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Criteria for acetylcysteine treatment and clinical outcomes after paracetamol poisoning Expert Rev. Clin. Pharmacol. 5(3), 311–318 (2012)
W Stephen Waring Acute Medical Unit, York Hospital, Wigginton Road, York, YO31 8HE, UK Tel.: +44 1904 726276
[email protected]
Acetylcysteine is an effective antidote for paracetamol (acetaminophen) poisoning, but different treatment criteria exist internationally. In the UK, acetylcysteine is indicated by paracetamol concentrations higher than the Prescott nomogram or higher than 50% of the nomogram in patients with increased susceptibility to liver toxicity. In the USA, a single ‘150-line’ nomogram has been used that removes the need for additional clinical risk assessment. The latter approach has recently been adopted in Australia, New Zealand and elsewhere. Few data exist to allow direct comparison of these different international approaches. An existing database of 1191 patients admitted to hospital after paracetamol overdose identified that the 4-h equivalent paracetamol concentration was: ≥200 mg/l in 163 patients (15.6%; 95% CI: 13.3–18.2%), ≥150 mg/l in 264 (24.3%; 95% CI: 21.5–27.5%) and ≥100 mg/l in 426 patients (39.3%; 95% CI: 35.6–43.2%), and acute liver injury occurred in 3.7% (95% CI: 1.4–8.0%), 2.3% (95% CI: 0.8–5.0%) and 1.9% (95% CI: 0.8–3.7%), respectively. The different indications for acetylcysteine used by the UK and USA would result in similar numbers of patients treated, although the criteria would define patients with different characteristics and patterns of overdose. The relative merit of these different international approaches to acetylcysteine administration is considered in this article. Keywords : acetylcysteine • acetaminophen • antidote • drug toxicity • liver injury • nomogram • paracetamol • poisoning • risk assessment
For more than 30 years acetylcysteine has been recognized as an effective antidote for paracetamol overdose, and is capable of preventing hepatotoxicity if given sufficiently early after ingestion [1] . In the UK, the National Poisons Information Service advises acetylc ysteine administration based on the extent of paracetamol exposure and considers the presence or absence of risk factors for liver toxicity [2] . The Prescott nomogram, or so-called ‘200-line’, is used to identify significant exposure after paracetamol overdose and is used to indicate acetylcysteine. This nomogram is plotted from 200 mg/l (1320 μmol/l) at 4 h to 30 mg/l (200 μmol/l) at 15 h (Figure 1) . The occurrence of liver injury depends not only upon the quantity ingested, but also the duration of exposure to high concentrations, fasting status and the rate and extent of formation of paracetamol metabolites. In order to take account of these factors, a more aggressive ‘100-line’ (50% of the standard www.expert-reviews.com
10.1586/ECP.12.15
nomogram) is used for patients considered to be at high risk of liver injury due to prior use of drugs capable of inducing hepatic P450 enzymes, regular excess ethanol consumption, malnourishment and the presence of liver disease [2–5] . Despite these criteria, some patients develop acute liver injury at paracetamol concentrations below the appropriate treatment thresholds and despite administration of acetylcysteine [6–8] . This has raised concerns that a more widespread use of acetylcysteine treatment might be warranted in some circumstances, or that conventional risk assessment fails to recognize some patients with increased susceptibility to liver toxicity. This has led to a recent review by the Medicines and Healthcare Products Regulatory Authority, and follows a number of important regulatory responses to clinical toxicology data; for example, the legislation concerning paracetamol pack size and the recent withdrawal of paracetamol preparations containing
© 2012 Expert Reviews Ltd
ISSN 1751-2433
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200
1.3
180
1.2 1.1 ‘150-line’
1.0
140
0.9
120
0.8
100
Normal treatment line (‘200-line’)
0.7 0.6
80
0.5 0.4
60
0.3
40
0.2
Plasma [paracetamol] (mmol/l)
160 Plasma [paracetamol] (mg/l)
Waring
Additionally, acetylcysteine is prone to dose calculation errors, which has resulted in very serious adverse effects in some patients [18,19] . Few data exist concerning the relative merits of these different risk-assessment strategies. In particular, it is uncertain what impact the USA guidelines might have on the number of patients treated with acetylcysteine if this were to be incorporated into clinical practice in the UK. The aim of this review was to examine an existing database to allow comparison of the numbers and characteristics of patients that would be identified by both assessment methods. Methods Study design
