Clinical Toxicology (2013), 51, 855–863 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2013.844824
CRITICAL CARE
Antidote removal during haemodialysis for massive acetaminophen overdose M. L. A. SIVILOTTI,1,2,4 D. N. JUURLINK,4,5,6 J. S. GARLAND,3 I. LENGA,5 R. POLEY,1 L. N. HANLY7 and M. THOMPSON4,5 1Department
of Emergency Medicine, Queen’s University, Kingston, ON, Canada of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada 3Department of Medicine, Queen’s University, Kingston, ON, Canada 4Ontario Poison Centre, Toronto, ON, Canada 5Department of Medicine, University of Toronto, Toronto, ON, Canada 6Department of Pediatrics, Health Policy, Management and Evaluation, University of Toronto, ON, Canada 7Department of Physiology and Pharmacology, University of Western Ontario, London, Canada
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Context. Haemodialysis is sometimes used for patients with massive acetaminophen overdose when signs of “mitochondrial paralysis” (lactic acidosis, altered mental status, hypothermia and hyperglycaemia) are present. The role of haemodialysis is debated, in part because the evidence base is weak and the endogenous clearance of acetaminophen is high. There is also concern because the antidote acetylcysteine is also dialyzable. We prospectively measured serum acetylcysteine concentrations during haemodialysis in three such cases. Case details. Three adults each presented comatose and acidemic 10 to ∼ 18 h after ingesting 1000mg/kg of acetaminophen. Two were hypothermic and hyperglycaemic. Serum lactate concentrations ranged from 7 mM to 12.5 mM. All three were intubated, and initial acetaminophen concentrations were as high as 5980 μM (900 μg/mL). An intravenous loading dose of 150 mg/kg acetylcysteine was initiated between 10.8 and ∼ 18 h post ingestion, and additional doses were empirically administered during haemodialysis to compensate for possible antidote removal. A single run of 3–4 h of haemodialysis removed 10–20 g of acetaminophen (48–80% of remaining body burden), reduced serum acetaminophen concentrations by 56–84% (total clearance 3.4–7.8 mL/kg/min), accelerated native acetaminophen clearance (mean elimination half-life 580 min pre-dialysis, 120 min during and 340 min post-dialysis) and corrected acidemia. Extraction ratios of acetylcysteine across the dialysis circuit ranged from 73% to 87% (dialysance 3.0 to 5.3 mL/kg/min). All three patients recovered fully, and none developed coagulopathy or other signs of liver failure. Discussion. When massive acetaminophen ingestion is accompanied by coma and lactic acidosis, emergency haemodialysis can result in rapid biochemical improvement. As expected, haemodialysis more than doubles the clearance of both acetaminophen and acetylcysteine. Because acetylcysteine dosing is largely empirical, we recommend doubling the dose during haemodialysis, with an additional half-load when dialysis exceeds 6 h. Keywords Acetaminophen; N-acetylcysteine; Haemodialysis; Mitochondria
Introduction
risk and may not be immediately available. More importantly, the endogenous clearance of acetaminophen is high ( 3 mL/kg/min when the elimination half-life is 4 h). Less well recognized is that the antidote acetylcysteine also has pharmacokinetic properties (molecular weight 163 daltons, volume of distribution 0.24–0.5L/kg, rapid intercompartment equilibration)12–17 favouring removal by haemodialysis. Moreover, because the antidote is safe, widely available and highly effective shortly after acetaminophen overdose (precisely when haemodialysis might be most helpful), haemodialysis is rarely necessary following acetaminophen overdose.7,10 Some believe that extracorporeal removal may be helpful in rare cases of massive acetaminophen overdose when features of so-called “mitochondrial paralysis” develop, including altered mental status, lactic acidosis and other metabolic derangements.11,9,18,19,6,20–24 Importantly, this
The role of haemodialysis in selected cases of acetaminophen poisoning remains controversial.1–11 Acetaminophen itself is efficiently cleared from the circulation by haemodialysis, as predicted by its pharmacokinetic properties (molecular weight 151 daltons, volume of distribution 1 L/kg, low protein binding and rapid intercompartment equilibration). However, haemodialysis is invasive, carries Received 26 July 2013; accepted 9 September 2013. Prior Presentations: Presented at the North American Congress of Clinical Toxicology, October 2012, Las Vegas NV (awarded Informa Research Abstract Award) Address correspondence to Dr. Marco Sivilotti, Department of Emergency Medicine, Queen’s University, 76 Stuart St., Kingston, ON K7L 2V7, Canada. Voice: (613) 548-2368. Fax: (613) 548-1374. E-mail marco. [email protected].
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process occurs much earlier and is mechanistically different from the coma and acidemia seen in fulminant hepatic failure, which develop several days after overdose and signal a poor prognosis.25,26,10 In contrast, mitochondrial paralysis develops within hours of massive acetaminophen overdose, appears to be reversible,27,20–24,11 and may be due to direct toxicity of the parent drug itself.28–31 Speculation exists that haemodialysis may mitigate this toxicity by rapidly removing the parent drug from the circulation. For these reasons, we have occasionally performed haemodialysis for massive acetaminophen overdose patients presenting early with altered mental status and lactic acidosis. Because the published literature regarding haemodialysis for acetaminophen overdose is sparse, we assembled a prospective case series of massive acetaminophen overdose treated with haemodialysis. We were particularly interested in measuring acetylcysteine concentrations during haemodialysis to better characterize its kinetics, and to inform more rational dosing recommendations for this antidote during haemodialysis.
venous haematocrits were similar (i.e. 0.45, and no net fluid removal) and blood flow was nearly constant at 400 mL/min.33 The approximate cumulative amount eliminated by dialysis was then estimated by incorporating this dialysance into the instantaneous central mass balance, integrating over the duration of haemodialysis and assuming an estimated endogenous clearance of 3.2 mL/kg/min.12 Acetaminophen kinetics were calculated using leastsquares regression based on first-order elimination during both the pre- and post-dialysis phases. The during-dialysis elimination rate was then calculated using either measured or extrapolated serum concentrations at the start and the end of dialysis. The corresponding total body clearance was estimated for each phase using a volume of distribution of 0.8 L/kg. To estimate the amount and fraction of acetaminophen removed by dialysis, we compared the serum acetaminophen concentration at the end of haemodialysis with an extrapolated estimate had dialysis not taken place based on pre-dialysis data. The university research ethics board approved this investigation.
Materials and methods Acetylcysteine assay Total acetylcysteine concentrations were measured in batches using high-performance liquid chromatography (HPLC) using a modification of the protocol by Jacobsen et al.32 Briefly, the surface tension of samples was minimized by the addition of n-amyl alcohol, and dithiol bonds were reduced with sodium borohydride. Hydrochloric acid was added to neutralize any remaining sodium borohydride. A fluorescing agent, monobromobimane, derivatized thiols within the samples. Any large proteins were precipitated from the sample solution with the addition of perchloric acid, followed by centrifugation at 9000g for 5 min. The supernatant was neutralized with the addition of 2 M citrate in 10 M NaOH and samples were centrifuged for an additional 5 min at 9000g. 100 μL of each sample supernatant was transferred to glass inserts and 5 μL was injected into the HPLC system for analysis. Samples were analyzed in duplicate by a Hewlett Packard 1090 LC system. Analytes were separated on a 15 cm 3.9 mm, 5 μm Novapak C18 column maintained at 40°C. The mobile phase (Pump A: 4% acetonitrile/25 mM ammonium formate buffer, pH 3.8 with formic acid; pump B: 70% acetonitrile/10 mM KH2PO4 buffer, pH 3.0 with phosphoric acid) was run at 0.5 mL/min. Analytes were detected on a Waters 474 scanning fluorescence detector set to an excitation of 390 nm and emission of 80 nm. The assay accuracy was 1.3%, and its precision was 2.0%. Pharmacokinetic calculations Acetylcysteine pharmacokinetics were calculated based on mass balance in the central compartment, with intermittent infusion and dialysis. The serum dialysance (i.e. extracorporeal clearance) was estimated using the mean arterio–venous extraction ratio, under the assumption that arterial and
Case series Case 1 A 65-year-old female with long-standing major depressive disorder and lupus was found by her husband unresponsive in a pool of vomitus nearly 11 h after an acute overdose of approximately 60 g of acetaminophen and an undisclosed number of prednisone tablets. A signed organ donation card and suicide note were found nearby. He reported that she began vomiting during the night, but seemed responsive as recently as 4 h before being found. Her other medications (etidronate/calcium carbonate, vitamin D 1000 IU and acetylsalicylic acid 81 mg daily) were all accounted for. On arrival she was unresponsive to pain, her pupils 3 mm and reactive, her gag reflex absent and her bladder distended. There was no response to naloxone 0.4 mg intravenously, so she was given succinylcholine, intubated and mechanically ventilated (Table 1). A non-contrast head CT was unremarkable. Her laboratory findings (Table 2) were notable for the following: pre-intubation venous pH 7.33, pCO2 34 mmHg, bicarbonate 17 mM (ABL800 Flex, Radiometer Medical, Table 1. Case summaries: features at initial presentation.
