a) There is some debate as to the effect of coingestion of medications that decrease gastrointestinal motility (anticholinergic and opioids) may have on the reliability of a 4-hour acetaminophen concentration for risk stratification. Some experts recommend obtaining a second acetaminophen concentration 8 hours postingestion and starting acetylcysteine if either concentration is above the possible toxicity line. Similar recommendations have been made regarding sustained-release acetaminophen products.

a) Patients who present early following a massive ingestion (serum acetaminophen concentration greater than 500 mcg/mL) may have coma, metabolic acidosis, and hyperglycemia with normal serum transaminases. These patients generally recover with supportive care (airway management, fluid resuscitation) and early acetylcysteine therapy.

a) Acetylcysteine should be administered to any patient at risk for hepatic injury (either serum acetaminophen concentration above the possible toxicity line on the Rumack-Matthew Nomogram, or history of ingesting more than 150 mg/kg and serum concentration not available or time of ingestion not known) and to patients who have hepatic injury and a history of acetaminophen overdose.
b) ORAL: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours. The FDA-approved protocol is for 72 hours (17 maintenance doses); however, many toxicologists will stop therapy early in patients who do not develop toxicity and continue therapy beyond 72 hours for patients who develop significant toxicity. Please contact your local poison center for guidance.
c) INTRAVENOUS: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion. The FDA-approved protocol is for 16 hours of treatment at 6.25 mg/kg/hr (a total of 100 mg/kg). However, many toxicologists recommend checking serum transaminases and serum acetaminophen concentration prior to stopping therapy. If the transaminases are elevated or if the serum acetaminophen concentration is still detectable, the maintenance infusion is often continued until acetaminophen is not detectable and liver enzymes and INR are improving, and the patient is clinically improving. Contact your local poison center for guidance.
d) LIVER FAILURE: Treat patients with liver failure with intravenous acetylcysteine 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion until resolution of encephalopathy, decreasing serum transaminase, and improving coagulopathy.

a) There is no specific antidote.

a) EVALUATION: Failure to determine an accurate time of ingestion can result in patients being misclassified for their risk of liver injury. Failure to consider the possible effects of anticholinergic medications or opioids on the accuracy of the 4-hour acetaminophen concentration for risk stratification.
b) TREATMENT: Failure to decontaminate patients who are less than 2 hours post ingestion. Ending treatment for patients who have elevated transaminases or detectable serum acetaminophen concentrations.

a) The Done nomogram is not useful, it can both overestimate and underestimate the severity of toxicity.
b) Single determinations of salicylate levels are not sufficient because absorption may be delayed and erratic. Do not discharge patients unless it is clear that serial salicylate concentrations are declining.
c) Sedation or intubation of a patient compromises the patient's own respiratory drive, and has been associated with abrupt decompensation, likely due to worsening metabolic acidosis and increasing the salicylate concentration in the CNS. If the patient requires intubation, it is imperative that respiratory alkalosis be maintained.
d) Hypokalemia will interfere with urinary alkalinization (potassium reabsorbed and hydrogen ion excreted in renal tubules) and needs to be corrected for urinary alkalinization to be successful. In young children, the initial respiratory alkalosis from salicylate intoxication is transient, they often have a predominant metabolic acidosis (and in severe cases also respiratory alkalosis) on presentation.

a) TOXICOLOGIC: Carbon tetrachloride, hepatotoxic mushrooms, halothane, idiosyncratic drug reactions, pennyroyal oil, or iron. OTHER: Shock liver, viral hepatitis

a) The differential diagnosis includes conditions that present with an anion gap metabolic acidosis (e.g., iron, methanol, isopropanol, sepsis, alcoholic ketoacidosis). Salicylate toxicity should also be considered in elderly patients with an altered mental status.

a) ACETAMINOPHEN

a) SALICYLATE

a) BENORILATE: Dizziness has been reported with benorilate therapy (Sweetman, 2002).

a) BENORILATE: Tinnitus and hearing loss have occurred with benorilate, and have been related to high serum salicylate concentrations (Aylward, 1973; Hingorani, 1973; Hope-Simpson, 1973).

a) BENORILATE: Drowsiness has been reported with benorilate therapy (Sweetman, 2002).

a) BENORILATE: Disorientation has been reported with benorilate therapy (Sweetman, 2002).

a) Rebound headache is reported as a potential adverse effect of products containing acetaminophen, aspirin, and caffeine (ie, such as Excedrin Migraine) when taken frequently, then abruptly discontinued. Additionally, overuse of these products may result in headaches (Evans, 1999).

a) ACETAMINOPHEN: Coma and metabolic acidosis have been reported within 3 to 4 hours of acetaminophen overdose in the absence of hepatotoxicity or co-ingestants. These occurred in patients with extremely large ingestions (75 to 100 g in adults and 10 g in a 1-year-old boy) and/or extremely high plasma acetaminophen concentrations (over 800 mcg/mL at 4 to 12 hours postingestion) (Flanagan & Mant, 1986) (Zezulka & Wright, 1982) (Leih-Lai et al, 1984; Kadri et al, 1988). Other causes of acidosis should be ruled out.
b) SALICYLATES: Confusion, coma, and seizures may develop in serious poisonings (Posner & Plum, 1967; Done, 1960). Coma following an altered mental status may be delayed 24 to 48 hours following chronic salicylate poisoning (Dove & Jones, 1982).

a) SALICYLATES: Extreme muscle rigidity has been described in 3 patients who expired from salicylism (McGuigan, 1987).

a) SALICYLATES: Asterixis has been noted in patients receiving chronic excessive salicylate therapy for rheumatoid arthritis (Anderson, 1981). Asterixis may occur in the absence of tinnitus.

a) SALICYLATES: Cerebral edema was found in 31% of fatal cases in a series of 177 salicylate poisonings (Thisted et al, 1987).

a) Nausea, indigestion, and heartburn have all been reported with benorilate (Sweetman, 2002). It reportedly causes less gastric irritation and occult blood loss than aspirin (Wright, 1976; Hanks, 1985).
b) Danhof et al (1972) found that benorilate in doses of 4 and 8 g/day for 28 days caused no significant increase in fecal blood loss compared to controls in 12 healthy volunteers.

a) BENORILATE: Constipation has been reported with benorilate therapy (Sweetman, 2002).

a) CASE REPORT/BENORILATE: Watery diarrhea was reported in a 67-year-old woman receiving benorilate 1600 mg 5 times a day for rheumatoid arthritis. The patient experienced colicky abdominal pain within 10 minutes of taking a dose, followed by the urge to defecate 5 minutes later. Symptoms resolved promptly upon discontinuation of therapy (Marshall & Sheridan, 1973).