An existing dataset had originally been constructed during a prospective, observational study of consecutive patients that 0 0.0 attended the Emergency Department of 0 2 4 6 8 10 12 14 16 18 20 22 24 the Royal Infirmary of Edinburgh after Interval after ingestion (h) paracetamol overdose between 1 March 2005 and 30 June 2006 [20] . This is a terFigure 1. Different treatment nomograms used to determine the need for tiary referral hospital serving a catchment acetylcysteine after single time point ingestion of paracetamol. population of approximately 500,000 that Modified with permission from the University of Wales College of Medicine, Therapeutics receives approximately 75,000 emergency and Toxicology Centre, Cardiff, UK. department presentations annually. A standextropropoxyphene [9] . A particularly difficult issue is the lack of dardized data collection sheet had been used to record age, gender, clinical data to support the factors purported to increase susceptibil- date and time of overdose, quantity ingested, co-ingested drugs ity to liver injury, which are based solely upon animal experiments. and ethanol, risk factors for hepatotoxicity, serum paracetamol Moreover, the application of criteria to identify ‘high-risk’ patients concentration, acetylcysteine administration, and duration of is highly subjective in clinical practice [10,11] . hospital stay. Treatment had been delivered in accordance with From an international perspective, there are a number of different current TOXBASE® recommendations, the standard resource for approaches to identify patients with sufficiently high risk to merit poisoning management advice in the UK. In brief, intravenous acetylcysteine treatment. For example, the Rumack–Matthew nomo- acetylcysteine is indicated if serum paracetamol concentration is gram, or so-called ‘150-line’ is plotted 25% lower than the standard above the ‘200-line’ nomogram, or above the ‘100-line’ and the Prescott nomogram and has been used extensively in the USA for patient considered at high risk due to prior use of enzyme-inducing many years [12] . Australia and New Zealand have recently adopted drugs (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, this approach, having previously used the same model as the UK [13] . St John’s wort), chronic liver disease, malnutrition, nutritional Elsewhere, more inclusive indications for acetylcysteine administra- deficiency or chronic ethanol excess defined by regular consumption have been employed. For example, patients in Denmark receive tion of more than 21 units (168 g) per week in men or 14 units acetylcysteine irrespective of the extent of paracetamol exposure (112 g) in women [21] . Acetylcysteine is also indicated after a stagand regardless of whether any clinical risk factors exist [14] . The gered overdose involving more than 150 mg/kg in the previous latter approach has not been accepted widely due, at least in part, 24 h or 75 mg/kg in the presence of risk factors [22] . Acetylcysteine to the frequent occurrence of adverse effects of acetylcysteine in 300 mg/kg is infused intravenously over 20.25 h, based on the up to 40% of treated patients [15] . These include the occurrence of patient’s weight up to 110 kg. After treatment, if serum creatinine anaphylactoid reactions in approximately 15% of patients, char- and liver biochemistry are normal, and international normalized acterized by flushing, hypotension, tachycardia and wheeze [15,16] . ratio is ≤1.3, then the patient may be considered for discharge. Such reactions appear to be mediated by acetylcysteine concentra- If not, then an extended acetylcysteine infusion and further tion-dependent histamine release, and occur most commonly in monitoring of blood tests and clinical status are indicated [23–25] . patients with a prior history of asthma. Somewhat paradoxically, paracetamol protects against development of anaphylactoid reac- Data collection & analysis tions, and these adverse reactions occur more commonly in patients Primary outcome measures were acetylcysteine administration with comparatively low serum paracetamol concentrations [15,17] . and the occurrence of alanine transaminase ≥1000 U/l as a widely 20
312
High-risk treatment line (‘100-line’)
0.1
Expert Rev. Clin. Pharmacol. 5(3), (2012)
Review
Criteria for acetylcysteine treatment & clinical outcomes after paracetamol poisoning
• Those that did not require acetylcysteine;
250
228 Men Women
189
200
169 150 Patients (n)
accepted indicator of acute liver injury, albeit of limited prognostic value [26,27] . Knowledge of the paracetamol concentrations and interval after ingestion were used to define groups into those with below the ‘100-line’, between the ‘100-line’ and ‘150-line’, between the ‘150-line’ and ‘200line’, and above the ‘200-line’, as previously described [28] . Acute overdose was defined as one taken at a single time point (up to 1 h), whereas a staggered overdose was considered if ingestion was over a more prolonged period. It is not possible to determine paracetamol exposure or to back-extrapolate an equivalent 4 h concentration after a staggered overdose. Length of stay in hospital was considered as the number of episodes beyond midnight. Three categories were determined:
124 124 95
100
80 62
50
43
35
14 10 20–29
1.3
99
93 (93.9%)
5 (5.4%)
16 (17.2%)
High risk
64
64 (100.0%)
1 (1.6%)
9 (14.1%)
Total
163
157 (96.3%)
6 (3.8%)
25 (15.9%)
55
29 (52.7%)
0 (0.0%)
3 (10.3%)
High risk
44
44 (100.0%)**
0 (0.0%)
2 (4.5%)
Total
99
73 (73.7%)
0 (0.0%)
5 (6.8%)
Between ‘100-line’ and ‘150-line’ No risk factors
All
Patients, n (%)
No risk factors
Between ‘150-line’ and ‘200-line’ No risk factors
Below ‘100-line’
Patients (n)
96
21 (21.9%)
1 (4.8%)
2 (9.5%)
High risk
66
63 (95.5%)***
1 (1.6%)
3 (4.8%)
Total
162
84 (51.9%)
2 (2.4%)
5 (6.0%)
No risk factors
424
16 (3.8%)
1 (6.3%)
1 (6.3%)
High risk
197
23 (11.7%)
0 (0.0%)
1 (4.3%)
Total
621
39 (6.3%)
1 (2.6%)
2 (5.1%)
No risk factors
674
159 (23.6%)
7 (4.4%)
22 (13.8%)
High risk
371
194 (52.3%)***
2 (1.0%)*
15 (7.7%)
Total
1045
353 (33.8%)
9 (2.5%)
37 (10.5%)
*p