Age (year), sex Mass (kg) Dose APAP (mg/kg) Delay to discovery (h) Glasgow Coma Scale (/15) Heart rate (/min) Blood pressure (mmHg) Temperature (°C) Capillary glucose (mM) Given naloxone Endotracheally intubated
Case 1
Case 2
Case 3
65, female 51 1,140 11 3 70 101/56 34.6 oral 13.9 Yes Yes
59, male 98 1,000 19 5 96 110/70 31.5 rectal 10.5 Yes Yes
20, female 50 1,200 10 7 118 124/75 36.6 axilla 6.3 No Yes
Clinical Toxicology vol. 51 no. 9 2013
Haemodialysis for massive APAP overdose 857
Serum APAP (μM) Treatment line multiple* ψ (mM h) Initial blood gases: pH PvCO2 (mmHg) HCO3 (mM) Sodium (mM) Potassium (mM) Chloride (mM) Total CO2 (mM) Creatinine (μM) Lactate (mM) Osmolality (mmol/kg) INR AST (units/L) ALT (units/L) APAP AT (μM units/L)
Case 1
Case 2
Case 3
4030 15x 42.2 Venous 7.33 34 17 138 3.6 107 18 82 7.0 310 1.1 56 25 226,000
5980 14x 36.7 Arterial 7.32 22 12 143 5.5 96 5 26 12.5
2806 10.x 20.9 Venous 7.16 39 13 139 3.8 107 16 96 8.7 303 1.5 102 66 286,000
1.2 31 40 239,000
y represents the pre-treatment area under the serum acetaminophen vs. time curve, using a lag time of 6 h and threshold of 300 μM as per Sivilotti et al.39; for minimum estimates in Case 2, an 8-hour interval between ingestion and activation of EMS was assumed. APAP, acetaminophen; n/a, not applicable; n/d, not done. *“Treatment line multiple” represents the vertical distance of the timed serum acetaminophen concentration above the 1000 μM (150 μg/mL) at 4 h treatment line threshold from the Rumack-Matthew nomogram (i.e. 15x is 15-fold greater than the corresponding serum acetaminophen concentration at which treatment is recommended, based on time post ingestion).
Denmark); lactate 7.0 mM, acetaminophen 4030 μM (609μg/mL) and amylase 562 units/L (UniCel DxC 800 Synchron, Beckman Coulter). Her ethanol, salicylates and urine toxicology immunoassay (Triage™ TOX Drug Screen, Biosite International) were otherwise negative. She received a loading dose of 8.25 g (∼ 150 mg/kg) acetylcysteine intravenously over 1 h beginning at 13.5 h post ingestion.
The repeat acetaminophen concentration shortly thereafter was 2913 μM (440 μg/mL, apparent elimination half-life 9.4 h). Repeat venous blood gases showed a pH of 7.30, PvCO2 32 mmHg and bicarbonate 15 mM. Because of the profoundly depressed mental status, lactic acidosis and the persistently high serum acetaminophen concentration, haemodialysis was started approximately 17.5 h post-ingestion (filter Optiflux 200, Fresenius Medical Care, Waltham MA; bath: potassium 4 mM, dextrose 11.1 mM, calcium 1.25 mM, bicarbonate 35 mM; target blood flow 400 mL/min, dialysate 800 mL/min and no net fluid removal). Haemodialysis lasted just over 3 h and was well tolerated. Based on the expectation that haemodialysis would also remove acetylcysteine, the 2nd phase of the Edinburgh acetylcysteine protocol was empirically doubled (i.e. (∼ 100 mg/kg or 5.5 g over 4 h) during haemodialysis, an additional 4 g (∼ 80 mg/kg) was infused over 1 h at the end of haemodialysis and the 3rd phase of 8.25 g/day (∼ 100 mg/kg/16 h) was extended until 50 h post ingestion. At the end of dialysis, the pH was 7.46, the bicarbonate 23 mM and the lactate 0.3 mM. The clinical course and relevant test results are shown in Fig. 1, and pharmacokinetics are summarized in Table 3. The patient made a full recovery, with peak AST of 106 units/L and peak ALT of 70 units/L (local reference range 35 units/L) measured just prior to dialysis, peak INR of 1.6 the next morning, and otherwise normal laboratory values on subsequent testing. She was transferred to the psychiatric service on hospital Day 4, and was last known to be alive 4 years later. Case 2 A 59-year-old male with a history of depression was found unresponsive at 16:30 h, nearly 20 h after he was last seen
65-year-old woman with acute ingestion of ~58g APAP 10000
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12
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36
Acetylcysteine infusion (mg/kg/h)
Serum acetaminophen, acetylcysteine or lactate concentrations (μM)
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Table 2. Laboratory values at presentation.
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Time post ingestion (h)
Fig. 1. Case 1 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. haemodialysis interval is represented by the vertical grey bars. The Rumack-Matthew nomogram treatment threshold is shown as a solid diagonal line, and dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Copyright © Informa Healthcare USA, Inc. 2013
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acetylcysteine
kinetics
during
Case 1
Case 2
Case 3
9.4 1.2 6.0
13.6 2.7 6.0
6.1 1.9 4.8
0.99 7.8 1.5 80% 10.
0.7 3.4 1.6 48% 20.
1.5 5.0 1.9 67% 4.5
n/a n/a n/a
0.81 3.0 58
0.73 5.3 76
Acetaminophen Elimination Half-life (h) Pre-haemodialysis During haemodialysis Post-haemodialysis Total clearance (mL/kg/min) Pre-haemodialysis During haemodialysis Post-haemodialysis Body burden removed Dose removed by HD (g) Acetylcysteine Extraction ratio Dialysance (mL/kg/min) Dose removed by HD (mg/kg)
Total body clearance is shown for acetaminophen, whereas dialysance (clearance across the dialysis membrane alone) is shown for acetylcysteine. APAP, acetaminophen; HD, haemodialysis; n/a, insufficient data to estimate.
well. Paramedics noted an intact gag reflex, and naloxone was administered with minimal response. He was transported to a community hospital with assisted ventilations by bagvalve-mask. On hospital arrival, his rectal temperature was 31.5°C, and he was intubated for airway protection (Table 1). His prescribed medications were metformin, valsartan, rosuvastatin, ramipril and acetylsalicylic acid; other family members reportedly took zopiclone and lorazepam. The initial serum electrolytes were remarkable for a total carbon dioxide 5 mM, and after 100 meq NaHCO3 intravenously the arterial pH was 7.32, PaCO2 22 mmHg, and bicarbonate 12 mM. The venous lactate was 12.5 mM (Ortho Clinical Diagnostics, Rochester NY). The patient
was empirically treated with vancomycin and piperacillin/ tazobactam, and started on a continuous infusion of NaHCO3 at 200cc/h. Arrangements were made to transfer the patient to a tertiary care intensive care unit. A serum acetaminophen concentration of 5980 μM (903 μg/mL) was eventually reported by the local laboratory (Table 2). Salicylates, ethanol, methanol, ethylene glycol, isopropyl alcohol and acetone were undetectable in the serum. Urine toxicology by immunoassay was otherwise negative. The patient later denied co-ingestants other than acetaminophen. A loading infusion of 150 mg/kg acetylcysteine was given over 15 min at 2130 h prior to transfer, and the patient continued on the intermittent intravenous protocol (subsequent doses of 70 mg/kg intravenously every 4 h as per Smilkstein et al.34) shortly after arrival at the referral hospital. Vitamin K 10 mg and D10W 50cc/h were also administered intravenously. A CT scan of the head was unremarkable, and repeat bloodwork at the receiving hospital was notable for acetaminophen 4390 μM (663 μg/mL), ammonia 73 μM (normal 47–65μM) and methaemoglobin fraction 12%. Haemodialysis was started shortly thereafter (filter: RX18AX, Asahi Kasei Medical, New York NY; bath: sodium 140 mM, potassium 3 mM, calcium 1.25 mM, bicarbonate 42 mM; heparin 1000U bolus followed by 1000U/h; blood flow 350–400 mL/min, dialysate 800 mL/min, no net fluid removal). An additional acetylcysteine infusion of 12.5 mg/kg/h was empirically added during dialysis to compensate for its dialysance. Following 3 h and 20 min of haemodialysis, the serum acetaminophen had fallen to 1810 μM (273 μg/mL), the lactate was 0.8 mM, the arterial pH 7.41, bicarbonate 25 mM and methaemoglobin fraction 7.9% (Table 3; Fig. 2). The patient developed pneumococcal pneumonia and was briefly on vasopressors. The following laboratory abnormalities peaked around Day 4:
59-year-old male with acute ingestion of >100g APAP 300
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–6
6
18 Time post EMS activation (h)
30
Acetylcysteine infusion (mg/kg/h)
Serum acetaminophen, acetylcysteine or lactate concentrations (μM)
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Table 3. Acetaminophen haemodialysis.