a) SUMMARY: The risk of serious upper gastrointestinal tract bleeding or perforation, as shown in epidemiological studies, increases approximately 2-fold with the use of low dose chronic aspirin; the risk is also increased following daily doses of acetaminophen 2000 mg and higher. The risk is dose-dependent with each drug, with a greater risk following the combined use of acetaminophen and aspirin (Garcia-Rodriguez & Hernandez-Diaz, 2001).

a) CASE REPORT/SALICYLATES: Gastric perforation has been reported after an aspirin ingestion in a 65-year-old woman without evidence of previous peptic ulcer disease (Robins et al, 1985). A 48-year-old woman without previous renal or GI complaints developed renal failure and perforated peptic ulcer after an acute aspirin ingestion (Christensen & Schmidt, 1987).
b) CASE SERIES: In Malaysia, an analgesic powder, "Chap Kaki Tiga", containing 53% aspirin and 27% acetaminophen and 20% caffeine in the old formulation, or 600 mg aspirin only in the new preparation, has resulted in upper gastrointestinal hemorrhages following regular chronic use. Sixty-eight patients with a history of Chap Kaki Tiga ingestion were reported with upper GI hemorrhage. Four of these patients developed perforated gastric ulcers. All patients were administered hematinics and H2 receptor antagonists (See, 1996).

a) ACETAMINOPHEN

a) PEDIATRIC

a) SALICYLATE

a) SUMMARY

a) BENORILATE

a) ACETAMINOPHEN

a) SALICYLATES: Oliguric renal failure has been reported secondary to rhabdomyolysis (Leventhal et al, 1989).

a) An Ad Hoc Committee of the International Study Group on analgesics and nephropathy, following review of extensive epidemiologic data on the relationship of nonphenacetin combined analgesics, concluded that sufficient evidence was lacking to associate combination analgesics, including acetaminophen with aspirin, with an increased risk of nephropathy over single agent formulations (Feinstein et al, 2000).

a) Metabolic acidosis has been reported within 3 to 4 hours of acetaminophen overdose in the absence of hepatotoxicity or co-ingestants

a) Acid-base disturbances vary with age and are a combination of metabolic and respiratory effects.
b) Salicylate toxicity may be grouped into 3 stages of intoxication, based on plasma and urine pH (Hall & Rumack, in press).
c) In STAGE 1, hyperventilation due to direct respiratory center stimulation produces a respiratory alkalosis. A compensatory renal excretion of potassium, sodium, and bicarbonate results in an alkaline urine pH (greater than 6) and an alkaline plasma pH (greater than 7.4).
d) In STAGE 2, the plasma pH remains alkaline, with a compensatory metabolic acidosis. As potassium becomes depleted intracellularly, hydrogen ions are excreted, resulting in an acidic urine pH (less than 6).
e) In STAGE 3, potassium and bicarbonate depletion are nearly complete and a shift in hydrogen ion to the extracellular space results in an acidic plasma pH and acidic urine pH, as the kidney is excreting H+ instead of K+.

a) Both acute and chronic intoxications usually present with a picture of mixed respiratory alkalosis and metabolic acidosis (Anderson et al, 1976; Gabow et al, 1978).
b) The blood is often alkalemic with the pH greater than 7.4 despite a very low serum bicarbonate. Severe acidosis may not occur until 12 to 24 hours following an acute ingestion (Temple, 1978).
c) Persistent alkalosis is common in adults and severe persistent acidosis complicates the pediatric overdose.
d) In children, acidosis (pH <7.32) was noted more frequently in those who were chronically poisoned compared to acute intoxication (Gaudreault et al, 1982).

a) This was seen in 16 patients admitted within 15 hours of overdose with plasma acetaminophen concentrations above the treatment decision line (200 mg/L at 4 hours to 30 mg/L at 15 hours).

a) ACETAMINOPHEN: Thrombocytopenia was reported in patients who ingested the following amounts:

a) In a series of 160 subjects administered acetaminophen for 1 week, no evidence of methemoglobinemia was found (Rumack & Matthew, 1975).

a) CASE REPORT: Diffuse myalgias and a peak CPK concentration of 36,200 IU/L were reported in a 42-year-old woman after ingestion of 40 g of aspirin. Oliguric renal failure subsequently developed. No hyperthermia was noted (Leventhal et al, 1989).
b) Rhabdomyolysis has also been noted in combination drug overdoses involving aspirin (Skjoto & Reikvam, 1979; Bismuth et al, 1972).

a) ACETAMINOPHEN: Hyperglycemia is uncommon following acetaminophen overdosage. Acetaminophen appears to interfere with the blood glucose measurement using a yellow springs instrument glucose analyzer (YSIGA) resulting in a falsely elevated blood glucose level.
b) SALICYLATE: Hyperglycemia may be seen in the severely salicylate poisoned patient (Done & Temple, 1971).

a) SUMMARY: Hypoglycemia is more common in children and in chronic salicylate ingestions.
b) CASE REPORT: A 72-year-old man with psoriasis and renal failure developed refractory hypoglycemia associated with topical application of a cream containing 10% salicylic acid to over 90% of his body surface area twice daily for 1 month. The patient had a serum salicylate concentration of 44 mg/dL (3.2 mmol/L) (Raschke et al, 1991).

a) ACETAMINOPHEN HYPERSENSITIVITY REACTIONS: A series of 5 cases of hypersensitivity reactions in Europe have been reported in adults who ingested 500 to 1000 mg of acetaminophen and developed the following symptoms within 15 minutes to 1 hour: bronchospasm (3), urticaria (4), hypotension (1), and collapse (1) (Stricker et al, 1985).

a) Studies have shown the ability of fetal and neonatal liver cells to oxidize drugs during the first part of gestation and to form reactive metabolites which could cause liver damage (Rollins et al, 1979). Therefore, the human fetus may be at risk from acetaminophen overdose.
b) CONCLUSION - It is recommended that treatment with oral NAC be given to pregnant APAP overdose patients as soon as possible after the overdose and that delivery NOT be induced before the protocol is completed (Riggs et al, 1989).
c) CASE REPORT - A woman at 36 weeks gestation ingested 22.5 g acetaminophen (resulting in a 4 1/2 hour postingestion acetaminophen blood level of 200 mcg/mL) (1323.2 mcmol/L) and was started on and completed the N-acetylcysteine protocol.
d) PROSPECTIVE STUDY - A study of 113 cases of APAP overdose in various stages of pregnancy could not demonstrate malformation from either APAP or NAC treatment.
e) CASE REPORT - A woman who ingested 64 grams of APAP at 15 weeks gestation and who was treated with NAC 20 hours postingestion, developed severe liver toxicity but recovered. A normal infant was delivered at 32 weeks gestation (Ludmir et al, 1986).
f) SURVEY - A questionnaire-directed survey conducted among medical and healthcare personnel inquiring about drug intake of pregnant patients concluded that paracetamol overdose per se is not necessarily an indication for termination of pregnancy (McElhatton, 1990).

