A3: Antidotes in Depth

Robert G. Hendrickson; Mary Ann Howland

INTRODUCTION

N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP)

overdoses. If administered early, NAC can then prevent APAP induced hepatotoxicity. If administered after the

onset of hepatotoxicity, NAC improves outcomes and decreases mortality. NAC may also limit hepatotoxicity

from other xenobiotics that result in glutathione depletion and free radical formation, such as cyclopeptide-

containing mushrooms, carbon tetrachloride, chloroform, pennyroyal oil, clove oil, and possibly liver failure from

chronic valproic acid use.31 Finally, NAC may be useful in the management of adults with fulminant hepatic

failure caused by nontoxicologic etiologies.20,75,81,84,149

HISTORY

Shortly after the first case of APAP hepatotoxicity was reported, Mitchell described the protective effect of

glutathione.97,127 Prescott113 first suggested NAC for APAP poisoning in 1974. Early experiments demonstrated

that NAC could prevent APAP-induced hepatotoxicity in mice and that the oral (PO) and intravenous (IV) routes

were equally efficacious when treatment was initiated early after ingestion.106 Several groups96,112,113,126 performed

human research with oral and IV NAC in the 1970s. The US Food and Drug Administration (FDA) approved

NAC for oral use in 1985 and for IV use in 2004.

PHARMACOLOGY

Chemistry

NAC is a thiol containing (R-SH) compound that is deacetylated to cysteine, an amino acid used intracellularly.

The amino acids cysteine glycine and glutamate are used to synthesize glutathione.123

Related Xenobiotics

Cysteamine, methionine, and NAC, which are all glutathione precursors or substitutes, have been used

successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than

NAC, and methionine is less effective than NAC. Therefore, NAC has emerged as the preferred

treatment.110,137,160,162

Mechanism of Action

NAC has several distinct roles in the treatment of APAP poisoning. Early after ingestion when APAP is being

metabolized to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI. After

hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free

radical scavenging, increasing oxygen delivery, increased mitochondrial adenosine triphosphate (ATP)

production, antioxidant effects, and alteration of microvascular tone.

NAC effectively prevents APAP induced hepatotoxicity if it is administered before glutathione stores are

depleted to 30% of normal. This level of depletion occurs approximately 6 to 8 hours following toxic APAP

ingestion.112,120 In this preventive role, NAC acts primarily as a precursor for the synthesis of glutathione.77 The

availability ofcysteine is the rate-limiting step in the synthesis of glutathione, and NAC is effective in

replenishing diminished supplies of both cysteine and glutathione. Additional minor mechanisms of NAC in

preventing hepatotoxicity include acting as a substrate for sulfation,139 as an intracellular glutathione substitute

by directly binding to NAPQI,29 and by enhancing the reduction of NAPQI to APAP.78,135

After NAPQI covalently binds to hepatocytes and other tissues,120 NAC modulates the subsequent cascade of

inflammatory events in a variety of ways.55 NAC may act directly as an antioxidant or as a precursor to

glutathione. Glutathione protects cells against electrophilic compounds by acting as both a reducing agent and

an antioxidant.124 NAC improves oxygen delivery38,55,146,163,164 and utilization in extrahepatic organs such as the

brain, heart, and kidney, probably by improving blood flow in the microvasculature, although the exact

mechanism is unclear.83,133 In addition, NAC increases hepatic mitochondrial ATP production in mice129 and

demonstrates a suppressive action on macrophages, neutrophils, leukocyte endothelial cell adhesion, and

cytokines.75

Pharmacokinetics/Pharmacodynamics

Administered NAC is present in plasma in the reduced or oxidized state and is either free or bound to plasma

proteins or with other thiols and SH groups to form mixed disulfides such as NAC–cysteine.111 NAC has a

relatively small volume of distribution (0.5 L/kg), and protein binding is 83%. NAC is metabolized to many sulfur

containing compounds such ascysteine, glutathione, methionine, cystine, and disulfides, as well as conjugates

of electrophilic compounds, that are not routinely measured.47,105,111 Thus, the pharmacodynamic study of NAC is

complex. In addition, the pharmacokinetics of NAC are complicated based on whether total or free NAC is

being measured.111

Pharmacokinetics of Oral N-Acetylcysteine.