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Fig. 2. Case 2 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. Acetylcysteine concentrations drawn from the inlet of the dialysis circuit are shown as filled; from the outlet as open. Haemodialysis interval is represented by the vertical grey bars. Dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations. Because the precise time of ingestion is unknown, the time intervals are from emergency medical services (EMS) activation, and the Rumack-Matthew line is not shown (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Clinical Toxicology vol. 51 no. 9 2013
Haemodialysis for massive APAP overdose 859 20-year-old woman with acute ingestion of ~60g APAP
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Acetylcysteine infusion (mg/kg/h)
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Fig. 3. Case 3 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. Acetylcysteine concentrations drawn from the inlet of the dialysis circuit are shown as filled; from the outlet as open. Haemodialysis interval is represented by the vertical grey bars. The Rumack-Matthew nomogram treatment threshold is shown as a solid diagonal line, and dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx).
AST 1868 units/L, ALT 1961 units/L, bilirubin 35 μmol/L, INR 1.5, troponin I 7.19μg/L, creatinine 103 μM, platelets nadir 54 109/L. Acetylcysteine was stopped on Day 4. He was extubated on Day 13, and was discharged home 1 week later with essentially normal laboratory values. Case 3 A 20-year-old female ingested 60 g acetaminophen, and up to 32 g ibuprofen, 2.2 g pseudoephedrine and 144 mg chlorpheniramine. She was found obtunded in a pool of vomitus and urine approximately 10 h later. Her regular medications were citalopram 20 mg BID and oral contraceptives. On arrival she was unresponsive to voice, and a loading infusion of 7.5 g acetylcysteine was begun within 30 min of arrival. She was immediately transferred to a nearby tertiary care hospital, and intubated on arrival for decreasing level of consciousness (Table 1). A second infusion of acetylcysteine at 12.5 mg/kg/h was begun shortly thereafter. The initial serum acetaminophen concentration was 2806 μM (424 μg/mL), lactate 8.7 mM (UniCel DxC 800 Synchron, Beckman Coulter), and anion gap 16 mM. Her ethanol, salicylates and urine toxicology immunoassay (Triage™ TOX Drug Screen, Biosite International) were otherwise negative. An arterial blood gas obtained just prior to dialysis was pH 7.39, PaCO2 19 mMHg and bicarbonate 11 mM (Table 2). A single, 4 h and 14 min session of haemodialysis (filter Optiflux 200, Fresenius Medical Care, Waltham MA; bath: potassium 4 mM, dextrose 11.1 mM, calcium 1.25 mM, bicarbonate 35 mM; blood flow 400–455 mL/min, dialysate 500 mL/min, no net fluid removal) was well tolerated. The acetylcysteine infusion was briefly doubled during the first 2 h of dialysis. Immediately post dialysis the pH was Copyright © Informa Healthcare USA, Inc. 2013
7.49 and bicarbonate 25 mM (Table 3; Fig. 3). The acetylcysteine infusion was reduced to 6.25 mg/kg/h after haemodialysis, and continued until hospital Day 5. She was extubated on Day 2, and her liver function tests subsequently normalized (peak INR 1.6 and AST 145 units/L on hospital Day 1, peak ALT 213 units/L Day 3). Acetylcysteine was discontinued 107 h post ingestion, and she was transferred to a psychiatric hospital on hospital Day 5 and discharged home 3 days later.
Discussion Consistent with prior case reports,10,22,21,27,35,36,11,24,23,6 these cases confirm that acetaminophen alone, at a sufficiently high dose, can cause coma and lactic acidosis within 10 h of ingestion. Each patient was intubated and mechanically ventilated. We observed that each of our cases exhibited rapid reversal of metabolic acidosis and the removal of substantial amounts of acetaminophen during a relatively short run of haemodialysis.1,37 While this case series cannot establish that haemodialysis improved clinical outcomes, none of the patients developed coagulopathy, despite elevated acetaminophen by aminotransferase multiplication products.38 Only one patient developed an AST or ALT over 1000 units/L, despite having ψ parameters39 which predicted at least a 45% probability of hepatotoxicity. We also estimate that substantial amounts of acetylcysteine were removed during relatively short runs of haemodialysis. There are few published data on the pharmacokinetics of intravenous acetylcysteine, and even fewer at doses used for acetaminophen overdose.15,40,13,33,12,14,41,17,42 In 17 overdose patients, Prescott et al. reported plasma total acetylcysteine concentrations averaged 600 μM at the end of the second infusion of 50 mg/kg/4h and 200 μM
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(range 68–550 μM) at the end of the third infusion, similar to concentrations we observed in our cases.12 Pakravan et al. reported somewhat lower mean total plasma acetylcysteine concentrations of 250 μM in 18 overdose patients near the end of the second infusion.42 For reference, serum concentrations of the amino acid cysteine are normally between 140 and 270 μM.32,16 Plasma acetylcysteine clearances of 3.2 mL/kg/min have been measured in overdose patients,12 1.1 mL/kg/min in patients with cirrhosis,14 0.32 mL/kg/ min in end-stage renal patients,33 0.5 mL/kg/min in preterm neonates,43 and between 1.5 and 3.5 mL/kg/min in healthy volunteers.40,15,13,14 The dialysance we observed is therefore similar to if not greater than native clearance. Soldini et al. calculated a dialysance of 5.5 1.0 L/h at much smaller doses, and estimated that about half the administered dose would be removed during 4 h of dialysis. Therefore, if haemodialysis is being contemplated for any reason in a patient receiving acetylcysteine, it is imperative to recognize that dialysis will remove the antidote. Recognizing the empirical basis for acetylcysteine dosing,44,45,12 its wide safety margin,46,47 and the potential for confusion and errors when individualizing dosing,48–50 one straightforward recommendation would be to double the dosing intensity of whichever protocol was being followed during haemodialysis. Thus, the so-called “2nd bag” of the Edinburgh protocol would be increased from 12.5 mg/kg/h to 25 mg/kg/h, while the intermittent intravenous protocol could be ordered as 70 mg/kg q2h rather than q4h. If haemodialysis lasts more than 6 h for a patient receiving the Edinburgh protocol, an additional half-load of 75 mg/kg could be infused at the end of dialysis in the rare eventuality that acetaminophen concentrations remain high. This practice is consistent with the shift to matching acetylcysteine dosing based on serial acetaminophen concentrations, and is easily adapted to other dosing strategies that have recently been proposed.44,50–52 It must be emphasized that haemodialysis is generally not necessary for acetaminophen overdose.7 First, the vast majority of patients are not candidates for haemodialysis, either because they present early (in which case acetylcysteine will be effective) or because they present late and the remaining body burden of acetaminophen is too small to warrant extracorporeal removal. Second, for patients with established hepatic failure, the benefits of haemodialysis are uncertain.9,53,54 Third, it is rare to encounter the massive serum acetaminophen concentrations seen in the patients reported in our case series, which are an order of magnitude higher than the treatment threshold of the Rumack-Matthew nomogram based on the time of ingestion, and typically signify ingestions of more than 1000 mg/kg. Haemodialysis entails some morbidity, delay and cost, which need to be balanced against an uncertain benefit. Finally, the capacity for haemodialysis to remove the antidote, acetylcysteine, and thereby reduce its efficacy must also be considered. The international collaborative Extracorporeal Treatments in Poisoning workgroup55 is soon to issue their consensus recommendation regarding haemodialysis for acetaminophen overdose. (Dr. M. Ghannoum, personal communication, July 2013).