a) Salicylate readily crosses the placenta and chronic maternal ingestion may be associated with an increased incidence of stillbirths, antepartum and postpartum bleeding, prolonged pregnancy and labor, and lower birth weight infants (Corby, 1978).
b) There is no conclusive evidence that salicylate is teratogenic but large doses taken near or at term have resulted in mild salicylism in the neonate (Lynd et al, 1976; Garrettson et al, 1975).
c) Rumack et al (1981) demonstrated an increased incidence of intracranial hemorrhage in infants whose mothers had ingested aspirin during the last week of pregnancy.
d) In a case control study reported by Stuart et al (1982) maternal ingestion of aspirin within 5 days of delivery resulted in hemostatic abnormalities in both mother and offspring.
e) CASE REPORT - A 27-year-old severely schizophrenic, bulimic woman admitted to occasional analgesic use during pregnancy. Salicylate levels on cord and maternal blood at the time of delivery were found to be 61 mg/dL and 53 mg/dL, respectively.
f) CASE REPORT - A 22-year-old woman, 8 months pregnant, ingested 32.5 g of aspirin. She presented with tinnitus, emesis, and hyperventilation. Fetus had normal cardiac sounds. Fetal movements were evident at 15 hours post admission, but not at 20 hours post admission.
g) In a longitudinal prospective study in 1974-5, aspirin was taken by 46% of women during the first half of pregnancy.

a) CONCLUSION - Maternal ingestion of recommended doses of acetaminophen does not appear to present a risk to the nursing infant.
b) Acetaminophen appears to partition into the milk of lactating mothers with peak concentrations of 10 to 15 mcg/mL one to two hours following a single maternal oral dose of 650 mg (Berlin et al, 1980).

a) Maternally ingested salicylates are excreted in the breast milk with peak levels lower than those for plasma (Anderson, 1977); therapeutic doses of aspirin during the breast feeding period is considered safe (Findlay et al, 1981).

a) In one study serum acetaminophen levels drawn less than 4 hours after overdose were useful in predicting need for NAC therapy. At acetaminophen levels greater than 200 mg/L, NAC therapy was needed; at levels less than 200 mg/L, NAC was not needed (Paloucek & Gorman, 1992).
b) In another study, an acetaminophen level of less than 100 mcg/mL drawn between 2 and 4 hours after ingestion had a negative predictive value of .98 when compared with an acetaminophen level drawn 4 hours or more after ingestion (Douglas et al, 1994). Further studies are needed before acetaminophen levels drawn before 4 hours can be used to guide therapy.

a) An initial plasma acetaminophen level should be drawn 4 or more hours postingestion and plotted on the nomogram. An additional level should be drawn 4 to 6 hours after the first level and plotted on the nomogram. If either level is above the possible risk treatment line on the Rumack-Matthew Nomogram, an entire course of NAC should be administered or, if initiated, completed. If both levels are below the possible risk treatment line, then NAC therapy may be withheld or, if initiated, discontinued.
b) For assistance with ingestions of Tylenol Extended Relief(R) please call the Rocky Mountain Poison Center, toll free, at 1-800-525-6115.

a) Cp4h (in mcg/mL) = (0.59) (mg/kg dose)

a) The acetaminophen nomogram determines the need for specific antidote therapy. It is used to interpret a single plasma level obtained 4 to 24 hours after a single acute ingestion. Levels obtained before 4 hours or after 24 hours cannot be interpreted, nor can levels obtained after chronic or repeated ingestion.
b) A level above the lower or "treatment" line predicts risk for delayed hepatotoxicity and the need for the full NAC treatment regimen.
c) CAUTIONS FOR USE: This nomogram is to be used in conjunction with the POISINDEX(R) Acetaminophen Management.

a) In one study of 2534 patients treated with NAC, a half-life of greater than 4 hours had a positive predictive value of 0.22 and a negative predictive value of 0.96 in predicting peak AST greater than 1000 International Units/L (Douglas et al, 1994). A level above the possible toxicity line had a positive predictive value of 0.15 and a negative predictive value of 0.98 in the same group of patients. Half-life determination offers no advantage over obtaining a single level.

a) Additional levels should be drawn every 2 to 4 hours to assure declining levels. Concretions of aspirin or sustained release or enteric coated preparations may not reach peak levels until 24 hours postingestion (McGuigan, 1986).
b) DELAYED RELEASE: Overdosage with sustained released salicylate preparations will result in prolonged absorption and sustained plasma levels. In one case the serum salicylate level did not peak until 24 hours after the overdose, despite emergency treatment within a hour (Wortzman & Grunfeld, 1987a).

a) Follow renal and hepatic function tests in moderate and severe salicylate poisoned patients until the serum salicylate concentration is consistently falling.

a) The Done's nomogram has been shown to underestimate and overestimate toxicity after salicylate ingestion (Surapathana et al, 1970; McGuigan, 1986; Dugandzic et al, 1989). Its use cannot be recommended.

