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 hepatotoxicity2. Identify treatment strategies for acetaminophen poisoning3. Evaluate the duration of intravenous N-acetylcysteine in acetaminophen poisoning4. Indicate clinical endpoints where the continuation of N-acetylcysteine beyond the FDA-approved

regimen may be warranted

D. Turner 2

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

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

1893

1st used in medicine

1950

Appeared commercially

in U.S.

1960’s Popularity &

widespread use increased

1966 1st case

reports of toxicity

1990’s APAP overdoses: 56,000 ER visits

26,000 hospitalizations 458 deaths

2005

~28 billion doses of APAP-containing

products purchased in U.S.

2008

AAPCC Report: 152,173 exposures

122 deaths

Direct costs of

APAP overdose: ~$87 million annually

D. Turner 3

Acetaminophen Pharmacokinetics

Table 1: APAP Pharmacokinetics1,6 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

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)

D. Turner 4

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 5

Figure 4: Clinical Stages of Acute APAP Toxicity5

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

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

D. Turner 6

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 7

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 8

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

Mins = minutes; hrs = hours; q4h = every 4 hours

Intravenous NAC Oral NAC

Protocol 21-hour regimen

3 doses 72-hour regimen

18 doses

Dosing Regimen Load: 150 mg/kg over 60 mins 2

nd dose: 50 mg/kg over 4 hrs

3rd

dose: 100 mg/kg over 16 hrs

Load: 140 mg/kg Maintenance: 70 mg/kg q4h

Preparation Dilute in 5% dextrose in water Dilute 20% solution 3:1 with soda or 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

Metabolism Hepatic

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

D. Turner 9

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

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

0%

10%

20%

30%

40%

50%

60%

70%

0-4h 4-8h 8-12h 12-16h 16-20h 20-24h No NAC

AST

>1

00

0

Treatment Delay (hours)

D. Turner 10

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 11

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 Undetectable APAP

(n=70)

Elevated AST, ALT or APAP

(n=7)

p-value

Age (yrs)* 26.4 ± 14.4 46.9 ±17.1 0.003

Product, n (%) Combo product With coingestants With ethanol

25 (35.7) 33 (47.1) 9 (12.9)

6 (85.7) 3 (42.9) 2 (28.6)

0.015 1.000 0.261

Plasma APAP (mg/dL) Max concentration

*

Time to max*

205.6 ± 75.6

4.5 ± 0.9

402.4 ± 164.8

15.4 ± 25.0

<0.001 0.156

Treatment With charcoal, n (%) Time to NAC

*

45 (64.3) 5.7 ± 1.6

5 (71.4) 5.6 ± 1.0

1.000 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 12

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

Normal AST and ALT at 21 hours of IV NAC

NAC discontinued

Retroactively obtained APAP level after cessation of IV NAC: 112 mcg/mL

AST/ALT increased (275/464) at 40 hours PI

Oral NAC initiated

Liver function deteriorated

Required transplant

Time to NAC: 4 hours

Subsequent APAP levels remained above treatment line on nomogram

Patient received continuous, uninterrupted IV NAC and intensive supportive care

Patient expired on hospital day 7

Autopsy findings: centrilobular necrosis of liver, focal tubular necrosis of kidney, and acute bronchopneumonia

Author’s Comments

Despite early “time to NAC”, hepatotoxicity occurred in 5.2% (4/77) of patients

Propose a patient-tailored approach to discontinuation of IV NAC

Further study needed to determine optimal IV NAC regimen

Take Home Points

Suggests 21-hour IV NAC regimen may be suboptimal in some patients

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 13

Smith SW, et al. Ann Pharmacother. 2008;42:1333-1339.25 Patient Demographics

78 year old male

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

ALT: 22 IU/L

INR and bilirubin normal

SCr: 3.4 mg/dL

Serum salicylate and ethanol concentrations negative

UDS: +benzodiazepines

UA: +leukocyte esterase

PCC Recommendations: Initiate AC

Obtain 4-hr APAP level Initiate IV NAC x21 hrs minimum

OR Until APAP level undetectable and

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 Comments

Patient on continuous, 1:1 observation; second ingestion during admission unlikely

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 Points

Massive APAP ingestion may lead to delayed and erratic APAP absorption

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 14

Schwartz EA, et al. Ann Emerg Med. 2009;54(3):421-423.26 Patient Demographics

48 year old female

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 Comments

Case raises concern that the 21-hr IV NAC course may not be sufficient for all early presenters

AC may have been beneficial if administered earlier

Time of ingestion could have occurred earlier than reported by family; unlikely

Take Home Points

Hepatotoxicity can develop despite early time to NAC and extended duration of therapy

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 15

Hendrickson RG, et al. J Med Toxicol. 2010;6:337-344.27 Case 1 Case 2 Case 3

Patient Demographics

38 year old female 25 year old male 16 year old male

Type of Ingestion

Single, acute

200 tablets containing APAP 325 mg (65 g) and hydrocodone 10 mg (2 g)

Single, acute

80 tablets containing APAP 325 mg (26 g) and diphenhydramine 25 mg (2 g)

Single, acute

200 tablets containing APAP 500 mg (100 g) and diphenhydramine 25 mg (5 g)

Presentation Awake, alert, oriented

BP 170/48; P 67; R 16

Appeared intoxicated

BP 124/82; P 143; R 22

Awake, alert, confused

BP 130/70; P 125

Laboratory UDS: +benzodiazepines, opiates

Ethanol: 148 mg/dL UDS: negative

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

No GI decontamination

IV NAC discontinued for 3.5 hrs contrary to PC advice

Time to NAC: 4 hrs

IV NAC continued without interruption

Time to NAC: 4 hrs

AC 50 g administered

Transferred to academic pediatric hospital

Outcome IV NAC restarted

APAP level peaked 8 hrs PI; rebounded 39 hrs PI

Transaminases peaked 97 hrs PI

IV NAC discontinued 111 hrs PI

Discharged on day 8

Tachycardia resolved over several hours

APAP level peaked 15 hrs PI; rebounded 37 hrs PI

Transaminases peaked 109 hrs PI

Somnolent; intubated

Whole bowel irrigation initiated

Received several 1 mg doses of physostigmine; mental status improved

APAP level peaked at 25 hrs PI; small spike at 42 hrs PI

Transaminases peaked 91 hrs PI

D. Turner 16

Author’s Comments

Report of delayed APAP peak and double peak pharmacokinetics

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 Points

APAP pharmacokinetics likely unpredictable in massive ingestions with or without presence of 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 17

APPENDIX A: Rumack-Matthew Nomogram6

D. Turner 18

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