Duration of Intravenous N-acetylcysteine

in Acetaminophen Poisoning
How should we approach the “killer” painkiller?

DeAnna W. Turner, Pharm.D.

PGY2 Emergency Medicine Pharmacy Resident
University Health System, San Antonio, Texas
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Sciences Center at San Antonio

October 25, 2013

Learning Objectives:
1. Describe the pathophysiology and toxicokinetics of acetaminophen-induced hepatotoxicity
2. Identify treatment strategies for acetaminophen poisoning
3. Evaluate the duration of intravenous N-acetylcysteine in acetaminophen poisoning
4. Indicate clinical endpoints where the continuation of N-acetylcysteine beyond the FDA-approved
regimen may be warranted
 Acetaminophen

I. History and epidemiology1-5

A. Acetaminophen (APAP; paracetamol; N-acetyl-p-aminophenol)
B. One of the most commonly used drugs in the United States (U.S.)
i. ~50 million adults take APAP-containing products weekly
C. Active ingredient in over 600 medications

Figure 1: Summary of APAP History and Epidemiology1-5

1960’s
1990’s
Popularity &
APAP overdoses:
widespread use
56,000 ER visits 2008
increased
1893 26,000 hospitalizations AAPCC Report:
st
1 used in 458 deaths 152,173 exposures
medicine 122 deaths

1966 Direct costs of

1950 1st case APAP overdose:
Appeared reports of ~$87 million annually
commercially toxicity 2005
in U.S. ~28 billion doses of
APAP-containing
products purchased
in U.S.

AAPCC = American Association of Poison Control Centers

II. Mechanism of action6

A. Antipyretic effects:
i. Inhibition of prostaglandin formation and release in central nervous system
ii. Inhibition of endogenous pyrogens at hypothalamic thermoregulatory centers
B. Analgesic effects:
i. Central inhibition of prostaglandin synthesis
ii. Elevation of pain threshold

III. Adverse effects7,8

A. Generally well tolerated at recommended therapeutic doses
B. No effect on platelets, coagulation, or cardiovascular and respiratory systems
C. Gastrointestinal complications uncommon
D. Rare but serious skin reactions have been reported
E. Hepatotoxicity prominent feature of overdose

D. Turner 2
 Acetaminophen Pharmacokinetics

Table 1: APAP Pharmacokinetics1,6

Immediate Release (IR) Extended Release (ER)
Absorption Rapid from GI tract Initially rapid; comparable to IR
Bioavailability 85% to 98%
Tmax 0.5 to 1 hr 0.5 to 3 hrs
Metabolism Primarily hepatic (see below)
Elimination t½ 2 to 3 hrs ~3 hrs
Prolonged ~1 hr in cirrhotic patients
Prolonged following toxic doses (≥4 hrs)
Excretion Urine (<5% unchanged)
GI = gastrointestinal; Tmax = time to maximum plasma concentration; hr = hour; hrs = hours

I. Metabolism1,4-6,9
A. APAP undergoes extensive hepatic metabolism via three pathways
i. Conjugation with glucuronide
ii. Conjugation with sulfate
iii. Oxidation via cytochrome P450 (CYP450) enzyme

II. APAP metabolism at therapeutic doses1,4-6,9

A. Approximately 85% undergoes phase II conjugation
i. Formation of glucuronidated and sulfated metabolites; renally excreted
ii. Glucuronidation predominant in adults
iii. Sulfation predominates in children until ~12 years of age
B. Up to 10% undergoes phase I oxidation
i. Formation of toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI)
ii. Detoxified by conjugation with glutathione (GSH) to inert cysteine and mercapturic acid
metabolites; renally excreted
iii. CYP2E1 primary enzyme responsible for oxidation
a. CYP1A2, CYP3A4, and CYP2D6 also involved
C. ~5% excreted unchanged in urine

Figure 2: APAP metabolism at therapeutic doses5

D. Turner 3
 Acetaminophen-Induced Hepatotoxicity

I. APAP metabolism at toxic doses1,4-6,9

A. Glucuronidation and sulfation become saturated
B. Continued production of NAPQI results in depletion of GSH stores
C. Excess NAPQI binds cellular proteins and leads to cell injury once 70% of GSH stores depleted