Oral NAC is rapidly absorbed, but its bioavailability is low (10%–30%) because of significant first-pass

metabolism.47,105,111 The mean time to peak serum concentration is 1.4 ± 0.7 hours. The mean elimination half-life

is 2.5 ± 0.6 hours and is linear with increasing dose up to 3200 mg/m2/day given as a single daily dose. Inter-

subject serum NAC concentrations vary tenfold.105 Chronic administration leads to a decrease in plasma

concentrations from a Cmax of 8.9 mg/L (55 µmol/L) at the end of 1 month to 5.1 mg/L (31 µmol/L) at the end of 6

months.105

Conflicting in vitro30,73,127 and in vivo28,45,101,117 data regarding the concomitant use of PO NAC and activated

charcoal suggest that the resultant bioavailability of NAC is either decreased or unchanged. This interaction is

likely of limited clinical importance, and PO or IV NAC can be initiated without concern for activated charcoal

interaction (Chap. 35).

Pharmacokinetics of IV N-Acetylcysteine.

When only free NAC was analyzed, healthy volunteers given 600 mg IV NAC achieved peak serum NAC

concentration of 49 mg/L (300 µmol/L) with a half-life of 2.27 hours compared with a peak serum concentration

of 2.6 mg/L (16 µmol/L) after 600 mg PO.24Serum concentrations after IV administration of an initial loading

dose of 150 mg/kg over 15 minutes reach approximately 500 mg/L (3075 µmol/L).111 A steady-state serum

concentration of 35 mg/L (10–90 mg/L) is reached in approximately 12 hours with the standard IV

protocol.111 Approximately 30% is eliminated renally.

Once in the blood, IV and PO NAC have a similar half-life (2–2.5 hours). This half-life is increased in the setting

of severe liver failure or end-stage kidney disease because of a reduction in clearance.67,100

Intravenous vs. Oral Administration.

As in the case of many issues related to APAP toxicity, the choice of PO versus IV NAC is complex. The

available information suggests that each has advantages and disadvantages, and each may be more

appropriate than the other in certain settings. Because no controlled studies have compared IV with PO NAC,

conclusions about the relative benefit of each are largely speculative.

With the exception of fulminant hepatic failure, for which only the IV route has been investigated, IV and PO

NAC administration are equally efficacious in treating patients with APAP toxicity.114 Some data suggest that IV

NAC may be slightly more efficacious when given less than 12 hours after an overdose and that PO NAC is

significantly more efficacious when given after 16 hours after overdose; however, this study compared patient

groups that differed by decade of treatment and by country. It remains unclear if these differences are true or

clinically relevant.114,172,173 In addition, any difference in outcome for patients who are treated after 16 hours

almost certainly is related to theduration and total dose of NAC therapy rather than the route itself. The decision

of which route to use should depend on the rate of adverse events, safety, availability, and ease of use.

Efficacy should not be a consideration.

Safety is the best understood of these issues. Nausea and vomiting may occur in up to 20% of patients treated

with PO NAC compared to 7% with IV NAC.57 Diarrhea and headache are prevalent, but there is no credible

evidence of more serious complications resulting from PO NAC. Reports of skin rash and unusual

complications are rare.97 In contrast, IV NAC is associated with a 14% to 18%72 rate of anaphylactoid reactions,

although rates of 2% to 6% are reported in retrospective trials.63,68,168,175 Most of these reactions are mild and

include rash, flushing, nausea, and vomiting.10,72,130,140,177Anaphylactoid reactions may be severe in approximately

1% of cases72,94,176 and in rare instances may lead to hypotension and death.7,17,35,68,89,93,106,140,173,174 Anaphylactoid

reactions are attributed to both the dose and concentration of NAC and are caused by a non IgE mediated

release of histamine from mast cells and mononucleocytes.32 APAP inhibits mast cell histamine release;

therefore, a higher APAP concentration at the time of NAC delivery decreases the risk of anaphylactoid

reactions.32,166 The anaphylactoid reaction rate is decreased by using a more dilute NAC solution68,72,175 and by

slowing NAC infusions in some studies.28 In one prospective study, prolongation of the loading infusion from 15

to 60 minutes did not decrease the anaphylactoid rate significantly (from 18% to 14%).48,63,72,88