The deep coma and early lactic acidosis seen in our patients may be due to direct toxicity of acetaminophen itself, and is distinct from the well-accepted mechanism of hepatocellular toxicity from the electrophilic NAPQI metabolite following glutathione depletion.28,29,30,10,31,56 Coma and hypothermia are common features of prior human case reports,27,35,57,11,20,6 as well as in mice,30 and may reflect mitochondrial toxicity of the parent drug in the brain, where bioactivation to NAPQI is minimal. If the parent drug is responsible, acetylcysteine per se is unlikely to help, and rapid extracorporeal removal may represent a better treatment strategy. While the precise target of mitochondrial toxicity remains speculative, a 4 g dose of acetaminophen in healthy volunteers causes rapid and profound down-regulation of both nuclear and mitochondrial genes involved in oxidative phosphorylation, especially Complex I, accompanied by a persistent submolar rise in serum lactate.58 High concentrations of acetaminophen impair the first step of the electron transport chain in mammalian cells.56,28,29,10 One group has suggested that inhibition of the pyruvate dehydrogenase complex may also be involved.57 Acetaminophen overdose is increasingly recognized as a relatively common cause of lesser degrees of lactic acidosis, confusion and lethargy.59,31 It is important to appreciate that these phenomena are distinct from the lactic acidosis and hepatic encephalopathy that develop days after acetaminophen overdose, and which often signify irreversible hepatic failure.26 Furthermore, this condition should not be confused with pyroglutamic acidemia (5-oxoprolinuria) which is due to inhibition of the γ-glutamyl cycle and can happen rarely following therapeutic doses of acetaminophen.60–62 While some previous cases were also treated with extracorporeal removal techniques such as continuous renal replacement therapy23,11 or charcoal hemoperfusion,18,19 we identified only one prior report of haemodialysis within 12 h of presentation.6,36,21 Thus, this case series supplements the prior literature by reporting our experience with immediate haemodialysis for such patients. Interestingly, our data suggest that haemodialysis accelerated acetaminophen removal both during and after haemodialysis. In only one prior report involving a young child does the reported data suggest an improvement in native acetaminophen clearance after dialysis.6 The remaining available literature on human acetaminophen elimination kinetics suggests instead relatively constant post-peak acetaminophen elimination in a given individual with or without extracorporeal removal63,38,64,65 even at very high serum concentrations.37,11 We speculate that the characteristically long post-peak elimination half-lives observed within 24 h of massive ingestions may be a consequence of direct mitochondrial toxicity rather than merely delayed absorption, while delayed elimination beyond 24 h reflects established, irreversible hepatic failure.63,38,64,66 While ongoing absorption is possible, each of our cases ingested an immediate-release formulation of acetaminophen.67 Elimination half-lives of eight or more hours (endogenous clearance below 1.4 mL/kg/min) have been observed Clinical Toxicology vol. 51 no. 9 2013
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Haemodialysis for massive APAP overdose 861 at the highest serum acetaminophen concentrations19,36, 37,6,21,11,57,27,37 When circulating parent-drug concentrations remain very elevated in such cases, one can envision an increased cumulative body burden of NAPQI that may overwhelm the usual 300 mg/kg dose of intravenous acetylcysteine.68–71 By extension, haemodialysis would reduce this mismatch between toxic metabolite production and thiol donor regeneration provided it removed parent drug faster than the antidote. Of note, in such cases with delayed elimination, endogenous acetaminophen clearance has slowed to the point that haemodialysis will contribute substantially to parent drug removal, unlike smaller overdoses in which acetaminophen clearance exceeds 3 mL/kg/ min. However, the cause and significance of delayed acetaminophen elimination shortly after overdose are not well established at present.72,64 Some limitations of our observations merit emphasis. We assayed total acetylcysteine (i.e. after dithiol bonds reduced), including the fraction bound to circulating proteins.40,13 It remains uncertain to what degree the bound fraction is available for thiol donation and glutathione regeneration in the liver. Other authors have used methods that remove plasma protein-bound acetylcysteine, as well as using much smaller doses (e.g. 400 or 600 mg), so the kinetic estimates may not be directly comparable.15,40,17 Neither total nor reduced circulating drug concentration necessarily reflects hepatocellular levels or antidotal efficacy. The precision of our kinetic estimates are limited by the small number of samples collected and the assumptions inherent to kinetic modelling. We did not quantify acetylcysteine nor acetaminophen recovered in dialysate. Nevertheless, our estimate of dialysance is unlikely to be inflated given the high extraction ratios and the absence of net fluid removal during the entire dialysis session. Finally, the manufacturers of the lactate assay were unable to provide information on the possibility of interference by pyroglutamic acid, but we believe that lactate was the predominant organic acid present.
Conclusions In summary, we report that when massive acetaminophen ingestion is accompanied by coma, lactic acidosis and prolonged elimination half-life of the parent drug, immediate haemodialysis may result in rapid biochemical improvement. Interestingly, a short haemodialysis session can accelerate endogenous parent drug elimination post-dialysis. As expected, haemodialysis more than doubles the overall clearance of both the drug and its antidote, acetylcysteine, during dialysis. Recognizing that acetylcysteine dosing is largely empirical, we recommend that the dosing of acetylcysteine be at least doubled whenever patients being treated with acetylcysteine undergo haemodialysis, and that a half-load be re-administered when a dialysis session exceeds 6 h.
Acknowledgments We are indebted to Dr. Murray Cutler for use of laboratory space and for preparing the solutions used in the Copyright © Informa Healthcare USA, Inc. 2013
acetylcysteine assay. We are also indebted to the other physicians and healthcare providers that cared for these patients at the Kingston General and Oshawa General Hospitals.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. Supported by a Doctoral Research Award from the Pediatric Oncology Group of Ontario and the Canadian Institutes of Health Research (LNH).
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42. Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol 2008; 46:697–702. 43. Ahola T, Fellman V, Laaksonen R, Laitila J, Lapatto R, Neuvonen PJ, Raivio KO. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol 1999; 55: 645–650. 44. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol 2012; 50: 91–98. 45. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Clin Toxicol 2002; 40:3–20. 46. Heard K, Schaeffer TH. Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol 2011; 49:423–425. 47. Bailey B, Blais R, Letarte A. Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med 2004; 44:401–406. 48. Ferner RE, Langford NJ, Anton C, Hutchings A, Bateman DN, Routledge PA. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol 2001; 52:573–577. 49. Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother 2008; 42:766–770. 50. Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity (June). Ann Pharmacother 2011; 45: 713–720. 51. Shen F, Coulter CV, Isbister GK, Duffull SB. A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose. Clin Toxicol 2011; 49:643–647. 52. Klein-Schwartz W, Doyon S. Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin Pharmacother 2011; 12:119–130. 53. Schiodt FV, Clemmesen JO, Hansen BA, Larsen FS. Cerebral edema due to hemodialysis in paracetamol-induced fulminant hepatic failure. Scand J Gastroenterol 1995; 30:927–928. 54. Steadman RH, Van Rensburg A, Kramer DJ. Transplantation for acute liver failure: perioperative management. Curr Opin Organ Transplant 2010; 15:368–373. 55. Lavergne V, Nolin TD, Hoffman RS, Roberts D, Gosselin S, Goldfarb DS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology. Clin Toxicol 2012; 50:403–413. 56. Porter KE, Dawson AG. Inhibition of respiration and gluconeogenesis by paracetamol in rat kidney preparations. Biochem Pharmacol 1979; 28:3057–3062. 57. Truitt CA, Curry SC, Canning JE, French R. Large APAP OD with fixed pupils, optic pallor, massive lactic acidosis, elevated lactate/ pyruvate ratio, and hyperalaninemia with full recovery and minimal hypertransaminasemia (abstract). Clin Toxicol 2010; 48:610. 58. Fannin RD, Russo M, O’Connell TM, Gerrish K, Winnike JH, Macdonald J, et al. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 2010; 51:227–236. 59. Zein JG, Wallace DJ, Kinasewitz G, Toubia N, Kakoulas C. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med 2010; 28:798–802. 60. Green TJ, Bijlsma JJ, Sweet DD. Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis. Can J Emerg Med 2010; 12:449–452. 61. Zand L, Muriithi A, Nelsen E, Franco PM, Greene EL, Qian Q, El-Zoghby ZM. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation. Am J Med Sci 2012; 344:501–504. 62. Reddi AS, Kunadi AR. Recurrent anion gap metabolic acidosis in a woman with vertebral disc disease. Am J Emerg Med 2011; 29:962.e3–e8. Clinical Toxicology vol. 51 no. 9 2013
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63. Prescott LF, Roscoe P, Wright N, Brown SS. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971; 1:519–522. 64. Schiodt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 2002; 71:221–225. 65. Saiao A, Chan B, Isbister GK. Pharmacokinetics and outcomes in massive paracetamol overdose (abstract). Clin Toxicol 2012; 50:276. 66. Forrest JA, Roscoe P, Prescott LF, Stevenson IH. Abnormal drug metabolism after barbiturate and paracetamol overdose. Br Med J 1974; 4:499–502. 67. Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J 2010; 40:72–76. 68. Smith SW, Howland MA, Hoffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and
Supplementary material available online Supplementary Table 1 to be found online at http://informa healthcare.com/doi/abs/10.3109/15563650.2013.844824
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69.
70.
71.
72.
hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother 2008; 42: 1333–1339. Doyon S, Klein-SchwartzW. Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad Emerg Med 2009; 16:34–39. Schwartz EA, Hayes BD, Sarmiento KF. Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine. Ann Emerg Med 2009; 54:421–423. Bihari S, Verghese S, Bersten AD. Delayed and prolonged elevated serum paracetamol level after an overdose – possible causes and implications. Crit Care Resusc 2011; 13:275–277. Rumack BH, Meredith TJ, Peterson RG, Prescott LF, Vale JA. Panel discussion. Management of acetaminophen overdose. Arch Intern Med 1981; 141:3.