Figure 3: APAP Metabolism at Toxic Doses5

II. APAP-induced hepatotoxicity4,5,9-13

A. Defined as transaminase >1000 IU/L
B. Davidson D, et al. reported first cases of hepatotoxicity with APAP overdose
C. Liver damage can occur in four conditions
i. Excessive APAP intake
ii. Excessive CYP450 enzyme activity
iii. Decreased capacity for glucuronidation or sulfation
iv. Depletion of GSH stores

III. Clinical manifestations4,5,9-12

A. Initial symptoms of APAP poisoning often mild and nonspecific
B. Some patients remain asymptomatic
C. Unreliable predictor of subsequent hepatotoxicity

D. Turner 4
 Figure 4: Clinical Stages of Acute APAP Toxicity5

First 24 hours 24 to 72 hours 72 to 96 hours 4 days to 2 weeks

VI. Mechanisms of APAP-induced liver necrosis2,5

A. Liver described functionally by the acinus; morphologically by the lobule (Figure 4)
i. Acinus: tissue located between adjacent portal triads; contains zones of differing metabolic
function
B. Greatest concentration of CYP450 enzymes located closest to hepatic vein (Zone 3)
C. Necrosis confined primarily to hepatocytes in centrilobular regions (Zone 3)

Figure 5: Hepatic Architecture5

*THV = terminal hepatic vein

D. Turner 5
 D. Covalent binding to protein adducts
i. Covalent binding of APAP to protein associated with hepatotoxicity
ii. Immunohistochemical analysis of liver sections in mice revealed high correlation between
presence of APAP-protein adducts and toxicity
iii. Adducts visible in liver sections within 15 minutes of dosing; confined to centrilobular
hepatocytes by one hour
iv. Hepatocytes with APAP-protein adducts developed necrosis
E. Oxidative stress
i. GSH an important factor in antioxidant defense
ii. Depletion of GSH by NAPQI in APAP overdose renders hepatocytes highly susceptible to
oxidant injury
F. Alterations in hepatic blood flow
i. Hepatotoxicity reported with hepatic congestion in rodents and humans
a. Congestion results from red blood cell accumulation within endocytic vacuoles and the
Space of Disse
b. Sinusoidal lumen collapse
G. Mitochondrial injury
i. Importance of mitochondrial dysfunction in APAP toxicity unclear
ii. Likely mechanism involves mitochondrial permeability transition (MPT)
a. Abrupt increase in inner mitochondrial membrane permeability
b. Associated with large increase in oxidative stress, mitochondrial swelling, and reduced
ATP synthesis
H. Inflammation, cytokines, and chemokines
i. Complex role of inflammation in mediation of APAP toxicity
ii. Kupffer cell activation thought to mediate hepatotoxicity
iii. Mechanistic role controversial
I. Intracellular signaling
i. c-Jun N-terminal kinase (JNK) activation potential mechanism associated with mediation of
APAP-induced MPT
ii. Both JNK activation and MPT associated with increased oxidative stress

VII. Hepatotoxicity Risk Assessment5

A. Toxic exposure classified as:
i. Acute ingestion
a. >10 g or 200 mg/kg as single ingestion
ii. Repeated supratherapeutic ingestion (RSTI)
a. >6 g or 150 mg/kg per 24-hour period for at least two consecutive days
iii. Pediatrics (<6 years)
a. 200 mg/kg as single ingestion or unknown amount
iv. Note: Values are empiric and widely used as recommendations for emergency evaluation
a. Numerous factors may determine the toxic threshold dose
B. Rumack-Matthew nomogram (APPENDIX A)
i. Derived from retrospective analysis of APAP overdose patients and their clinical outcomes
ii. Used to distinguish patients likely to suffer hepatotoxicity
iii. Limitations:
a. Useful for single, acute ingestions
b. Time of ingestion must be known
c. Validated for use up to 24 hours after acute ingestion
iv. Nomogram modified in 1976
a. 25% reduction from original “200 treatment line”  increased safety margin
b. Modified treatment suggested at the “150 line”
a. Now most commonly used treatment line in U.S.