Minor reactions, such as rash, generally do not require treatment, rarely recur, and do not preclude

administration of subsequent NAC doses.11,140,175,178 Even when urticaria, angioedema, and respiratory symptoms

develop, they usually are easily treated, and NAC can be subsequently restarted with a very low incidence of

recurrence.11,108,130,178Although proper dosing of IV NAC is very safe, it nevertheless must be considered less safe

than PO NAC because of the possibility of severe anaphylactoid reactions, the risk of dosing errors,56,58,98 and

the possibility of incomplete or delayed treatment because of anaphylactoid reactions.63,108

IV NAC is dosed using a complex three-bag preparation system (see Dosing and Administration below) that

has led to an up to 33% error rate including 19% of patients having a greater than 1 hour interruption of

NAC.56 Attempts at simplifying this system are described but have not been adequately studied for general

use67,136 (Table A3–1).

TABLE A3–1. Three-Bag Method Dosage Guide1 for Patients Weighing ≥ 40 kga

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Additional safety concerns have involved dosing for both small children and obese adults. The IV NAC dosing

regimen includes a milligrams per kilogram dose in a fixed water volume, leading to variability of IV NAC

concentration.27,63 This leads to a large solute-free water administration in children, with the potential for

hyponatremic seizures.149 The NAC high concentration in obese adults potentially risks an increased rate of

anaphylactoid reactions. Thus, alternative dosing strategies have been developed for children (constant 3%

concentration)27 and obese adults (ceiling weight of 100 kg; seeDosing).42

The main disadvantage of the NAC PO formulation is the high rate of vomiting and the concern that vomiting

may delay therapy.114 Delays in administration of NAC are correlated with an increased risk of

hepatotoxicity.141 The IV route avoids an increased rate of vomiting in patients who typically are already

nauseated and avoids the use of high-dose antiemetics that may alter mental status.94 A potential disadvantage

of PO NAC is that its absorption may be delayed up to one hour compared with IV NAC.61 Finally, PO NAC

doses may be difficult to administer to patients with altered mental status because of aspiration risks; IV NAC

offers a distinct advantage in these instances.

One theoretical, albeit unproven, advantage of PO NAC early in the course of toxicity is that direct delivery via

the portal circulation yields a higher concentration of NAC in the target compartment of toxicity, the liver.

Because of this first-pass clearance, PO NAC results in circulating NAC 20 to 30 fold lower than after IV

dosing, suggesting that most PO NAC is taken up by the liver.24,61 However, an elevated serum NAC

concentration may be an advantage of IV NAC administration when the liver is not the only target organ of

NAC, such as liver failure accompanied by cerebral edema or in pregnancy.

Several economic analyses have concluded that IV NAC is less expensive than PO NAC,92,93 whereas others

have concluded the opposite.79 However, the majority of cost is associated with length of hospital stay and

since none of these studies have taken into account that many patients treated with PO NAC now receive

shorter courses than 72 hours,19,34 the studies do not represent current use.

Prior to the availability of the current IV formulation in the United States, the PO formulation was used

intravenously with an excellent safety profile41,68,175 and without published evidence of infectious or febrile

consequences.41,68 The IV use for this purpose is not generally recommended, but was historically effective and

necessary in cases in which only the PO formulation was available and the patient had intractable vomiting or

APAP induced fulminant hepatic failure.79

Specific Indications for IV NAC.

In addition to decisions based on cost, duration, safety, and ease of use, three situations exist for which the

available information suggests IV NAC is preferable to PO NAC: (1) fulminant hepatic failure, (2) inability to

tolerate PO NAC, and (3) APAP poisoning in pregnancy. Each of these requires further study for validation, but

all three seem well supported by current information.

Fulminant hepatic failure is an important indication for IV NAC. IV is the only route that has been studied in liver

failure.71 Although PO NAC may be effective, it has not been formally studied. Second, evidence that (some or

all of) the benefit of NAC in liver failure is extrahepatic suggests that IV NAC is preferable.56 IV NAC results in

higher serum NAC concentrations, which presumably leads to more NAC delivery to critical organs. Finally,

concomitant gastrointestinal bleeding, use of lactulose, and other factors make IV NAC more practical.