CRITICAL CARE
Antidote removal during haemodialysis for massive acetaminophen overdose M. L. A. SIVILOTTI,1,2,4 D. N. JUURLINK,4,5,6 J. S. GARLAND,3 I. LENGA,5 R. POLEY,1 L. N. HANLY7 and M. THOMPSON4,5 1Department
of Emergency Medicine, Queen’s University, Kingston, ON, Canada of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada 3Department of Medicine, Queen’s University, Kingston, ON, Canada 4Ontario Poison Centre, Toronto, ON, Canada 5Department of Medicine, University of Toronto, Toronto, ON, Canada 6Department of Pediatrics, Health Policy, Management and Evaluation, University of Toronto, ON, Canada 7Department of Physiology and Pharmacology, University of Western Ontario, London, Canada
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2Department
Context. Haemodialysis is sometimes used for patients with massive acetaminophen overdose when signs of “mitochondrial paralysis” (lactic acidosis, altered mental status, hypothermia and hyperglycaemia) are present. The role of haemodialysis is debated, in part because the evidence base is weak and the endogenous clearance of acetaminophen is high. There is also concern because the antidote acetylcysteine is also dialyzable. We prospectively measured serum acetylcysteine concentrations during haemodialysis in three such cases. Case details. Three adults each presented comatose and acidemic 10 to ∼ 18 h after ingesting 1000mg/kg of acetaminophen. Two were hypothermic and hyperglycaemic. Serum lactate concentrations ranged from 7 mM to 12.5 mM. All three were intubated, and initial acetaminophen concentrations were as high as 5980 μM (900 μg/mL). An intravenous loading dose of 150 mg/kg acetylcysteine was initiated between 10.8 and ∼ 18 h post ingestion, and additional doses were empirically administered during haemodialysis to compensate for possible antidote removal. A single run of 3–4 h of haemodialysis removed 10–20 g of acetaminophen (48–80% of remaining body burden), reduced serum acetaminophen concentrations by 56–84% (total clearance 3.4–7.8 mL/kg/min), accelerated native acetaminophen clearance (mean elimination half-life 580 min pre-dialysis, 120 min during and 340 min post-dialysis) and corrected acidemia. Extraction ratios of acetylcysteine across the dialysis circuit ranged from 73% to 87% (dialysance 3.0 to 5.3 mL/kg/min). All three patients recovered fully, and none developed coagulopathy or other signs of liver failure. Discussion. When massive acetaminophen ingestion is accompanied by coma and lactic acidosis, emergency haemodialysis can result in rapid biochemical improvement. As expected, haemodialysis more than doubles the clearance of both acetaminophen and acetylcysteine. Because acetylcysteine dosing is largely empirical, we recommend doubling the dose during haemodialysis, with an additional half-load when dialysis exceeds 6 h. Keywords Acetaminophen; N-acetylcysteine; Haemodialysis; Mitochondria
Introduction
risk and may not be immediately available. More importantly, the endogenous clearance of acetaminophen is high ( 3 mL/kg/min when the elimination half-life is 4 h). Less well recognized is that the antidote acetylcysteine also has pharmacokinetic properties (molecular weight 163 daltons, volume of distribution 0.24–0.5L/kg, rapid intercompartment equilibration)12–17 favouring removal by haemodialysis. Moreover, because the antidote is safe, widely available and highly effective shortly after acetaminophen overdose (precisely when haemodialysis might be most helpful), haemodialysis is rarely necessary following acetaminophen overdose.7,10 Some believe that extracorporeal removal may be helpful in rare cases of massive acetaminophen overdose when features of so-called “mitochondrial paralysis” develop, including altered mental status, lactic acidosis and other metabolic derangements.11,9,18,19,6,20–24 Importantly, this
The role of haemodialysis in selected cases of acetaminophen poisoning remains controversial.1–11 Acetaminophen itself is efficiently cleared from the circulation by haemodialysis, as predicted by its pharmacokinetic properties (molecular weight 151 daltons, volume of distribution 1 L/kg, low protein binding and rapid intercompartment equilibration). However, haemodialysis is invasive, carries Received 26 July 2013; accepted 9 September 2013. Prior Presentations: Presented at the North American Congress of Clinical Toxicology, October 2012, Las Vegas NV (awarded Informa Research Abstract Award) Address correspondence to Dr. Marco Sivilotti, Department of Emergency Medicine, Queen’s University, 76 Stuart St., Kingston, ON K7L 2V7, Canada. Voice: (613) 548-2368. Fax: (613) 548-1374. E-mail marco. [email protected].
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process occurs much earlier and is mechanistically different from the coma and acidemia seen in fulminant hepatic failure, which develop several days after overdose and signal a poor prognosis.25,26,10 In contrast, mitochondrial paralysis develops within hours of massive acetaminophen overdose, appears to be reversible,27,20–24,11 and may be due to direct toxicity of the parent drug itself.28–31 Speculation exists that haemodialysis may mitigate this toxicity by rapidly removing the parent drug from the circulation. For these reasons, we have occasionally performed haemodialysis for massive acetaminophen overdose patients presenting early with altered mental status and lactic acidosis. Because the published literature regarding haemodialysis for acetaminophen overdose is sparse, we assembled a prospective case series of massive acetaminophen overdose treated with haemodialysis. We were particularly interested in measuring acetylcysteine concentrations during haemodialysis to better characterize its kinetics, and to inform more rational dosing recommendations for this antidote during haemodialysis.
venous haematocrits were similar (i.e. 0.45, and no net fluid removal) and blood flow was nearly constant at 400 mL/min.33 The approximate cumulative amount eliminated by dialysis was then estimated by incorporating this dialysance into the instantaneous central mass balance, integrating over the duration of haemodialysis and assuming an estimated endogenous clearance of 3.2 mL/kg/min.12 Acetaminophen kinetics were calculated using leastsquares regression based on first-order elimination during both the pre- and post-dialysis phases. The during-dialysis elimination rate was then calculated using either measured or extrapolated serum concentrations at the start and the end of dialysis. The corresponding total body clearance was estimated for each phase using a volume of distribution of 0.8 L/kg. To estimate the amount and fraction of acetaminophen removed by dialysis, we compared the serum acetaminophen concentration at the end of haemodialysis with an extrapolated estimate had dialysis not taken place based on pre-dialysis data. The university research ethics board approved this investigation.
Materials and methods Acetylcysteine assay Total acetylcysteine concentrations were measured in batches using high-performance liquid chromatography (HPLC) using a modification of the protocol by Jacobsen et al.32 Briefly, the surface tension of samples was minimized by the addition of n-amyl alcohol, and dithiol bonds were reduced with sodium borohydride. Hydrochloric acid was added to neutralize any remaining sodium borohydride. A fluorescing agent, monobromobimane, derivatized thiols within the samples. Any large proteins were precipitated from the sample solution with the addition of perchloric acid, followed by centrifugation at 9000g for 5 min. The supernatant was neutralized with the addition of 2 M citrate in 10 M NaOH and samples were centrifuged for an additional 5 min at 9000g. 100 μL of each sample supernatant was transferred to glass inserts and 5 μL was injected into the HPLC system for analysis. Samples were analyzed in duplicate by a Hewlett Packard 1090 LC system. Analytes were separated on a 15 cm 3.9 mm, 5 μm Novapak C18 column maintained at 40°C. The mobile phase (Pump A: 4% acetonitrile/25 mM ammonium formate buffer, pH 3.8 with formic acid; pump B: 70% acetonitrile/10 mM KH2PO4 buffer, pH 3.0 with phosphoric acid) was run at 0.5 mL/min. Analytes were detected on a Waters 474 scanning fluorescence detector set to an excitation of 390 nm and emission of 80 nm. The assay accuracy was 1.3%, and its precision was 2.0%. Pharmacokinetic calculations Acetylcysteine pharmacokinetics were calculated based on mass balance in the central compartment, with intermittent infusion and dialysis. The serum dialysance (i.e. extracorporeal clearance) was estimated using the mean arterio–venous extraction ratio, under the assumption that arterial and
Case series Case 1 A 65-year-old female with long-standing major depressive disorder and lupus was found by her husband unresponsive in a pool of vomitus nearly 11 h after an acute overdose of approximately 60 g of acetaminophen and an undisclosed number of prednisone tablets. A signed organ donation card and suicide note were found nearby. He reported that she began vomiting during the night, but seemed responsive as recently as 4 h before being found. Her other medications (etidronate/calcium carbonate, vitamin D 1000 IU and acetylsalicylic acid 81 mg daily) were all accounted for. On arrival she was unresponsive to pain, her pupils 3 mm and reactive, her gag reflex absent and her bladder distended. There was no response to naloxone 0.4 mg intravenously, so she was given succinylcholine, intubated and mechanically ventilated (Table 1). A non-contrast head CT was unremarkable. Her laboratory findings (Table 2) were notable for the following: pre-intubation venous pH 7.33, pCO2 34 mmHg, bicarbonate 17 mM (ABL800 Flex, Radiometer Medical, Table 1. Case summaries: features at initial presentation.