D. Turner 6
 v. Following acute overdose
a. Obtain a four-hour APAP level
b. Plot on Rumack-Matthew nomogram
C. Pitfalls
i. Misclassification of hepatotoxicity risk
a. Failure to determine accurate time of ingestion
ii. Failure to consider possible effects of coingestants and formulation on absorption
iii. Failure to identify patient with RSTI of APAP

Management of Acetaminophen Toxicity

I. Initial management consists of gastrointestinal (GI) decontamination, timely use of N-acetylcysteine (NAC)
antidote, and supportive care

II. GI Decontamination5
A. Consider in patients who present within four hours after toxic ingestion of APAP
B. Recommended treatment
i. Activated charcoal 1 g/kg orally
C. Contraindications
i. Sedated or lethargic patients who may be unable to protect their airway
ii. Not recommended for asymptomatic patients presenting more than four hours post-ingestion
iii. Presence of intestinal obstruction
D. Gastric lavage and induced emesis not recommended; less effective and delays administration of
antidote

III. N-acetylcysteine (NAC)5

A. Antidote: Mainstay for treatment or prevention of APAP-induced hepatotoxicity

IV. Transplantation9,14
A. Serious toxicity may progress to fulminant hepatic failure
i. Require expert management in specialized unit with transplant capability
B. Transplantation can be life saving
C. Challenge: Identification of patients who will die of FHF and those who will spontaneously recover with
supportive care
D. Prognostic criteria
i. Model for End-Stage Liver Disease (MELD) score
a. Higher MELD score on admission to intensive care unit associated with progression to
encephalopathy
b. Continued MELD score increase over first few days after onset of encephalopathy
predictive of death
ii. Acute Physiology and Chronic Health Evaluation (APACHE) II score
a. Sensitive tool predictive of patients likely to progress to FHF

D. Turner 7
 N-acetylcysteine

I. History15,16
A. NAC first suggested as antidote to APAP overdose in 1974
i. IV formulation used in Australia, Europe, and Canada
ii. Studies of oral formulation began in U.S. in late 1970’s
B. Oral NAC approved by U.S. Food and Drug Administration (FDA) in 1985
C. IV NAC not approved in U.S. until 2004

II. Mechanism of action5,15

A. Not fully understood
B. Prevention of hepatic necrosis via two theoretical beneficial effects
i. Restoration of hepatic glutathione
ii. Scavenging of free radicals (antioxidant)

Table 2: Summary of NAC Dosage Forms17

Intravenous NAC Oral NAC
21-hour regimen 72-hour regimen
Protocol
3 doses 18 doses
Load: 150 mg/kg over 60 mins
nd Load: 140 mg/kg
Dosing Regimen 2 dose: 50 mg/kg over 4 hrs
rd Maintenance: 70 mg/kg q4h
3 dose: 100 mg/kg over 16 hrs
Dilute 20% solution 3:1 with soda or
Preparation Dilute in 5% dextrose in water
orange juice to prepare 5% solution
Stability Up to 24 hrs at room temperature Use within 1 hr of preparation
Distribution 0.47 L/kg
Hepatic
Metabolism
Deacetylated by liver to cysteine or oxidation to diacetylcysteine
Elimination t½ ~6 hrs
Excretion Urine
Limitations Anaphylactoid reactions (10 – 20%) Unpleasant odor and taste
Nausea and vomiting (~33%)
Dose must be repeated if emesis
occurs within 1 hr of administration
Mins = minutes; hrs = hours; q4h = every 4 hours

D. Turner 8
III. “Time to NAC”5,18-22
A. Independent risk factor for development of hepatotoxicity
B. Treatment window
i. Optimal outcome when IV or PO NAC administered within eight hours post-ingestion
ii. Optimal “decision-time window” between four-hour APAP level and eight-hour goal to NAC
initiation

Figure 6: Effect of Delay to Initiation of NAC Therapy5,18

70%
60%
50%
AST >1000

40%
30%
20%
10%
0%
0-4h 4-8h 8-12h 12-16h 16-20h 20-24h No NAC
Treatment Delay (hours)