Common indications for IV NAC are for patients with very high APAP concentrations who are approaching or

are more than 6 to 8 hours from the time of ingestion as well as those who are unable to tolerate PO NAC

following a brief aggressive trial of antiemetic therapy. Use of IV NAC is logical to prevent further delays and

resultant loss of NAC efficacy, even without proof that continued vomiting significantly limits NAC absorption.

The most controversial indication for IV NAC use is during pregnancy. Administration of IV NAC to the mother

has the theoretical advantage of increased delivery to the fetus over PO NAC use. IV administration

circumvents first-pass metabolism, presumably exposing the fetal circulation to higher maternal serum

concentrations. Some studies have suggested that placental transfer of NAC to the fetus is

limited.66,133 However, one case series found that the NAC concentration in cord or neonatal blood after PO

maternal NAC administration equaled the NAC concentration that is achieved in patients treated with PO

NAC.64 Of course, an equivalent serum NAC concentration does not prove adequacy of therapy. Unlike the

neonates studied, patients treated with PO NAC have extensive first-pass hepatic uptake before NAC entry into

the serum, where NAC concentration was measured.24,61 Whether serum NAC concentration in the neonates

studied reflects any significant hepatic NAC delivery is uncertain.

ROLE IN ACETAMINOPHEN TOXICITY

In acute overdose, treatment with NAC should be initiated if the serum APAP concentration is plotted on or

above the treatment line on the Rumack-Matthew nomogram or the patient’s history suggests an acute APAP

ingestion of 150 mg/kg or greater and the results of blood tests will not be available within 8 hours of ingestion.

In patients with chronic APAP ingestions, treatment with NAC should be initiated if either aspartate

aminotransferase (AST) is above normal or the APAP concentration is above 10 µg/mL (Chap. 35).

IV NAC is approved by the FDA for treatment of potentially hepatotoxic quantity of APAP within 8 to 10 hours

following ingestion. The oral formulation is approved for use in a 72 hour protocol for APAP toxicity.

ROLE IN NONACETAMINOPHEN POISONING

Diverse investigations of NAC as a treatment for a number of xenobiotics associated with free radical or

reactive metabolite toxicity are reported. Some of these xenobiotics include acrylonitrile, amatoxins, cadmium,

chloroform, carbon tetrachloride, cyclophosphamide, 1,2-dichloropropane, doxorubicin, eugenol, pulegone,

ricin, and zidovudine.31,44,47,154,155,157,162 NAC has not been studied well enough for any of these xenobiotics in

humans to definitively recommend it as a therapeutic intervention. However, the best evidence supports the

use of NAC in cases of acute exposures to cyclopeptide-containing mushrooms and carbon

tetrachloride.31,47,162 NAC has also decreased cisplatin-induced nephrotoxicity in both rats and human cell

cultures, although in vivo human data are sparse.7,122 NAC may be considered in cases of acute pennyroyal oil

(ie, pulegone) or clove oil (eg, eugenol) ingestions based on their similarities to APAP-induced hepatoxicity.

Both pulegone and eugenol are converted to reactive metabolites that deplete glutathione, leading to

centrilobular hepatic necrosis.153, 154, 155, and 156 NAC may be effective in treating patients with hepatotoxicity from

chronic valproate use, given the evidence that the 2,4-diene valproic acid metabolite acts as an electrophile

and reduces hepatic glutathione. However, there is no evidence that NAC is effective in treating patients with

acute valproate toxicity and no evidence or theoretical efficacy in treating valproate-induced hyperammonemia.

In animal studies NAC increases the excretion of several metals and other elements, including boron,

cadmium, chromium, cobalt, gold, and methylmercury.13,15,31,59 The clinical usefulness of this effect remains

unclear.