Age (year), sex Mass (kg) Dose APAP (mg/kg) Delay to discovery (h) Glasgow Coma Scale (/15) Heart rate (/min) Blood pressure (mmHg) Temperature (°C) Capillary glucose (mM) Given naloxone Endotracheally intubated
Case 1
Case 2
Case 3
65, female 51 1,140 11 3 70 101/56 34.6 oral 13.9 Yes Yes
59, male 98 1,000 19 5 96 110/70 31.5 rectal 10.5 Yes Yes
20, female 50 1,200 10 7 118 124/75 36.6 axilla 6.3 No Yes
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Serum APAP (μM) Treatment line multiple* ψ (mM h) Initial blood gases: pH PvCO2 (mmHg) HCO3 (mM) Sodium (mM) Potassium (mM) Chloride (mM) Total CO2 (mM) Creatinine (μM) Lactate (mM) Osmolality (mmol/kg) INR AST (units/L) ALT (units/L) APAP AT (μM units/L)
Case 1
Case 2
Case 3
4030 15x 42.2 Venous 7.33 34 17 138 3.6 107 18 82 7.0 310 1.1 56 25 226,000
5980 14x 36.7 Arterial 7.32 22 12 143 5.5 96 5 26 12.5
2806 10.x 20.9 Venous 7.16 39 13 139 3.8 107 16 96 8.7 303 1.5 102 66 286,000
1.2 31 40 239,000
y represents the pre-treatment area under the serum acetaminophen vs. time curve, using a lag time of 6 h and threshold of 300 μM as per Sivilotti et al.39; for minimum estimates in Case 2, an 8-hour interval between ingestion and activation of EMS was assumed. APAP, acetaminophen; n/a, not applicable; n/d, not done. *“Treatment line multiple” represents the vertical distance of the timed serum acetaminophen concentration above the 1000 μM (150 μg/mL) at 4 h treatment line threshold from the Rumack-Matthew nomogram (i.e. 15x is 15-fold greater than the corresponding serum acetaminophen concentration at which treatment is recommended, based on time post ingestion).
Denmark); lactate 7.0 mM, acetaminophen 4030 μM (609μg/mL) and amylase 562 units/L (UniCel DxC 800 Synchron, Beckman Coulter). Her ethanol, salicylates and urine toxicology immunoassay (Triage™ TOX Drug Screen, Biosite International) were otherwise negative. She received a loading dose of 8.25 g (∼ 150 mg/kg) acetylcysteine intravenously over 1 h beginning at 13.5 h post ingestion.
The repeat acetaminophen concentration shortly thereafter was 2913 μM (440 μg/mL, apparent elimination half-life 9.4 h). Repeat venous blood gases showed a pH of 7.30, PvCO2 32 mmHg and bicarbonate 15 mM. Because of the profoundly depressed mental status, lactic acidosis and the persistently high serum acetaminophen concentration, haemodialysis was started approximately 17.5 h post-ingestion (filter Optiflux 200, Fresenius Medical Care, Waltham MA; bath: potassium 4 mM, dextrose 11.1 mM, calcium 1.25 mM, bicarbonate 35 mM; target blood flow 400 mL/min, dialysate 800 mL/min and no net fluid removal). Haemodialysis lasted just over 3 h and was well tolerated. Based on the expectation that haemodialysis would also remove acetylcysteine, the 2nd phase of the Edinburgh acetylcysteine protocol was empirically doubled (i.e. (∼ 100 mg/kg or 5.5 g over 4 h) during haemodialysis, an additional 4 g (∼ 80 mg/kg) was infused over 1 h at the end of haemodialysis and the 3rd phase of 8.25 g/day (∼ 100 mg/kg/16 h) was extended until 50 h post ingestion. At the end of dialysis, the pH was 7.46, the bicarbonate 23 mM and the lactate 0.3 mM. The clinical course and relevant test results are shown in Fig. 1, and pharmacokinetics are summarized in Table 3. The patient made a full recovery, with peak AST of 106 units/L and peak ALT of 70 units/L (local reference range 35 units/L) measured just prior to dialysis, peak INR of 1.6 the next morning, and otherwise normal laboratory values on subsequent testing. She was transferred to the psychiatric service on hospital Day 4, and was last known to be alive 4 years later. Case 2 A 59-year-old male with a history of depression was found unresponsive at 16:30 h, nearly 20 h after he was last seen
65-year-old woman with acute ingestion of ~58g APAP 10000
300
250
1000
200
150
100
100
50
10
0
12
24
36
Acetylcysteine infusion (mg/kg/h)
Serum acetaminophen, acetylcysteine or lactate concentrations (μM)
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Table 2. Laboratory values at presentation.
0 48
Time post ingestion (h)
Fig. 1. Case 1 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. haemodialysis interval is represented by the vertical grey bars. The Rumack-Matthew nomogram treatment threshold is shown as a solid diagonal line, and dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Copyright © Informa Healthcare USA, Inc. 2013
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acetylcysteine
kinetics
during
Case 1
Case 2
Case 3
9.4 1.2 6.0
13.6 2.7 6.0
6.1 1.9 4.8
0.99 7.8 1.5 80% 10.
0.7 3.4 1.6 48% 20.
1.5 5.0 1.9 67% 4.5
n/a n/a n/a
0.81 3.0 58
0.73 5.3 76
Acetaminophen Elimination Half-life (h) Pre-haemodialysis During haemodialysis Post-haemodialysis Total clearance (mL/kg/min) Pre-haemodialysis During haemodialysis Post-haemodialysis Body burden removed Dose removed by HD (g) Acetylcysteine Extraction ratio Dialysance (mL/kg/min) Dose removed by HD (mg/kg)
Total body clearance is shown for acetaminophen, whereas dialysance (clearance across the dialysis membrane alone) is shown for acetylcysteine. APAP, acetaminophen; HD, haemodialysis; n/a, insufficient data to estimate.
well. Paramedics noted an intact gag reflex, and naloxone was administered with minimal response. He was transported to a community hospital with assisted ventilations by bagvalve-mask. On hospital arrival, his rectal temperature was 31.5°C, and he was intubated for airway protection (Table 1). His prescribed medications were metformin, valsartan, rosuvastatin, ramipril and acetylsalicylic acid; other family members reportedly took zopiclone and lorazepam. The initial serum electrolytes were remarkable for a total carbon dioxide 5 mM, and after 100 meq NaHCO3 intravenously the arterial pH was 7.32, PaCO2 22 mmHg, and bicarbonate 12 mM. The venous lactate was 12.5 mM (Ortho Clinical Diagnostics, Rochester NY). The patient
was empirically treated with vancomycin and piperacillin/ tazobactam, and started on a continuous infusion of NaHCO3 at 200cc/h. Arrangements were made to transfer the patient to a tertiary care intensive care unit. A serum acetaminophen concentration of 5980 μM (903 μg/mL) was eventually reported by the local laboratory (Table 2). Salicylates, ethanol, methanol, ethylene glycol, isopropyl alcohol and acetone were undetectable in the serum. Urine toxicology by immunoassay was otherwise negative. The patient later denied co-ingestants other than acetaminophen. A loading infusion of 150 mg/kg acetylcysteine was given over 15 min at 2130 h prior to transfer, and the patient continued on the intermittent intravenous protocol (subsequent doses of 70 mg/kg intravenously every 4 h as per Smilkstein et al.34) shortly after arrival at the referral hospital. Vitamin K 10 mg and D10W 50cc/h were also administered intravenously. A CT scan of the head was unremarkable, and repeat bloodwork at the receiving hospital was notable for acetaminophen 4390 μM (663 μg/mL), ammonia 73 μM (normal 47–65μM) and methaemoglobin fraction 12%. Haemodialysis was started shortly thereafter (filter: RX18AX, Asahi Kasei Medical, New York NY; bath: sodium 140 mM, potassium 3 mM, calcium 1.25 mM, bicarbonate 42 mM; heparin 1000U bolus followed by 1000U/h; blood flow 350–400 mL/min, dialysate 800 mL/min, no net fluid removal). An additional acetylcysteine infusion of 12.5 mg/kg/h was empirically added during dialysis to compensate for its dialysance. Following 3 h and 20 min of haemodialysis, the serum acetaminophen had fallen to 1810 μM (273 μg/mL), the lactate was 0.8 mM, the arterial pH 7.41, bicarbonate 25 mM and methaemoglobin fraction 7.9% (Table 3; Fig. 2). The patient developed pneumococcal pneumonia and was briefly on vasopressors. The following laboratory abnormalities peaked around Day 4:
59-year-old male with acute ingestion of >100g APAP 300
10000
250
200
1000
150
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100
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10
–6
6
18 Time post EMS activation (h)
30
Acetylcysteine infusion (mg/kg/h)
Serum acetaminophen, acetylcysteine or lactate concentrations (μM)
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Table 3. Acetaminophen haemodialysis.