AST = aspartate aminotransferase

C. Likelihood of hepatotoxicity is low when NAC initiated within eight hours of APAP overdose
D. Risk of developing hepatotoxicity increases with delay of NAC beyond eight hours
E. However, NAC administration is associated with lower hepatotoxicity risk within 24 hours of acute
APAP ingestion compared to historical controls
i. Based on historical controls, without antidotal therapy, hepatotoxicity would be expected in
60% of patients
F. Pitfall
i. Treatment failures reported with 21-hour IV NAC regimen despite early administration

IV. Indications5,9
A. Need for treatment based on:
i. Serum APAP level drawn at least four hours post-ingestion
ii. Results from risk stratification on Rumack-Matthew nomogram
B. Special considerations
i. Unknown time of ingestion or >24 hours post-ingestion
a. Start NAC therapy immediately; do not delay for laboratory values
ii. RSTI
a. Treatment with NAC recommended if:
a. APAP level >10 mcg/mL
b. Transaminases >50 IU/L
c. Liver tenderness present
C. Once need for treatment is established, repeated APAP levels not necessary
i. Exception: Massive ingestion (>25 g) and/or ingestion of ER formulation

D. Turner 9
 Figure 7: Suggested Treatment Algorithm for Acute APAP Ingestion5,6,17

PI = post-ingestion; Rx = treatment

Clinical Question
I. With reports of treatment failures with IV NAC and lack of recommendations to guide duration, what should
clinicians consider when deciding to discontinue therapy per protocol or continue therapy beyond 21 hours?

II. Lack of randomized, controlled trials evaluating optimal duration of IV NAC23

A. Acute poisoning unpredictable
B. Patient enrollment difficult

III. Literature limited to case reports and case series

IV. Factors to consider during evaluation

A. Amount of APAP ingested
B. Presence of coingestants
C. Time to NAC: Within eight hours? Greater than eight hours post-ingestion? Unknown?
D. Clinical findings at 21 hours: APAP level, transaminases, coagulation tests

D. Turner 10
 Literature Review

Doyon S, et al. Acad Emerg Med. 2009;16:34-39.24

Purpose Evaluate effectiveness of IV NAC in early acute APAP overdose patients
Determine frequency of hepatotoxicity
Identify factors associated with need for prolonged therapy
Design Observational case series using retrospective Maryland poison center data and hospital charts
June 2004 – July 2007
Methods Inclusion criteria:
IV NAC administered within 8 hrs of acute ingestion
Plasma APAP concentration on or above treatment line on Rumack-Matthew nomogram
Documented AST, ALT, and APAP concentrations at end of 21-hr infusion

Exclusion criteria:
Coingestion of substance known to be hepatotoxic or affect coagulation (other than ethanol)
Underlying liver disease
NAC administered orally prior to IV NAC
21-hr IV NAC administered in wrong dose or wrong infusion rate
Lost to follow-up or insufficient data to determine outcome

Rumack-Matthew nomogram used to determine hepatotoxicity risk

Hepatotoxicity defined as transaminase >1000 IU/L

Results Characteristics of subjects:

77 patients enrolled; 52 (67.5%) female; median age = 22 years

Patient Comparison at 21 Hours

Variable Normal AST, ALT and Elevated AST, ALT p-value
Undetectable APAP or APAP
(n=70) (n=7)
*
Age (yrs) 26.4 ± 14.4 46.9 ±17.1 0.003
Product, n (%)
Combo product 25 (35.7) 6 (85.7) 0.015
With coingestants 33 (47.1) 3 (42.9) 1.000
With ethanol 9 (12.9) 2 (28.6) 0.261
Plasma APAP (mg/dL)
*
Max concentration 205.6 ± 75.6 402.4 ± 164.8 <0.001
*
Time to max 4.5 ± 0.9 15.4 ± 25.0 0.156
Treatment
With charcoal, n (%) 45 (64.3) 5 (71.4) 1.000
*
Time to NAC 5.7 ± 1.6 5.6 ± 1.0 0.817

Standard 21-hour protocol adequate for 70 patients (90.9%)

o Undetectable APAP level and normal AST and ALT at 21 hours of IV NAC therapy
7 patients received prolonged IV NAC (>21 hrs)
o At 21 hrs:
 6 patients had detectible APAP concentrations
 5 patients had abnormal AST and/or ALT
o 1 patient transitioned to PO NAC
o Time to NAC <8 hrs
o Duration of treatment: 36 – 144 hrs

