A3: Antidotes in Depth

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}

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 groups^{96,112,113,126} 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.

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 of cysteine 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 ­delivery^{38,55,146,163,164} 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 as cysteine, 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 C_max 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 vitro^30,73,127 and in vivo^{28,45,101,117} 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.²⁴ Serum 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 the duration 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.^{10,72,130,140,177} Anaphylactoid reactions may be severe in approximately 1% of cases^72,94,176 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 solution^68,72,175 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.^{11,108,130,178} Although 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 use^67,136 (Table A3–1).

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; see Dosing).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 profile^41,68,175 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.

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.

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 antineoplastic^3,36,84,123 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 PO^{5,21,25,39,50,70,138,152} or IV^12,43,91 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,⁶⁹ leading 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

Oral NAC may cause nausea, vomiting, flatus, diarrhea, gastroesophageal reflux, and dysgeusia; generalized urticaria occurs rarely. Generalized anaphylactoid reactions described following IV NAC dosing^{6,17,23,35,49,60,86,90,111,118,161,165} 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 with diphenhydramine 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.

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,^9,80,121,134 although IV and PO NAC have been used safely.^1,9 No adverse events were observed when preterm newborns were treated with IV NAC^1,4,109 (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

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 use^{34,140,170,176} (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

   1. 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.

   2. 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.

   3. 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).

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.

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.

• 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.

References