a) TRANSAMINASE LEVELS: ALT/SGPT and AST/SGOT may rise within 24 hours after ingestion and peak within 48 to 72 hours (Singer et al, 1995). Levels over 10,000 units/L are common.
b) BILIRUBIN: Plasma bilirubin may begin to rise within 24 hours of ingestion (Singer et al, 1995); peak level seldom exceeds 10 mg/dL.
c) ALBUMIN: Serum prealbumin concentrations decrease significantly after 36 hours and continue to decrease during liver failure, providing a true index of liver function (Hutchinson et al, 1980).
d) BLOOD GLUCOSE: Hyperglycemia is rare. Acetaminophen interferes with yellow springs instrument glucose analyzer giving falsely elevated concentrations (Farah, 1982). Acetaminophen can also elevate blood glucose concentrations determined using the Glucometer Elite and Accu-check advantage glucose meters (Cartier et al, 1998). An alternative method of blood glucose measurement should be employed before starting insulin therapy (Linden & Rumack, 1984).
e) Hypoglycemia may be seen 2 to 4 days postingestion with severe overdoses and hepatic failure.
f) ALPHA-FETOPROTEIN: Serum alpha-fetoprotein (AFP) has been commonly used as a marker of hepatocellular carcinoma. A prospective study was conducted, involving 239 patients with acetaminophen poisoning and an ALT level greater than 1000 Units/L. On the day of the peak ALT level, an increase in the AFP above 4 mcg/L occurred in 158 of 201 survivors (79%) compared with 11 of 33 non-survivors (33%), and, on day 1 after the maximum ALT levels, AFP values were significantly higher in survivors compared with non-survivors (9.2 +/- 9 mcg/L vs 2.4 +/- 0.8 mcg/L, respectively). The results of this study showed that serum AFP levels may be a strong prognostic indicator of outcome in the setting of acetaminophen-induced hepatotoxicity (Schmidt & Dalhoff, 2005).
g) SERUM PHOSPHATE: Although there have been reports that serum phosphate levels may be used as an early predictor of clinical outcome in patients with paracetamol-induced fulminant hepatic failure, a retrospective analysis was conducted to determine serum phosphate's predictive value in the setting of paracetamol-induced hepatotoxicity. The results of the study showed that serum phosphate concentrations were significantly higher in non-survivors or transplanted patients than in survivors on day 2 post-overdose (1.32 +/-1.06 mmol/L vs 0.66 +/-0.26 mmol/L, respectively), but not on day 3 (0.98 +/-0.81 mmol/L vs 0.64 +/-0.38 mmol/L, respectively), indicating that serum phosphate concentration is not a useful early predictor of outcome in paracetamol-induced hepatic failure (Ng et al, 2004).
h) RENAL FUNCTION TESTS: Renal insufficiency may develop 2 to 4 days after toxic ingestion, peak levels of BUN and creatinine may be delayed 7 to 10 days (Murphy et al, 1990). Generally, renal and hepatic toxicity develop concurrently; renal injury rarely develops alone (Campbell & Baylis, 1992). Hyperphosphatemia (greater than 1.2 mmol/L), occurring 48 to 96 hours after the overdose, and in the presence of both renal and hepatic dysfunction, is a poor prognostic indicator (Schmidt et al, 2002).
i) AMYLASE: Hyperamylasemia may develop 2 to 3 days following toxic ingestions with hepatic injury (Gilmore & Touvras, 1977a; Caldarola et al, 1985; Hord et al, 1992).
j) A variety of biochemical markers (ie, hemoglobin, pyruvate, calcium, and phenylalanine levels) were identified and combined to form a prognostic model that, when applied to patients at hospital admission, appeared to accurately predict the outcome of patients with fulminant hepatic failure. The prognostic tool was derived used a cohort of 97 patients and prospectively validated with a second cohort of 86 patients admitted to the Scottish Liver Transplant Unit for acetaminophen-induced fulminant hepatic failure. Hemoglobin, pyruvate, and phenylalanine levels were significantly lower in patients who either subsequently died or underwent transplantation compared with patients who spontaneously survived. This prognostic model of outcome in acetaminophen-induced fulminant hepatic failure appears to be as accurate a predictor as utilizing King's College Hospital criteria, but at an earlier stage of the patient's condition (Dabos et al, 2005).
k) ARTERIAL LACTATE: Hyperlactatemia has been suggested as a prognostic indicator in acetaminophen-induced fulminant hepatic failure and for possible inclusion as a modification to the King's College Hospital (KCH) criteria. A prospective study, conducted to determine whether arterial lactate measurements are valuable as a prognostic marker, showed that, although hyperlactatemia occurred more frequently in non-survivors than in survivors at admission (9.8 +/-6.5 mmol/L vs 5.2 +/- 4.2 mmol/L; p=0.00004) and at onset of hepatic encephalopathy (6.9 +/-5.6 mmol/L vs 3.2 +/-2 mmol/L; p less than 0.00001), adding arterial lactate measurements as a modification to the KCH criteria increased its sensitivity but reduced its specificity to less than 50%, indicating that this modification is not better than the existing KCH criteria (Schmidt & Larsen, 2006).

a) Obtain an arterial blood gas in symptomatic patients and follow until acid base abnormalities are improving.

a) Acetaminophen does not interfere with the prothrombin time assay (Van der Steeg et al, 1995).

a) Early elevations of aminotransferases and glutathione-S-transferase (GST) were the most sensitive and specific predictors of hepatotoxicity in a prospective study of patients treated with the 20-hour intravenous NAC protocol. Acetaminophen half-life and prothrombin time ratio were less reliable predictors (Donovan, 1987a).
b) GST is a more sensitive early predictor of moderate to severe liver damage and minor acute liver injury than is ALT/SGPT. F protein is intermediate between the 2 (Beckett et al, 1989).
c) A normal initial PT was a good predictor of favorable outcome (peak AST less than 1000 Units/L) in a series of 190 NAC treated acetaminophen overdose patients (Van der Steeg et al, 1995a).

a) Salicylates (Mace & Walker, 1979) (Reed et al, 1982), salicylamide (Chafetz et al, 1971), levodopa, methyldopa, dopamine, epinephrine (Andrews et al, 1982), and possibly cresol (Pitts, 1979) have been reported to interfere with colorimetric determination of acetaminophen levels, resulting in falsely elevated concentrations.
b) GLUCOSE: Acetaminophen may interfere with the blood glucose determination using a yellow springs instrument glucose analyzer (YSIGA) resulting in a falsely elevated blood glucose (Farah, 1982).
c) DIGOXIN: Serum digoxin-like immunoreactive substance levels which correlated with serum creatinine levels were found (mean 0.53 +/- 0.19 nanograms/ml) in 31 patients with acute acetaminophen overdose (Yang et al, 1988).
d) Acetaminophen may interfere with blood lactate measurements performed by certain blood gas analyzers. Blood acetaminophen level of 75 mcg/mL increased lactate levels by 20% using the Nova Stat Profile 9 analyzer and by 30% using the Ciba Corning Diagnostic 860 analyzer (Lacoma et al, 1997).
e) FALSE POSITIVE ETHYLENE GLYCOL results were obtained in 3 cases of fulminant hepatic failure due to chronic acetaminophen abuse with the use of the ethylene glycol assay by glucose dehydrogenase enzyme technique. The authors speculate the false positive results are probably due to increased LDH and/or lactate associated with liver failure and acidosis (Wax et al, 1999).
f) FALSE POSITIVE ACETAMINOPHEN levels may result in cases of unexplained liver failure in jaundiced patients (bilirubin levels >25 mg/dL) using the GDS Diagnostic Assay (acetaminophen not present by gas chromatography/mass spectometry (GC/MS)). Elevated serum bilirubin level was associated with measurable acetaminophen concentrations (178 mg/L) using the GDS Diagnostics assay in when acetaminophen was not detectable by GC/MS (Beuhler et al, 2002).
g) SALICYLATE: Laboratory interference with a dry reagent assay (Vitros analyzers) used for salicylate assays is reported, with false increases of salicylate values by as much as 5% to 10% with concurrent acetaminophen usage (Osterloh, 1998).