D. Turner 11
 Factors associated with elevated APAP, AST or ALT concentrations at 21 hrs
o Older age
o Higher max APAP concentration
o Ingestion of APAP combo product

Hepatotoxicity:
o 4/77 (5.2%) patients developed hepatotoxicity
o 2 patients with poor outcomes
 1 required transplantation
 1 expired

Patient 1 Patient 2
Time to NAC: 7 hours Time to NAC: 4 hours
Normal AST and ALT at 21 hours of IV NAC Subsequent APAP levels remained above
NAC discontinued treatment line on nomogram
Retroactively obtained APAP level after Patient received continuous, uninterrupted
cessation of IV NAC: 112 mcg/mL IV NAC and intensive supportive care
AST/ALT increased (275/464) at 40 hours PI Patient expired on hospital day 7
Oral NAC initiated Autopsy findings: centrilobular necrosis of
Liver function deteriorated liver, focal tubular necrosis of kidney, and
Required transplant acute bronchopneumonia

Author’s Despite early “time to NAC”, hepatotoxicity occurred in 5.2% (4/77) of patients
Comments Propose a patient-tailored approach to discontinuation of IV NAC
Further study needed to determine optimal IV NAC regimen
Take Home Suggests 21-hour IV NAC regimen may be suboptimal in some patients
Points Hepatotoxicity may develop despite uninterrupted IV NAC administration
Delayed hepatic injury may occur with detectable APAP level and cessation of IV NAC at 21 hours
hrs = hours; hr = hour; AST = aspartate aminotransferase; ALT = alanine aminotransferase; yrs = years; SD = standard deviation
*Mean ± SD

D. Turner 12
Smith SW, et al. Ann Pharmacother. 2008;42:1333-1339.25
Patient 78 year old male
Demographics 61 kg
Medical History CAD, renal insufficiency, PVD, anxiety
No prior history of overdose
Surgical History CABG, left nephrectomy, left AKA
Medications Metoprolol, sertraline, lorazepam (inaccessible to him; accounted for by family)
Type of Ingestion Single, acute
~96 IR APAP 500 mg tablets (48 g)  787 mg/kg
Presentation Drowsy, confused to date, clear speech
BP 131/66; P 68; R 14
Laboratory APAP level: 264 mcg/mL (~2.25 hrs PI)
AST: 8 IU/L PCC Recommendations:
ALT: 22 IU/L Initiate AC
INR and bilirubin normal Obtain 4-hr APAP level
SCr: 3.4 mg/dL Initiate IV NAC x21 hrs minimum
Serum salicylate and ethanol concentrations negative OR
UDS: +benzodiazepines Until APAP level undetectable and
UA: +leukocyte esterase aminotransferase normal
Clinical Course Time to NAC: 5 hrs
AC not given (confused; aspiration risk)
APAP level: 281 mcg/mL (~6.25 hrs PI)
At conclusion of 21-hr NAC course
o APAP level: 116 mcg/mL
o Transaminases normal
IV NAC discontinued
Outcome ~48 hrs PI
o APAP level: 228 mcg/mL
o AST: 395 IU/L
o ALT: 453 IU/L
IV NAC restarted after ~24-hr hiatus
Transaminases continued to rise until 5 days PI
o Peak AST: 4350 IU/L
o Peal ALT: 5621 IU/L
INR peak: 6.6
SCr: 4.2 mg/dL
Continued on IV NAC until normalization of all laboratory values
Discharged home on hospital day 12
Author’s Patient on continuous, 1:1 observation; second ingestion during admission unlikely
Comments In-patient medications excluded APAP-containing regimens
Reanalysis of serum specimens confirmed double-peak APAP levels
Case differs from other reports of double-peak APAP levels
o Absence of coingestants or combo APAP product; absence of ER APAP formulation
Initial APAP solubility most likely exceeded with massive ingestion
Potential mesenteric insufficiency and altered gastric emptying due to PVD and CAD
Enterohepatic recycling possible contributor to erratic APAP absorption
Take Home Massive APAP ingestion may lead to delayed and erratic APAP absorption
Points Residual APAP can persist after completion of 21-hr IV NAC course
Discontinuation of NAC with detectable APAP levels may result in delayed hepatic injury
Duration should be based on clinical findings obtained prior to completion of 21-hr protocol
*CAD = coronary artery disease; PVD = peripheral vascular disease; CABG = coronary artery bypass graft; AKA = above knee amputation; PI =
post-ingestion; UDS = urine drug screen; UA = urinalysis; AC = activated charcoal; PCC = Poison Control Center