0 42
Fig. 2. Case 2 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. Acetylcysteine concentrations drawn from the inlet of the dialysis circuit are shown as filled; from the outlet as open. Haemodialysis interval is represented by the vertical grey bars. Dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations. Because the precise time of ingestion is unknown, the time intervals are from emergency medical services (EMS) activation, and the Rumack-Matthew line is not shown (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Clinical Toxicology vol. 51 no. 9 2013
Haemodialysis for massive APAP overdose 859 20-year-old woman with acute ingestion of ~60g APAP
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100
50
10
0
12
24 Time post ingestion (h)
36
Acetylcysteine infusion (mg/kg/h)
Serum acetaminophen, acetylcysteine or lactate concentrations (μM)
10000
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Fig. 3. Case 3 laboratory values and acetylcysteine dosing. Serum acetaminophen (solid squares), acetylcysteine (triangles) and lactate (diamonds) concentrations are shown on the left y-axis; acetylcysteine dosing rate (dark lines) on the right y-axis. Acetylcysteine concentrations drawn from the inlet of the dialysis circuit are shown as filled; from the outlet as open. Haemodialysis interval is represented by the vertical grey bars. The Rumack-Matthew nomogram treatment threshold is shown as a solid diagonal line, and dashed lines show the first-order linear regression line fitted to the pre- and post-dialysis acetaminophen concentrations (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx).
AST 1868 units/L, ALT 1961 units/L, bilirubin 35 μmol/L, INR 1.5, troponin I 7.19μg/L, creatinine 103 μM, platelets nadir 54 109/L. Acetylcysteine was stopped on Day 4. He was extubated on Day 13, and was discharged home 1 week later with essentially normal laboratory values. Case 3 A 20-year-old female ingested 60 g acetaminophen, and up to 32 g ibuprofen, 2.2 g pseudoephedrine and 144 mg chlorpheniramine. She was found obtunded in a pool of vomitus and urine approximately 10 h later. Her regular medications were citalopram 20 mg BID and oral contraceptives. On arrival she was unresponsive to voice, and a loading infusion of 7.5 g acetylcysteine was begun within 30 min of arrival. She was immediately transferred to a nearby tertiary care hospital, and intubated on arrival for decreasing level of consciousness (Table 1). A second infusion of acetylcysteine at 12.5 mg/kg/h was begun shortly thereafter. The initial serum acetaminophen concentration was 2806 μM (424 μg/mL), lactate 8.7 mM (UniCel DxC 800 Synchron, Beckman Coulter), and anion gap 16 mM. Her ethanol, salicylates and urine toxicology immunoassay (Triage™ TOX Drug Screen, Biosite International) were otherwise negative. An arterial blood gas obtained just prior to dialysis was pH 7.39, PaCO2 19 mMHg and bicarbonate 11 mM (Table 2). A single, 4 h and 14 min session of haemodialysis (filter Optiflux 200, Fresenius Medical Care, Waltham MA; bath: potassium 4 mM, dextrose 11.1 mM, calcium 1.25 mM, bicarbonate 35 mM; blood flow 400–455 mL/min, dialysate 500 mL/min, no net fluid removal) was well tolerated. The acetylcysteine infusion was briefly doubled during the first 2 h of dialysis. Immediately post dialysis the pH was Copyright © Informa Healthcare USA, Inc. 2013
7.49 and bicarbonate 25 mM (Table 3; Fig. 3). The acetylcysteine infusion was reduced to 6.25 mg/kg/h after haemodialysis, and continued until hospital Day 5. She was extubated on Day 2, and her liver function tests subsequently normalized (peak INR 1.6 and AST 145 units/L on hospital Day 1, peak ALT 213 units/L Day 3). Acetylcysteine was discontinued 107 h post ingestion, and she was transferred to a psychiatric hospital on hospital Day 5 and discharged home 3 days later.
Discussion Consistent with prior case reports,10,22,21,27,35,36,11,24,23,6 these cases confirm that acetaminophen alone, at a sufficiently high dose, can cause coma and lactic acidosis within 10 h of ingestion. Each patient was intubated and mechanically ventilated. We observed that each of our cases exhibited rapid reversal of metabolic acidosis and the removal of substantial amounts of acetaminophen during a relatively short run of haemodialysis.1,37 While this case series cannot establish that haemodialysis improved clinical outcomes, none of the patients developed coagulopathy, despite elevated acetaminophen by aminotransferase multiplication products.38 Only one patient developed an AST or ALT over 1000 units/L, despite having ψ parameters39 which predicted at least a 45% probability of hepatotoxicity. We also estimate that substantial amounts of acetylcysteine were removed during relatively short runs of haemodialysis. There are few published data on the pharmacokinetics of intravenous acetylcysteine, and even fewer at doses used for acetaminophen overdose.15,40,13,33,12,14,41,17,42 In 17 overdose patients, Prescott et al. reported plasma total acetylcysteine concentrations averaged 600 μM at the end of the second infusion of 50 mg/kg/4h and 200 μM
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(range 68–550 μM) at the end of the third infusion, similar to concentrations we observed in our cases.12 Pakravan et al. reported somewhat lower mean total plasma acetylcysteine concentrations of 250 μM in 18 overdose patients near the end of the second infusion.42 For reference, serum concentrations of the amino acid cysteine are normally between 140 and 270 μM.32,16 Plasma acetylcysteine clearances of 3.2 mL/kg/min have been measured in overdose patients,12 1.1 mL/kg/min in patients with cirrhosis,14 0.32 mL/kg/ min in end-stage renal patients,33 0.5 mL/kg/min in preterm neonates,43 and between 1.5 and 3.5 mL/kg/min in healthy volunteers.40,15,13,14 The dialysance we observed is therefore similar to if not greater than native clearance. Soldini et al. calculated a dialysance of 5.5 1.0 L/h at much smaller doses, and estimated that about half the administered dose would be removed during 4 h of dialysis. Therefore, if haemodialysis is being contemplated for any reason in a patient receiving acetylcysteine, it is imperative to recognize that dialysis will remove the antidote. Recognizing the empirical basis for acetylcysteine dosing,44,45,12 its wide safety margin,46,47 and the potential for confusion and errors when individualizing dosing,48–50 one straightforward recommendation would be to double the dosing intensity of whichever protocol was being followed during haemodialysis. Thus, the so-called “2nd bag” of the Edinburgh protocol would be increased from 12.5 mg/kg/h to 25 mg/kg/h, while the intermittent intravenous protocol could be ordered as 70 mg/kg q2h rather than q4h. If haemodialysis lasts more than 6 h for a patient receiving the Edinburgh protocol, an additional half-load of 75 mg/kg could be infused at the end of dialysis in the rare eventuality that acetaminophen concentrations remain high. This practice is consistent with the shift to matching acetylcysteine dosing based on serial acetaminophen concentrations, and is easily adapted to other dosing strategies that have recently been proposed.44,50–52 It must be emphasized that haemodialysis is generally not necessary for acetaminophen overdose.7 First, the vast majority of patients are not candidates for haemodialysis, either because they present early (in which case acetylcysteine will be effective) or because they present late and the remaining body burden of acetaminophen is too small to warrant extracorporeal removal. Second, for patients with established hepatic failure, the benefits of haemodialysis are uncertain.9,53,54 Third, it is rare to encounter the massive serum acetaminophen concentrations seen in the patients reported in our case series, which are an order of magnitude higher than the treatment threshold of the Rumack-Matthew nomogram based on the time of ingestion, and typically signify ingestions of more than 1000 mg/kg. Haemodialysis entails some morbidity, delay and cost, which need to be balanced against an uncertain benefit. Finally, the capacity for haemodialysis to remove the antidote, acetylcysteine, and thereby reduce its efficacy must also be considered. The international collaborative Extracorporeal Treatments in Poisoning workgroup55 is soon to issue their consensus recommendation regarding haemodialysis for acetaminophen overdose. (Dr. M. Ghannoum, personal communication, July 2013).