NAC has been studied as an oncological chemopreventive and antineoplastic3,36,84,123 as well as for lung

injury,36,37 cardiac injury,143,144 multiorgan failure from trauma and sepsis,52,115,131,145 traumatic brain

injury,14,153,174 chronic obstructive pulmonary disease,148 ifosfamide-induced nephrotoxicity,53 postcardiac

surgery,87 hepatorenal syndrome,62H. pylori infections,88 necrotizing enterocolitis,151 sickle cell disease,102 and

bipolar disorder.18 NAC has extracellular antimutagenic effects, enhances repair of nuclear DNA damaged by

carcinogens, and inhibits malignant cell invasion and metastases.36,104,116 Rescue NAC therapy has been studied

with high-dose APAP (> 20 g/m2) used as chemotherapy in patients with select advanced malignancies.74,169

NAC has been extensively studied to determine its effects on IV contrast-induced nephropathy. Pretreatment

with either PO5,21,25,39,50,70,138,152 or IV12,43,91 formulations has been studied before angiography with mixed results.

Absolute creatinine change in the positive studies remains quite small and is typically below 0.2

mg/dL.51,76 Recent large randomized trials found no reduction in the risk of nephrotoxicity after intravascular

angiographic procedures2 or in emergency department computed tomography,159 and current knowledge

suggests that NAC is ineffective for these indications.51,58,76,103,128

NAC has been studied in the treatment of patients with non APAP-related acute liver failure with mixed results.

In a randomized trial in adults, NAC improved transplant-free survival in early non–APAP-related acute liver

failure (eg, mild encephalopathy), but had no effect in those with severe encephalopathy.81 However, although a

study using historic controls suggests that NAC improves survival in children with non–APAP-related acute liver

failure,75 a randomized study showed no difference in 1 year survival rates and a lower 1 year transplant-free

survival rate, particularly in children younger than 2 years of age.147

NAC has been used for decades in cases of cyclopeptide-containing mushroom poisoning, particularly

poisoning with Amanita phalloides. NAC therapy for amatoxin poisoning is largely based on the similarity of

toxicity of amatoxin to APAP, specifically delayed onset of centrilobular hepatic necrosis. Decreases in

intracellular glutathione stores were identified in isolated rat hepatocytes that were exposed by amanita

extracts,69leading to the reasonable conclusion that supplying the tissue with thiols may decrease toxicity. In

retrospective studies, patients treated with NAC had lower mortality rates than those treated with supportive

care;46 however, in animal studies, NAC has little effect on hepatotoxicity.158

ADVERSE EVENTS AND SAFETY ISSUES

Oral NAC may cause nausea, vomiting, flatus, diarrhea, gastroesophageal reflux, and dysgeusia; generalized

urticaria occurs rarely. Generalized anaphylactoid reactions described following IV NAC

dosing6,17,23,35,49,60,86,90,111,118,161,165 are not noted after PO therapy and may be related to rate, concentration, or high

serum NAC concentrations.16,111

While the IV route ensures delivery, rate-related anaphylactoid reactions occur in up to 18% of patients.72 Most

reactions are mild (6%) or moderate (10%) such as cutaneous reactions, nausea, and vomiting; severe

reactions such as bronchospasm, hypotension, and angioedema are rare (1%).1 Anaphylactoid reactions are

more common in patients with lower [APAP] (25% if APAP < 150 µg/mL) than in those with high [APAP] (3% if

APAP > 300 µg/mL),166 because APAP decreases histamine release from mononucleocytes and mast cells in a

dose-dependent manner.32

If hypotension, dyspnea, wheezing, flushing, or erythema occurs, then NAC should be stopped and standard

symptomatic therapy instituted. After the reaction resolves, NAC can be carefully restarted at a slower rate after

one hour, assuming NAC is still indicated. If the reaction persists or worsens, IV NAC should be discontinued

and a switch to PO NAC should be considered. Adverse reactions, confined to flushing and erythema, are

usually transient, and NAC can be continued with meticulous monitoring for systemic symptoms that indicate

the need to stop the NAC. Urticaria can be managed withdiphenhydramine with the same

precautions.11 Iatrogenic overdoses with IV NAC have resulted in severe reactions, hypotension, cerebral

edema, seizures, and death.1,11,58,90

IV NAC decreases clotting factors and increases the prothrombin time in healthy volunteers and overdose

patients without evidence of hepatic damage.65,85,99,107,167 This effect occurs within the first hour, stabilizes after 16

hours of continuous IV NAC, and rapidly returns to normal when the infusion is stopped.65 International

normalized ratio (INR) elevations are mild and are typically below 1.5 to 2.0. Because the INR is used as a

marker of the severity of toxicity and is one of the criteria for transplantation, this adverse effect of NAC should

always be considered when evaluating the patient’s condition. An elevated INR that remains below 2 without

other indicators of hepatic damage is probably related to the NAC.