a) Diflunisal may falsely elevate salicylate levels measured by the TDx(R) fluorescence polarization immunoassay, DuPont aca method or the Trinder colorimetric assay (Duffens et al, 1987).
b) Salicylate may falsely elevate serum carbon dioxide levels using the Technicon RA-1000 system (Shkrum et al, 1989).
c) FALSE POSITIVE TOXIC SERUM SALICYLATE LEVEL: A 45-year-old male with type II diabetes presented with a complaint of weakness and a report of only occasional aspirin use. Neuro exam was normal. Laboratory exam included a serum salicylate of 116.1 mg/dL, serum glucose 534 mg/dL, cholesterol 618 mg/dL and triglycerides 11,004 mg/dL. The blood was visibly lipemic. Post dialysis serum salicylate level was 115.9 mg/dL. A Trinder test on biological fluids was then performed and was found to be negative, and a urine salicylate level was also negative. The authors concluded that the elevated serum salicylate level was likely caused by interference from severe hypertriglyceridemia (Tuckler et al, 2001).
d) PSEUDOHYPERCHLOREMIA: Harchelroad (2008) reported falsely elevated chloride levels in 2 patients admitted for apparent salicylate overdose. Both presented with serum electrolytes and blood gas values that were consistent with acute respiratory alkalosis with metabolic compensation. However, serum chloride concentrations of 174 mEq/L and 146 mEq/L with salicylate concentrations of 8.1 mg/L and 4.5 mg/L, respectively were observed in these patients. Based on previous work, salicylates have been shown to produce falsely elevated chloride levels based on a linear relationship between chloride values and salicylate concentrations. In this report, falsely elevated chloride levels based on another cause were suspected, due to the magnitude of the increase. Previous reports of potentially interference using the Integra 800 ISE have been reported in the literature, and the manufacturer has suggested that the interaction may be due to the "age" of the electrode used. It has been suggested that the chloride ISE should be changed as frequently as every 4 weeks depending on use. The chloride electrodes had been used for at least 5 weeks using the Roche Cobas Integra 800 ion-selective electrode module in this institution (Zimmer et al, 2008).

a) Hematuria and proteinuria may develop with renal injury.

a) A qualitative urine acetaminophen screen (thin- layer chromatography) was compared to a qualitative serum acetaminophen screen in 88 patients following intentional ingestions. It was found that a negative urine acetaminophen was highly predictive of negative serum acetaminophen levels. The authors suggested that a negative urine screen may obviate the need for 4 hour quantitative serum levels. However, further validation is required (Perrone et al, 1999).

a) In a study of 155 patients with suspected salicylism or unexplained respiratory alkalosis and/or metabolic acidosis, the ferric chloride test had a sensitivity of 93.8%, a specificity of 75.4% and a negative predictive value of 98.4% in detecting salicylate in urine in patients with serum salicylate levels of 30 mg/dL or higher (Ford et al, 1994).
b) In a prospective study to evaluate and compare ferric chloride (FC) and Trinder reagent (TR) for the detection of ASA in urine samples, 180 patients with suspected overdose had a serum ASA measured. Of the 20 patients with an ASA concentration above 5 mg/dL (lowest detectable concentration), both reagents were 100% sensitive. Specificity of TR was 73% as compared to 71% for FC. Similar results were reported in 91% of cases for both reagents. A number of cases of false positive results (similar in both groups) were reported and may have been due to the presence of phenothiazines (especially chlorpromazine and thioridazine) or acetoacetate, a ketone. Despite similar findings between the reagents, the authors concluded that FC may be a more practical (i.e., longer shelf life) for use in the Emergency Department. Further study is suggested (Weiner et al, 2000).
c) In a descriptive study to assess the reactivity of ferric chloride with various commercially available salicylate-containing products (ie, regular and buffered acetylsalicylic acid, bismuth subsalicylate, methyl salicylate, physostigmine salicylate, salicylic acid, trolamine salicylate, and herbal tablets with salicin-containing willow bark (Salix sp.)), ferric chloride correctly identified each product as containing salicylate by 3 independent physician reviewers (Hoffman et al, 2002). Limitations of the study include a lack of testing of water-insoluble salicylate-containing products (e.g., salicylate in oil or an emulsion).

a) ECG

1) Colorimetric analysis may be reliable when performed by persons regularly engaged in this assay and who understand associated limitations (ie, assay range, interfering drug/substances, etc).
2) In certain circumstances the colorimetric assay, when performed by an experienced person, may be linear and accurate when the level is greater than 50 mcg/mL (330.8 mcmol/L).
3) Inaccuracies occur when the colorimetric assay is performed by inexperienced personnel and generally occurs outside the usual operating hours of the lab.
4) Care should be exercised when the decision NOT to treat with the antidote is made based on a level determined by the colorimetric method.
5) Bridges et al (1983) did a survey of all colorimetric methods and determined that the ferric reduction method appeared reasonably reliable with a sufficiently low cost to benefit a small hospital which performs infrequent tests.
6) LABORATORY INTERFERENCE: It is noteworthy that salicylates (Mace & Walker, 1976; Reed et al, 1982), salicylamide (Chafetz et al, 1971), levodopa, methyldopa, dopamine, epinephrine (Andrews et al, 1982), and possibly cresol (Pitts, 1979) have been reported to interfere with colorimetric determination of unchanged acetaminophen. This results in falsely elevated results.

1) A few drops of 10% ferric chloride added to 1 ml of urine will turn purple in the presence of even small quantities acetylsalicylic acid. False positive results may result from the presence of acetoacetic acid and phenylpyruvic acid (Flomenbaum et al, 2006). Positive results should be confirmed with a serum salicylate level (Broder, 1987; Charette et al, 1998).
2) The Ames Phenistix turns brown when either salicylates or phenothiazines are present in serum or urine. Adding 1 drop of 20 N sulfuric acid fades the color change for phenothiazines but not salicylates. The ferric chloride test is preferred as the color change is easier to detect (Flomenbaum et al, 2006).
3) FORENSICS: A method using ferric chloride on methanolic extract of hemolyzed whole blood has been described. The minimum salicylate level this method can detect is 5 mg/dL (Asselin & Caughlin, 1990).

1) HPLC has been used to detect salicylates and metabolites in the plasma. Limits of detection were 0.2 mcg/mL for parent compounds and 0.1 mcg/mL for metabolites (Dadgar et al, 1985).
2) An ADx(TM) Salicylate assay is available. Sensitivity is 5 mg/L; correlation coefficient is 0.996.
3) Other common methods for salicylate determination include a fluorescence polarization assay and a colorimetric assay (Adelman et al, 1991).
4) Salicylate and metabolites can be detected in urine using proton nuclear magnetic resonance spectroscopy (Vermeersch et al, 1988).

1) BLOOD GAS ANALYZERS: Lacoma et al (1997) evaluated two blood gas analyzers that measure lactate concentration and standard blood gas measurements (Nova Star Profile 9 and Ciba Corning Diagnostics {CCD} 860) to determine possible assay interference by toxic substances known to cause lactic acidosis. No significant interference was noted in either analyzer with plasma samples containing sodium salicylate.