The deep coma and early lactic acidosis seen in our patients may be due to direct toxicity of acetaminophen itself, and is distinct from the well-accepted mechanism of hepatocellular toxicity from the electrophilic NAPQI metabolite following glutathione depletion.28,29,30,10,31,56 Coma and hypothermia are common features of prior human case reports,27,35,57,11,20,6 as well as in mice,30 and may reflect mitochondrial toxicity of the parent drug in the brain, where bioactivation to NAPQI is minimal. If the parent drug is responsible, acetylcysteine per se is unlikely to help, and rapid extracorporeal removal may represent a better treatment strategy. While the precise target of mitochondrial toxicity remains speculative, a 4 g dose of acetaminophen in healthy volunteers causes rapid and profound down-regulation of both nuclear and mitochondrial genes involved in oxidative phosphorylation, especially Complex I, accompanied by a persistent submolar rise in serum lactate.58 High concentrations of acetaminophen impair the first step of the electron transport chain in mammalian cells.56,28,29,10 One group has suggested that inhibition of the pyruvate dehydrogenase complex may also be involved.57 Acetaminophen overdose is increasingly recognized as a relatively common cause of lesser degrees of lactic acidosis, confusion and lethargy.59,31 It is important to appreciate that these phenomena are distinct from the lactic acidosis and hepatic encephalopathy that develop days after acetaminophen overdose, and which often signify irreversible hepatic failure.26 Furthermore, this condition should not be confused with pyroglutamic acidemia (5-oxoprolinuria) which is due to inhibition of the γ-glutamyl cycle and can happen rarely following therapeutic doses of acetaminophen.60–62 While some previous cases were also treated with extracorporeal removal techniques such as continuous renal replacement therapy23,11 or charcoal hemoperfusion,18,19 we identified only one prior report of haemodialysis within 12 h of presentation.6,36,21 Thus, this case series supplements the prior literature by reporting our experience with immediate haemodialysis for such patients. Interestingly, our data suggest that haemodialysis accelerated acetaminophen removal both during and after haemodialysis. In only one prior report involving a young child does the reported data suggest an improvement in native acetaminophen clearance after dialysis.6 The remaining available literature on human acetaminophen elimination kinetics suggests instead relatively constant post-peak acetaminophen elimination in a given individual with or without extracorporeal removal63,38,64,65 even at very high serum concentrations.37,11 We speculate that the characteristically long post-peak elimination half-lives observed within 24 h of massive ingestions may be a consequence of direct mitochondrial toxicity rather than merely delayed absorption, while delayed elimination beyond 24 h reflects established, irreversible hepatic failure.63,38,64,66 While ongoing absorption is possible, each of our cases ingested an immediate-release formulation of acetaminophen.67 Elimination half-lives of eight or more hours (endogenous clearance below 1.4 mL/kg/min) have been observed Clinical Toxicology vol. 51 no. 9 2013
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Haemodialysis for massive APAP overdose 861 at the highest serum acetaminophen concentrations19,36, 37,6,21,11,57,27,37 When circulating parent-drug concentrations remain very elevated in such cases, one can envision an increased cumulative body burden of NAPQI that may overwhelm the usual 300 mg/kg dose of intravenous acetylcysteine.68–71 By extension, haemodialysis would reduce this mismatch between toxic metabolite production and thiol donor regeneration provided it removed parent drug faster than the antidote. Of note, in such cases with delayed elimination, endogenous acetaminophen clearance has slowed to the point that haemodialysis will contribute substantially to parent drug removal, unlike smaller overdoses in which acetaminophen clearance exceeds 3 mL/kg/ min. However, the cause and significance of delayed acetaminophen elimination shortly after overdose are not well established at present.72,64 Some limitations of our observations merit emphasis. We assayed total acetylcysteine (i.e. after dithiol bonds reduced), including the fraction bound to circulating proteins.40,13 It remains uncertain to what degree the bound fraction is available for thiol donation and glutathione regeneration in the liver. Other authors have used methods that remove plasma protein-bound acetylcysteine, as well as using much smaller doses (e.g. 400 or 600 mg), so the kinetic estimates may not be directly comparable.15,40,17 Neither total nor reduced circulating drug concentration necessarily reflects hepatocellular levels or antidotal efficacy. The precision of our kinetic estimates are limited by the small number of samples collected and the assumptions inherent to kinetic modelling. We did not quantify acetylcysteine nor acetaminophen recovered in dialysate. Nevertheless, our estimate of dialysance is unlikely to be inflated given the high extraction ratios and the absence of net fluid removal during the entire dialysis session. Finally, the manufacturers of the lactate assay were unable to provide information on the possibility of interference by pyroglutamic acid, but we believe that lactate was the predominant organic acid present.
Conclusions In summary, we report that when massive acetaminophen ingestion is accompanied by coma, lactic acidosis and prolonged elimination half-life of the parent drug, immediate haemodialysis may result in rapid biochemical improvement. Interestingly, a short haemodialysis session can accelerate endogenous parent drug elimination post-dialysis. As expected, haemodialysis more than doubles the overall clearance of both the drug and its antidote, acetylcysteine, during dialysis. Recognizing that acetylcysteine dosing is largely empirical, we recommend that the dosing of acetylcysteine be at least doubled whenever patients being treated with acetylcysteine undergo haemodialysis, and that a half-load be re-administered when a dialysis session exceeds 6 h.
Acknowledgments We are indebted to Dr. Murray Cutler for use of laboratory space and for preparing the solutions used in the Copyright © Informa Healthcare USA, Inc. 2013
acetylcysteine assay. We are also indebted to the other physicians and healthcare providers that cared for these patients at the Kingston General and Oshawa General Hospitals.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. Supported by a Doctoral Research Award from the Pediatric Oncology Group of Ontario and the Canadian Institutes of Health Research (LNH).
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42. Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol 2008; 46:697–702. 43. Ahola T, Fellman V, Laaksonen R, Laitila J, Lapatto R, Neuvonen PJ, Raivio KO. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol 1999; 55: 645–650. 44. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol 2012; 50: 91–98. 45. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Clin Toxicol 2002; 40:3–20. 46. Heard K, Schaeffer TH. Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol 2011; 49:423–425. 47. Bailey B, Blais R, Letarte A. Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med 2004; 44:401–406. 48. Ferner RE, Langford NJ, Anton C, Hutchings A, Bateman DN, Routledge PA. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol 2001; 52:573–577. 49. Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother 2008; 42:766–770. 50. Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity (June). Ann Pharmacother 2011; 45: 713–720. 51. Shen F, Coulter CV, Isbister GK, Duffull SB. A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose. Clin Toxicol 2011; 49:643–647. 52. Klein-Schwartz W, Doyon S. Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin Pharmacother 2011; 12:119–130. 53. Schiodt FV, Clemmesen JO, Hansen BA, Larsen FS. Cerebral edema due to hemodialysis in paracetamol-induced fulminant hepatic failure. Scand J Gastroenterol 1995; 30:927–928. 54. Steadman RH, Van Rensburg A, Kramer DJ. Transplantation for acute liver failure: perioperative management. Curr Opin Organ Transplant 2010; 15:368–373. 55. Lavergne V, Nolin TD, Hoffman RS, Roberts D, Gosselin S, Goldfarb DS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology. Clin Toxicol 2012; 50:403–413. 56. Porter KE, Dawson AG. Inhibition of respiration and gluconeogenesis by paracetamol in rat kidney preparations. Biochem Pharmacol 1979; 28:3057–3062. 57. Truitt CA, Curry SC, Canning JE, French R. Large APAP OD with fixed pupils, optic pallor, massive lactic acidosis, elevated lactate/ pyruvate ratio, and hyperalaninemia with full recovery and minimal hypertransaminasemia (abstract). Clin Toxicol 2010; 48:610. 58. Fannin RD, Russo M, O’Connell TM, Gerrish K, Winnike JH, Macdonald J, et al. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 2010; 51:227–236. 59. Zein JG, Wallace DJ, Kinasewitz G, Toubia N, Kakoulas C. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med 2010; 28:798–802. 60. Green TJ, Bijlsma JJ, Sweet DD. Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis. Can J Emerg Med 2010; 12:449–452. 61. Zand L, Muriithi A, Nelsen E, Franco PM, Greene EL, Qian Q, El-Zoghby ZM. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation. Am J Med Sci 2012; 344:501–504. 62. Reddi AS, Kunadi AR. Recurrent anion gap metabolic acidosis in a woman with vertebral disc disease. Am J Emerg Med 2011; 29:962.e3–e8. Clinical Toxicology vol. 51 no. 9 2013
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63. Prescott LF, Roscoe P, Wright N, Brown SS. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971; 1:519–522. 64. Schiodt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 2002; 71:221–225. 65. Saiao A, Chan B, Isbister GK. Pharmacokinetics and outcomes in massive paracetamol overdose (abstract). Clin Toxicol 2012; 50:276. 66. Forrest JA, Roscoe P, Prescott LF, Stevenson IH. Abnormal drug metabolism after barbiturate and paracetamol overdose. Br Med J 1974; 4:499–502. 67. Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J 2010; 40:72–76. 68. Smith SW, Howland MA, Hoffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and
Supplementary material available online Supplementary Table 1 to be found online at http://informa healthcare.com/doi/abs/10.3109/15563650.2013.844824
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69.
70.
71.
72.
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