D. Turner 13
Schwartz EA, et al. Ann Emerg Med. 2009;54(3):421-423.26
Patient 48 year old female
Demographics 55.5 kg
Medical History Chronic depression, prior suicide attempts
Type of Ingestion Single, acute
~150 tablets containing:
o APAP 500 mg (75 g)  1351 mg/kg
o Diphenhydramine 25 mg (3.75 g)  68 mg/kg
Presentation Unresponsive
Laboratory APAP level: 104 mcg/mL (4 hrs PI)
AST: 19 IU/L
ALT: 17 IU/L
INR: 1.04
SCr: 0.8 mg/gL
UDS: +amphetamines, benzodiazepines, phencyclidine
Clinical Course Time to NAC: 5 hrs
o Time of ingestion estimated by family members
APAP level: 181 mcg/mL (~24 hrs PI)
Transaminases normal
Minimal bowel sounds present
IV NAC continued beyond 21 hrs without interruption
Outcome BP 90/60 (responded to fluids; never required vasopressors)
QRS 140 ms (treated with sodium bicarbonate)
Intubated ~32 hrs PI
APAP level: 264 mcg/mL (~41.5 hrs PI)
~48 hrs PI
o Transferred to tertiary care facility
o BP 110/59; P 120; R 10; O2Sat 93%
o Pupils fixed at 5 mm; sclera anicteric
o APAP level: 256 mcg/mL
o AST: 182 IU/L
o ALT: 220 IU/L
o INR: 2.9
o SCr: 0.9 mg/dL
o Lactate 3.4 mmoL/L
Abdominal CT negative for medication bezoar 56 hrs PI
o Elected to administer AC 100 g and initiate whole bowel irrigation for 13 hrs
APAP level: 209 mcg/mL (~5 hrs after irrigation initiated; ~61 hrs PI)
APAP level: 508 mcg/mL (5 hrs after irrigation terminated; ~75 hrs PI)
Aminotransferases continued to rise
o Peak AST: ~6000 IU/L
o Peak ALT: ~8000 IU/L
Family requested withdrawal of care
APAP level decreased slowly; undetectable by 136 hrs PI
Author’s Case raises concern that the 21-hr IV NAC course may not be sufficient for all early presenters
Comments AC may have been beneficial if administered earlier
Time of ingestion could have occurred earlier than reported by family; unlikely
Take Home Hepatotoxicity can develop despite early time to NAC and extended duration of therapy
Points Emphasizes importance of reassessment prior to discontinuation of IV NAC, especially in patient’s
with anticipated delayed absorption due to coingestants or massive overdoses
Appropriate duration of IV NAC not determined
TOI = time of ingestion

D. Turner 14
Hendrickson RG, et al. J Med Toxicol. 2010;6:337-344.27
Case 1 Case 2 Case 3
Patient 38 year old female 25 year old male 16 year old male
Demographics
Type of Single, acute Single, acute Single, acute
Ingestion 200 tablets containing APAP 80 tablets containing APAP 200 tablets containing APAP
325 mg (65 g) and 325 mg (26 g) and 500 mg (100 g) and
hydrocodone 10 mg (2 g) diphenhydramine 25 mg (2 g) diphenhydramine 25 mg (5 g)
Presentation Awake, alert, oriented Appeared intoxicated Awake, alert, confused
BP 170/48; P 67; R 16 BP 124/82; P 143; R 22 BP 130/70; P 125
Laboratory UDS: +benzodiazepines, Ethanol: 148 mg/dL UDS: negative
opiates
Laboratory
Table 1: Case 1 Laboratory Values
PI (hr) 2 8 15 31 39 43 59 73 87 97 111 135 158
APAPmcg/mL 282 289 261 167 240 142 15 <5 <5 <5 <5 <5
AST IU/L 12 34 67 119 491 1409 1603 608 144 82
ALT IU/L 10 35 83 185 576 1765 2351 1672 988 683
INR 1.1 1.5 1.5 1.6 1.4 1.2 1.0