1) Patients with major symptoms (ie, tachypnea secondary to acidosis, dehydration, mental status changes, seizures) should be admitted to the Intensive Care Unit regardless of serum salicylate level.
2) A single oral dose of less than 150 mg/kg may result in some nausea, gastritis and vomiting however, serious symptomology is not expected (Temple, 1981). Patients can generally be treated at home with fluids and telephone follow-up consultation.
3) Toxicity may result from single oral doses of greater than 150 mg/kg. These patients cannot be managed at home and must be evaluated by a clinician. Significant toxicity may develop after ingestions in the range of 300 to 500 mg/kg, including metabolic acidosis, seizures, mental status depression (Temple, 1981).
4) Admission should be strongly considered regardless of the salicylate level in the very young and very old in chronic overdose and when the ingested tablets are enteric coated.
5) All suspected chronic poisonings should be evaluated by a health care provider.

1) Patients who require treatment with acetylcysteine are generally admitted to the hospital, although selected patients (presenting early with no evidence of liver injury) may be treated with acetylcysteine and managed in an emergency department observation unit.
2) Patients with acute liver failure should be admitted to an ICU and may require transfer to a facility with liver transplant criteria (Dart et al, 2006).

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Patients with an acetaminophen/salicylate overdose should receive a full dose of activated charcoal in an attempt to ensure that the amount absorbed will be nontoxic.

a) In patients presenting more than 8 to 12 hours after ingestion, administer a loading dose of NAC as soon as possible and discontinue if the initial level comes back below the treatment line.

a) ACETAMINOPHEN: Acetaminophen is well adsorbed by activated charcoal (Neuvonen et al ,1983; Bainbridge et al, 1977; Van de Graff et al, 1982).
b) SALICYLATES: Activated charcoal decreased salicylate absorption in crossover studies (Dawling et al, 1983; Eisen et al, 1991). In volunteer studies activated charcoal has been shown to be as effective (Danel et al, 1988).

a) CONCLUSION: There is no reason to withhold activated charcoal in a patient with acetaminophen overdose. Recent evidence suggests that activated charcoal may provide additional hepatoprotection in patients requiring NAC treatment for acetaminophen overdose.
b) Studies of adsorption of NAC onto charcoal have had conflicting results (North et al, 1981; Ekins et al, 1987) (Rensi et al, 1984).
c) ACTIVATED CHARCOAL HEPATOPROTECTION: In a prospective study of 122 patients with APAP overdose requiring NAC therapy, hepatotoxicity (peak SGOT greater than 125 Units/mL) developed in 4 of 82 patients receiving activated charcoal compared with 10 of 40 patients who did not receive activated charcoal (Spiller et al, 1994). Timing of the administration of activated charcoal and NAC less than or more than 2 hours apart did not affect outcome.
d) PHARMACOKINETICS: While there has been a suggestion that the dose of NAC should be increased to compensate for any charcoal adsorption (Krenzelok, 1986) (Chamberlain et al, 1993), this appears to be unnecessary (Smilkstein, 1994).
e) No positive relationship has been established between NAC serum concentrations and clinical effect, thus NAC/charcoal pharmacokinetic data should be applied to patient care with caution (Watson & McKinney, 1991).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Two small case series found that salicylate intoxicated patients treated with multiple dose activated charcoal had salicylate elimination half lives that were shorter than other patients not treated with multiple (Hillman & Prescott, 1985)or shorter half lives than previously published cases (Vertrees et al, 1990).
b) In a crossover study in 10 volunteers ingesting 2.88 grams acetylsalicylic acid suspension, a 9% decrease in bioavailability and an 18% decrease in urinary salicylate excretion was noted when 4 doses of 25 grams activated charcoal was administered every 2 hours beginning 4 hours postingestion (Kirshenbaum et al, 1990).
c) A controlled, randomized, 3-limbed crossover study in 9 volunteers (2.88 grams acetylsalicylic acid ingested) demonstrated no decrease in AUC after administration of multiple-dose activated charcoal during the post absorptive phase; no cathartic was given (Mayer et al, 1992).
d) Multiple dose vs single dose charcoal has been compared in volunteers who ingested therapeutic doses (650 mg every 4 hours x 3 days) until steady state. Multiple dose charcoal resulted in enhanced elimination during the 24 hours after absorption was complete (Yeakel et al, 1988).
e) Multiple doses of activated charcoal, administered over 12 hours, did not significantly increase the elimination of intravenously administered salicylate in male rabbits (Douidar et al, 1992).
f) In a crossover volunteer study the administration of three 50 gram doses of activated charcoal every 4 hours starting 1 hour after ingestion of 24 aspirin (81 mg each) decreased the urinary recovery of salicylate more than the administration of 1 or 2 doses of charcoal (Barone et al, 1988).
g) Because of the lack of clear benefit the routine use of multiple dose activated charcoal is not recommended for most patients with salicylate ingestion. Salicylate has been shown to desorb from activated charcoal in vivo (Filippone et al, 1987); the administration of a second dose of charcoal is reasonable to attempt to counteract desorption.
h) Salicylate absorption may be prolonged after ingestion of enteric coated or sustained release products and in patients with bezoar formation. Administration of a second dose of activated charcoal should be considered in patients with rising salicylate levels and those who have ingested enteric coated or sustained release preparations.

a) The effect of whole bowel irrigation (WBI) with 4 to 6 liters of polyethylene glycol solution beginning 30 minutes after ingestion of 2 or 4 grams of APAP was studied in volunteers (Hassig et al, 1993). WBI decreased peak APAP levels and area under the concentration vs time curve after ingestion of 4 grams and decreased urinary excretion of the mercapturic acid conjugate after ingestion of 2 or 4 grams. While early WBI appears to reduce APAP absorption, its role in APAP overdose is not currently defined.

a) A crossover study in 9 volunteers (2.88 grams acetylsalicylic acid suspension ingested) failed to demonstrate any enhanced excretion of drug following whole bowel irrigation beginning 4 hours postingestion) (Mayer et al, 1992).
b) In another study whole bowel irrigation was more effective in reducing salicylate absorption than single dose activated charcoal begun 4 hours after administration of enteric coated aspirin (Kirschenbaum et al, 1989).

a) Benorilate has to be absorbed and converted to become acetaminophen. Although this is said to occur "rapidly", no specific time frame is available.
b) In general, peak levels of acetaminophen are supposed to occur later in an ingestion and more "smoothly" (possibly a lower peak). This would have the potential to move the level (the point on the graph) to the right and down on the nomogram.
c) At this time it is unclear to what extent it would move this graph point, and in what direction. A four hour level may be somewhat useful as a general range-finder of toxicity.