SAFETY IN PREGNANCY AND NEONATES

Untreated APAP toxicity is a far greater threat to fetuses than is NAC treatment.33,119 NAC traverses the human

placenta and produces cord blood concentrations comparable to maternal blood concentrations.64 For treatment

of the pregnant patient with APAP toxicity, IV NAC (not PO NAC) has the advantage of assuring fetal delivery

of NAC due to reduction of the first pass metabolism. NAC is FDA Pregnancy Category B.

Limited data exist with regard to the management of neonatal APAP toxicity,9,80,121,134although IV and PO NAC

have been used safely.1,9 No adverse events were observed when preterm newborns were treated with IV

NAC1,4,109 (Chaps. 31 and 35). The elimination half-life of NAC in preterm neonates was 11 hours compared with

5.6 hours in adults.4 When treating neonates, IV administration has the advantage of assuring adequate

antidotal delivery and has been administered without adverse effects.4,109

DOSING AND ADMINISTRATION

The standard IV NAC protocol is a loading dose of 150 mg/kg up to a maximum of 15 g in 200 mL of 5%

dextrose in water (D5W) (for adults) infused over 60 minutes followed by a first maintenance dose of 50 mg/kg

up to a maximum of 5 g in 500 mL D5W (for adults) infused over 4 hours followed by a second maintenance

dose of 100 mg/kg up to a maximum of 10 g in 1000 mL D5W (for adults) infused over 16 hours (6.25 mg/kg/h).

When NAC is administered orally, the patient should receive a 140-mg/kg loading dose either orally or by

enteral tube. Starting 4 hours after the loading dose, 70 mg/kg should be given every 4 hours, for an additional

17 doses, for a total dose of 1330 mg/kg. The solution should be diluted to 5% and can be mixed with a soft

drink to enhance palatability. If any dose is vomited within one hour of administration, then the dose should be

repeated83 or IV delivery used. Antiemetics (eg, metoclopramide, or ondansetron) should be used to ensure

absorption.

Several other regimens, including 48 hours IV, 36 hours IV, 36 hours PO, and 20 hours PO protocols, are

described; however, none of these has been adequately studied for general use34,140,170,176 (Chap. 35).

Conceptually, NAC therapy should be started if the patient is at risk of toxicity, continued as long as is

necessary, and it should be stopped when the patient is no longer at risk of toxicity.171 For a detailed description

of the indications for treating APAP toxicity with NAC, see Chap. 35. Briefly, in acute overdoses (from 4–24

hours after ingestion), NAC therapy should be initiated if the initial APAP concentration falls above the

treatment line of the Rumack-Matthew nomogram. In acute overdoses where the patient arrives more than 24

hours following ingestion, then NAC should be started if the APAP concentration is detectable or if the AST is

elevated. In repeated supratherapeutic ingestions, NAC therapy should be initiated if either the APAP

concentration is detectable or the AST is elevated. For other scenarios, see Chap. 35.

Once the protocol is initiated, an APAP concentration and AST are evaluated prior to the end of the NAC

infusion (20 hours for IV NAC) or at 24 hours (for oral NAC). If the APAP concentration is undetectable and the

AST is normal, then NAC can safely be discontinued. NAC should be continued beyond the “protocol length” if

the APAP concentration remains detectable or the AST is significantly elevated. There are no data to support

what degree of AST elevation should be used as a cutoff for treatment. The NAC protocol should be continued

until the APAP concentration is undetectable, there is no evidence of hepatic failure, and the AST, if it were

elevated, is decreasing. If hepatic failure intervenes, then IV NAC should be administered at the dose of the

