry Neurosurgery Gastroenterology Traumatology Nephrology Pneumology Cardiology Oncology Total
1 (100%) 1 (100%)
59 (100%)
7 (100%)
16 (100%)
Transaminase impairment due to paracetamol No Yes Total
4 (100%) 4(100%)
5 (2.9%) 168 (97.1%) 173 (100%)
13 (100%) 13 (100%)
10 (55.6%) 8 (44.4%) 18 (100%)
3 (75%) 1 (25%)
110 (63.6%) 63 (36.4%)
4 (100%)
173 (100%)
5 (38.5%) 6 (46.2%) 2 (15.4%) 13 (100%)
2 (11.1%) 12 (66.7%) 4 (22.2%) 18 (100%)
4 (100%)
169 (97.7%) 4 (2.3%)
5 (27.8%) 13 (72.2%)
4 (100%)
173 (100%)
2 (15.4%) 3 (23.1%) 8 (61.5%) 13 (100%)
(n = 4) 8.25 (6–13)
(n = 107) 8 (1–80) (n = 4) 7 (4–11)
(n = 2) 3.75 (1–6.5) (n = 3) 3 (2–3)
(n = 4) 2.97 (1–5) (n = 12) 3.5 (2–32)
1 (25%) 3 (75%) 4 (100%) 3.01 (1–83.8) 12.5 (1–24) (n = 94) (n = 4) 2/2 (50%/50%) 1/3 (25%/75%) 0/4 (0%/100%) 0/4 (0%/100%)
112 (64.7%) 55 (31.8%) 173 (100%) 3.68 (0–371.4) 6 (1–48) (n = 2) (n = 154) 77/77 (44.5%/44.5%) 80/74 (46.2%/42.8%) 82/72 (47.4%/41.6%) 15/139 (8.7%/80.3%)
2 (15.4%) 9 (69.2%) 2 (15.4%) 13 (100%) 1.98 (0–71.38) 10 (6–24) (n = 3) (n = 12) 1/11 (7.7%/84.6%) 1/11 (7.7%/84.6%) 0/12 (0%/100%) 1/11 (7.7%/84.6%)
4 (22.2%) 14 (77.8%) 18 (100%) 2.89 (0.5–10.3) 48 (24–72) (n = 7) (n = 18) 4/14 (22.2%/77.8%) 0/18 (0%/100%) 0/18 (0%/100%) 1/17 (5.6%/94.4%)
Outcome Discharge from ED Discharge from WARD Death Total Type of regimen Acute Chronic Unknown Total Ingested dose Acute (gr) Median (range) Chronic (gr) Median (range) Ingestion of other drugs Yes No unknown Total Paracetamol level on admission lg/ml Time from ingestion to level test request (hours) Treatment (Yes/No) N-acetyl cysteine Gastric lavage Activated carbon Haemodialysis
2 (12.5%) 1 (6.3%) 1 (14.3%) 1 (14.3%) 1 (14.3%)
18 (100%)
ED, emergence department.
362 363 364 365 366 367 368
after symptoms have developed. Second, currently approximately 400 OTC medicines or prescription medicines containing some form of paracetamol, as single ingredient products or multiple ingredient (combination) products, are marketed in Spain. Patients may attempt to treat different symptoms at the same time with more than one product containing paracetamol and without knowing that they are at risk of a paracetamol overdose. Third, many consumers
do not know that paracetamol overdose can cause serious liver injury. In June 2009, an FDA advisory committee recommended that the maximum dosage at any given time should be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited (FDA, April 28, 2009a; FDA, June 29-30, 2009b). In January 2011, the FDA asked
Please cite this article in press as: Tong, H.Y., et al. Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand?. Regul. Toxicol. Pharmacol. (2015), http://dx.doi.org/10.1016/j.yrtph.2015.05.011
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H.Y. Tong et al. / Regulatory Toxicology and Pharmacology xxx (2015) xxx–xxx Table 3 Comparison of acute poisoning and chronic poisoning. Variables
Acute n = 180
n
Chronic n = 20
n
p
Age mean (SD) Males n (%)
35.1 (15.8) 50 (27.8%)
180 50
54.6 (19.8) 11 (55%)
20 11
3 ULN secondary to acetaminophen Yes n (%) No n (%) Total n (%)
7 (3.9%) 173 (96.1%) 180 (100%)
7 173 180
8 (40%) 12 (60%) 20 (100%)
8 12 20
3 ULN cases)
4 (2.2%) 176 (97.8%) 180 (100%)
4 176 18 0
3 (15%) 17 (85%) 20 (100%)
3 17 20
0.003
Rucam Improbable Possible Probable
3 (30%) 1 (10%) 6 (60%)
3 1 6
3 (27.3%) 1 (9.1%) 7 (63.6%)
3 1 7
Capella and LaPorte System Improbable Possible Probable
3 (30%) 3 (30%) 4 (40%)
3 3 4
3 (27.3%) 2 (18.2%) 6 (54.5%)
3 2 6
Treatment (Yes/No) N-acetyl cysteine Gastric lavage Activated carbon Unknown
78/82 (43.3/45.6%) 79/81 (43.9/45%) 80/80 (44.4/44.4%) 20 (11.1%)
160 160 160 20
5/15 (25/75%) 2/18 (10/90%) 2/18 (10/90%) 0 (0%)
20 20 20 0
0.045 0.001 0.001 0.239
Liver function Maximum ALT UI/L, median (range) Maximum AST UI/L, median (range) Maximum GGT UI/L, median (range) Maximum total bilirubin, mean (SD)
36 (15–5260) 27.5 (9–3785) 22 (3–4445) 0.6 (0.1–12.6)
106 106 99 95
858 (34–4800) 464 (43–12798) 273 (33–2182) 2.6 (0.5–19.9)
15 15 15 15