a) An adult developed delayed salicylism 17 hours after intentionally ingesting 200 325-mg tablets. He was admitted approximately 45 minutes after exposure and was alert and oriented with some nausea. Fifty grams of activated charcoal and normal saline at 150 mL/hr were administered. An initial salicylate and acetaminophen concentrations were undetectable. Respiratory alkalosis (pH 7.47, PC02 27 mm Hg, PO2 104 mm Hg, and HCO3 20 mEq/L) was observed shortly after admission. A second salicylate level obtained at 3 hours was 33 mg/dL and 35 mg/dL at 7 hours. Following observation for 8 hours the patient was transferred to psychiatric care and was readmitted 17 hours after initial presentation with decreased mental status, diaphoresis, and tachypnia. A repeat ABG revealed a mixed metabolic gap and respiratory acidosis (pH 7.08, PCO2 30 mm Hg, and PO2 73 mm Hg, and HCO3 10 mEq/L) with a salicylate level of 128 mg/dL. The patient had a witnessed seizure and died 20 hours after exposure. Careful monitoring of serial salicylate concentrations until they are in the nontoxic range is important, as delayed absorption may produce mildly elevated salicylate concentrations and initially mild toxicity (nausea and respiratory alkalosis in this patient) that may then progress to severe intoxication (Herres et al, 2009).
b) Delayed salicylate toxicity and no symptoms for the first 35 hours postingestion have been reported in one patient. The authors suggested that the delayed aspirin absorption may be due to enteric-coated or sustained-release dosage forms, salicylate-induced pylorospasm, and/or the formation of pharmacobezoars. If salicylate levels are not decreasing significantly every 4 to 6 hours, this suggests continued absorption or decreased excretion. Serial salicylate levels should be monitored until they are declining and in the nontoxic range. Treatment should not be discontinued until patients are asymptomatic (Rivera et al, 2004).

a) Obtain a plasma acetaminophen level 4 or more hours after ingestion and plot it on the Rumack-Matthew Nomogram. Levels obtained prior to 4 hours may not represent peak plasma levels and CANNOT be used to predict hepatotoxicity and need for NAC therapy. Greatest accuracy is obtained with samples done between 4 and 12 hours.

a) Concomitantly ingested drugs (particularly those with anticholinergic or opioid effects) or foods may affect gastric emptying and time to peak plasma level. Additional levels may be needed to determine the peak (Linden & Rumack, 1984; Tighe & Walter, 1994; Gesell & Stephan, 1996; Tsang & Nadroo, 1999).

a) A number of investigators have suggested that chronic ethanol exposure increases the risk of acetaminophen-induced hepatic injury. Conservative interpretation of acetaminophen levels in alcoholics has been recommended by some authors (Cheung et al, 1994; Seeff et al, 1986; Lauterburg & Velez, 1988).

a) After 24 hours postingestion, the presence of acetaminophen in the plasma may be documented, but interpretation of these levels is difficult. Because of increasing evidence of the beneficial effect of NAC instituted more than 24 hours after overdose, its use is recommended in patients presenting 24 hours or more postingestion who have measurable acetaminophen levels or biochemical evidence of hepatic injury (Parker et al, 1990; Harrison et al, 1990; Keays et al, 1991; Tucker, 1998; Buckley et al, 1999a).
b) Certain serum acetaminophen assays are insensitive below 10 mcg/mL (greater than 66.16 Standard International Units (micromole/L)), rendering the Rumack-Matthew Nomogram invalid in patients who present greater than 19 hours after acetaminophen ingestion with no recordable levels. The authors recommend that these patients receive NAC therapy until 24 hours since the last acetaminophen ingestion, at which point it can be discontinued providing there is no detectable serum acetaminophen or clinical or biochemical evidence of hepatotoxicity (Donovan et al, 1999).
c) In a population-based incidence and outcome study of acetaminophen poisoning, it was determined that atypical presenters, those whose risk cannot be estimated using the Rumack-Matthew Nomogram, represented 44% of the hospitalized patients and 83% of those who suffered significant hepatic injury. This group represents patients with the poorest outcome (Bond & Hite, 1999).
d) In late presenters following acetaminophen overdose, the best prognostic marker in established hepatotoxicity is the prothrombin time. Extended courses of NAC may be given until the prothrombin time improves (Jones, 2000).

a) N-acetylcysteine may be administered orally or intravenously. In patients who develop hepatic injury, NAC therapy should be continued until hepatic function improves.

a) Patients receiving NAC therapy should meet the following criteria:
b) EFFERVESCENT TABLET PREPARATION
c) ADVERSE EFFECTS

a) A shorter duration of oral NAC has been recommended for acute acetaminophen overdoses presenting within 24 hours of ingestion. Several small studies suggest that oral NAC loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours until the serum acetaminophen level is no longer detectable and aminotransferase levels are normal, is safe and effective (Betten et al, 2007; Tsai et al, 2005; Woo et al, 2000; Woo et al, 1995). Because of the shorter hospitalization and associated costs, this protocol may be preferable in patients presenting soon after an acute ingestion.

a) This is the standard FDA-approved dosing regimen used in Europe (Prescott protocol). NAC is used for prophylaxis/prevention of acetaminophen-induced hepatic injury. LOADING DOSE: 150 mg/kg in 200 mL of 5% dextrose, infuse intravenously over 60 minutes. MAINTENANCE DOSE: 50 mg/kg in 500 mL of 5% dextrose, infuse intravenously over 4 hours followed by 100 mg/kg in 1000 mL of 5% dextrose, infuse intravenously over 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979).
b) Acetadote(R) is available in 30-mL (200 mg/mL) single-dose glass vials(Prod Info ACETADOTE(R) IV injection, 2006).
c) In patients who develop hepatic injury secondary to acetaminophen, NAC therapy should be continued until serum acetaminophen concentration is undetectable and liver function improves (Smith et al, 2008).
d) To obtain more information, you can contact Cumberland Pharmaceuticals, Inc. at 1-866-767-5077.
e) CASE REPORT: A 78-year-old man, with a past medical history of coronary artery disease and renal insufficiency, intentionally ingested approximately 48 g of acetaminophen (ninety-six (96) 500-mg tablets) over a 1-hour period. Baseline laboratory data, on hospital admission, revealed a serum creatinine of 3.4 mg/dL, but normal liver enzyme levels (AST, 8 units/L; ALT, 22 units/L), bilirubin level, and prothrombin time (13.5 seconds). A serum acetaminophen level, obtained 2.25 hours postingestion, was 264 mcg/mL. Intravenous NAC was initiated 5 hours postingestion and continued for 21 hours. Because of normal liver enzyme and bilirubin levels, NAC was discontinued after 21 hours of therapy despite a serum acetaminophen concentration of 116 mcg/mL at the time NAC was discontinued. Intravenous NAC was restarted 24 hours later, at which time the patient's AST and ALT levels were 395 and 453 units/liter, respectively. Over the next few days, AST and ALT levels peaked at 4350 and 5621 units/L and his PT was 51.4 seconds. IV NAC was continued until normalization of lab values. The authors conclude that because of a possibility of delayed and erratic absorption following massive acetaminophen overdose ingestions, it is recommended that intravenous NAC should be continued until serum acetaminophen concentrations are undetectable and liver function improves (Smith et al, 2008).
f) PEDIATRIC
g) ADVERSE EFFECTS
h) ANAPHYLACTOID REACTIONS
i) FACIAL FLUSHING
j) PROTHROMBIN INDEX
k) DISCONTINUATION CRITERIA

a) It is recommended that NAC be given to those patients who develop acetaminophen-associated hepatic failure but cannot be risk stratified by the Rumack-Matthew Nomogram (Wolf et al, 2007).
b) In patients with hepatotoxicity or hepatic failure prolonged courses of NAC therapy may be needed. NAC should be continued, using one of the above regimens, until clinical and biochemical markers of hepatic injury improve.