Table 2: Case 2 Laboratory Values

PI (hr) 2 5 9 15 20 26 37 45 61 85 109 133 157 181
APAPmcg/mL 164 172 191 211 185 192 313 281 76 13 <5 <5 <5
AST IU/L 45 31 37 124 444 571 798 1153 415 166 81
ALT IU/L 22 17 18 82 311 2236 1528 981 692
INR 1.4 2.1 1.3 2.1 1.3 1.1

Table 3: Case 3 Laboratory Values

PI (hr) 2 6 25 30 36 42 50 66 79 91 97 103 109
APAPmcg/mL 225 418 479 385 313 354 272 138 76 37 22 15 <10
AST IU/L 17 41 44 85 125 505 1864 1929 8686 5892 3457 2045
ALT IU/L 16 63 73 131 205 836 1673 2986 ~11k 9046 7341 6566
INR 1.8 2.1 2.7 3.3 4.9 5.9 4.3 2.9 2.8 3.2

Clinical Course Time to NAC: 4 hrs Time to NAC: 4 hrs Time to NAC: 4 hrs
No GI decontamination IV NAC continued without AC 50 g administered
IV NAC discontinued for 3.5 interruption Transferred to academic
hrs contrary to PC advice pediatric hospital
Outcome IV NAC restarted Tachycardia resolved over Somnolent; intubated
APAP level peaked 8 hrs PI; several hours Whole bowel irrigation
rebounded 39 hrs PI APAP level peaked 15 hrs PI; initiated
Transaminases peaked 97 hrs rebounded 37 hrs PI Received several 1 mg doses
PI Transaminases peaked 109 of physostigmine; mental
IV NAC discontinued 111 hrs hrs PI status improved
PI APAP level peaked at 25 hrs
Discharged on day 8 PI; small spike at 42 hrs PI
Transaminases peaked 91
hrs PI

D. Turner 15
Author’s Report of delayed APAP peak and double peak pharmacokinetics
Comments Potential causalities of delayed absorption: low APAP solubility; decreased gastric emptying
Commonalities: large ingestions; presence of coingestants
Liver injury prominent feature of double peak phenomenon
Take Home APAP pharmacokinetics likely unpredictable in massive ingestions with or without presence of
Points coingestants
Patients at significant risk for double peak phenomenon and liver injury
Early IV NAC administration imperative for early presenters and should be continued until APAP and
aminotransferase concentrations are undetectable

Conclusion
I. Summary
o 21-hour IV NAC protocol may not be adequate for select cases of APAP toxic ingestion despite early
“time to NAC”
o Massive ingestion (>25 g), formulation, and presence of coingestants may lead to delayed APAP
absorption and altered pharmacokinetics
II. Recommendation
o Patient-tailored approach to discontinuation of IV NAC at 21 hours (Table 3)
o Reassess clinical endpoints prior to discontinuation of IV NAC at 21 hours
o Duration of IV NAC based on findings of clinical endpoint reassessment

Table 3: Duration of IV NAC – Patient-Tailored Approach

Prior to completion of 21-hour regimen: Obtain APAP, AST, ALT, and coagulation measurements
If answer is YES to ALL three questions  discontinue IV NAC at 21 hours

If answer is NO to ANY question  continue IV NAC beyond 21 hours

Repeat 3rd dose of 21-hour regimen (100 mg/kg over 16 hours)
Repeat clinical endpoints assessment prior to completion of 16-hour infusion

YES NO
APAP concentration undetectable?
Improving AST and ALT?
Documented peak with 30% decrease and continued decline
Improving coagulopathy (INR)?
Documented peak and INR <2?

D. Turner 16
APPENDIX A: Rumack-Matthew Nomogram6

D. Turner 17
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