“third bag” (16 hour infusion of 6.25 mg/kg/h) and continued until the patient has a normal mental status (or

recovery from hepatic encephalopathy)55 and the patient’s INR decreases below 2.0119 or until the patient

receives a liver transplant.26,54,71

For the rare patient who ingests exceptionally large doses of APAP, or who has prolonged and significantly

elevated APAP concentrations, consideration should be given to treating with greater amounts of NAC once

prolonged, massive APAP concentrations are evident.40,133,143 The rationale for increasing NAC dosing include

that the IV infusion rate (6.25 mg/kg/h) was derived to treat a 16 g ingestion of APAP.124 While it is effective for

most patients who ingest APAP, an ingestion that is several times larger than 16 g may require additional NAC.

In addition, published cases of patients who have developed hepatotoxicity despite early NAC therapy have

ingested more than 16 g of APAP and been treated with the IV (6.25 mg/kg/h) infusion.40,132,142 There are no

reported early NAC failures with the PO protocol.

No data exist to determine which, if any, alternative NAC dosing strategy is effective; however, it seems

reasonable to increase NAC dosing if the hepatic exposure to APAP (and therefore NAPQI) is prolonged and

massive. Several strategies have been theorized, but none have been studied. Potential strategies include:

1. Using the oral protocol for high-risk patients who can tolerate oral NAC

2. Administer both oral NAC and IV NAC simultaneously, an approach that increases initial loading and

total doses

3. Base the IV NAC dosing on the ingestion size or [APAP]:121

a. If the ingestion is between 16 and 32 g, or the initial [APAP] is between the “300 line” and the

“500 line,” then consider using 12.5 mg/kg/h as the 16 hour infusion rate.

b. If the ingestion is between 32 and 48 g, or the initial [APAP] is above the “500 line,” then

consider using 18.75 mg/kg/h as the 16 hour infusion rate.

c. If the ingestion is greater than 48 g, then consider using 25 mg/kg/h as the 16 hour infusion rate.

Your poison control center can help with the most current information (1-800-222-1222).

There are no specific dosing guidelines for patients who are obese. However, it may be reasonable to limit PO

and IV NAC dosing using a maximum weight of 100 kg. This maximum limit is not based on experimental

evidence; however, patients who are larger than 100 kg have an equivalent hepatic volume and similar

ingestion amounts as patients who weight less than 100 kg. Although dosing with a maximum weight is logical,

it has not yet been adequately studied in obese humans.

Previously dosing information for IV NAC was unavailable for patients weighing less than 40 kg, and problems

with osmolarity, sodium concentrations, and fluid requirements became apparent when improper dilutions were

used. The package insert now gives specific information for dosing in these patients (Table A3–2).

TABLE A3–2. Three-Bag Method Dosage Guide by Weight for Patients Weighing < 40 kga

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The IV dosing of NAC is complicated because three different preparations must be prepared with each based

on weight. A retrospective study estimated that there was a 33% medication error rate in the preparation and

delivery of IV NAC.56 To limit these errors, Tables A3–1 and A3–2 from the package insert, which give the

appropriate doses and dilutions for adults and patients weigh less than 40 kg.1 In addition, the following web

site has a dosage calculator: http://acetadote.com/dosecalc.php.

FORMULATION

NAC is available as a 20% concentration in 30 mL single-dose vials designed for dilution before IV

administration. NAC for PO administration is available in 10 mL vials of 10% and 20% for PO administration

and should also be diluted before administration.

SUMMARY

NAC is the primary antidote for APAP toxicity.

Limited evidence also supports NAC use in cyclopeptide containing mushroom toxicity (eg, Amanita

phalloides), carbon tetrachloride, and pulegone toxicity (pennyroyal oil).

NAC should be started if there is significant risk of toxicity and stopped when the risk of toxicity is gone

and any toxicity that had occurred is resolving.

Oral and IV NAC have essentially equivalent efficacy.

IV NAC has approximately an 18% risk of anaphylactoid reactions, most of which are mild, and oral

NAC has a 20% risk of vomiting.

Higher doses of NAC should be considered for cases of massive ingestion or cases in which a

prolonged high concentration of APAP is present.

Acknowledgment

Martin Jay Smilkstein, MD, contributed to this Antidote in Depth in a previous edition.

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