a) In a series of 4 pregnant patients who delivered while receiving NAC therapy for acetaminophen overdose, it was found that the mean cord blood (in one case with fetal demise cardiac blood was used) NAC level at the time of delivery was 9.4 mcg/mL, which is within the range normally seen in patients receiving therapeutic NAC (Horowitz et al, 1997). Administering NAC to the mother as soon as possible after the overdose is the most effective means of preventing hepatotoxicity in mother and fetus (Riggs et al, 1989).
b) NAC therapy should be continued in the infant if delivered before the mother completes the entire course of therapy. Infants born with biochemical evidence of acetaminophen-induced hepatic injury should continue to receive NAC until clinical and biochemical parameters improve.

a) Sixty cases of acetaminophen overdose without evidence of teratogenesis have been reported. Twenty-four had serum levels above the nomogram line. Nine women had spontaneous abortions or stillbirths. One fetal death was recorded in the second and third trimesters. One third-trimester hepatotoxic patient delivered a 32 week stillborn during the course of NAC treatment. The plasma acetaminophen concentration in the stillborn was 360 mcg/mL (therapeutic range is 10 to 20 mcg/mL) and the autopsy showed massive hepatic necrosis (Riggs et al, 1989).

a) CONCLUSION: Although one study demonstrates an increased survival rate (16 of 23 patients) following early hemoperfusion, more controlled clinical studies need to be performed before this procedure can be considered a routine treatment for acetaminophen-induced hepatic failure (Gimson et al, 1982).

a) A molecular adsorbent recirculating system (MARS), which is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchange columns, has been used following a massive acetaminophen overdose in a patient with hepatic encephalopathy (grade II), severe acidosis, INR of 7, and hepatorenal syndrome. The patient was rejected for liver transplantation. Albumin dialysis allowed time for hepatic regeneration during conventional supportive care in this case. A course of 5 consecutive 8-hour treatments was performed (McIntyre et al, 2002; Mitzner et al, 2000).
b) CASE REPORT: Single-pass albumin dialysis (SPAD) was successfully performed on a 41-year-old woman who developed hepatic failure following an acute acetaminophen overdose. Following ICU admission (hospital day 2), the patient had fulfilled King's criteria for transplantation (pH, 7.24; INR, 7.2; model for end-stage liver disease (MELD) score of 40); however, she was deemed unsuitable for transplantation due to psychosocial comorbidities. Approximately 10 hours post-ICU admission, the patient was started on continuous veno-venous hemodiafiltration for management of lactic acidosis and oliguria. On hospital day 3, SPAD was started, consisting of 14 hours/day for 4 days and 1 day of 21 hours for a total of 77 hours. Prior to SPAD, ALT and AST levels peaked at 6828 and 15,721 units/L, respectively. Following the last day of treatment, ALT and AST levels decreased to 596 and 126 units/L, respectively, and her INR was 2.1. The patient gradually recovered and was discharged 46 days post-presentation without sequelae (Karvellas et al, 2008).

a) Acetaminophen-induced hepatitis or hepatic failure has been treated at 16 to 68 hours after an overdose for 4 to 6 hours with the Liver Dialysis System (a single-access hemodiabsorption system for treatment of serious drug overdose and for treatment of hepatic encephalopathy). During this treatment in 10 patients, acetaminophen levels dropped an average of 73%. If acetaminophen levels were still measurable in plasma, treatment was repeated 24 or 48 hours later. In this group, liver enzymes normalized 24 hours after the last treatment and no patient required a liver transplant. No adverse effects due to this treatment were noted (Ash et al, 2002).

a) CASE REPORT: A 26-year-old woman, who underwent liver transplantation, developed primary nonfunctioning of the graft on postoperative day 4, with minimal bile output, discolored bile, coagulopathy, renal failure, and a grade IV coma requiring mechanical ventilation. Due to her deteriorating clinical condition, the patient was treated with modular extracorporeal liver support (MELS), consisting of a bioreactor that is charged with human liver cells and integrated into an extracorporeal circuit with continuous single pass albumin dialysis and continuous veno-venous hemodiafiltration. The human liver cells were obtained from a discarded cadaveric graft. After a total application time of 79 hours, the patient's plasma levels of total bilirubin and ammonia significantly decreased (21.1 mg/dL and 100 mcmol/L at start of therapy, respectively, to 10.1 mg/dL and 22.7 mcmol/L at end of therapy, respectively). Her kidney function also improved with a urine output of 1325 mL/24 hours at the end of therapy compared with 45 mL/24 hours prior to therapy, and her neurological status improved from a coma grade IV to a coma grade I allowing for extubation. On postoperative day 8, a suitable graft was found, MELS was stopped, and liver transplantation was performed. The patient's recovery was uneventful (Sauer et al, 2003). While there are currently no reports of the use of this system with acetaminophen-induced fulminant hepatic failure, it might be useful as a bridge to liver transplantation.

a) Liver transplantation has a definite but limited role in the management of patients with hepatic failure from acetaminophen toxicity (Larsen et al, 1995; Makin et al, 1995).
b) Of 14 patients with poor prognosis for survival after acetaminophen overdose who were registered for transplantation, 4 of 6 (67%) survived following transplant vs 1 of 8 (12.5%) who were not transplanted. Three of 15 (20%) control patients with similar prognosis who were not registered for transplantation survived (O'Grady et al, 1991).
c) In another study of 17 patients with poor prognosis referred for liver transplant, 7 of 10 patients who received a liver transplant survived compared with 1 of 7 who did not receive a transplant (Mutimer et al, 1994).
d) Reliable prognostic indicators for fatal outcome are needed, since those patients who recover without transplantation have complete recoveries(Harrison et al, 1990) (Tournaul et al, 1992).
e) Acidosis (pH less than 7.3), a continuing rise in prothrombin time or INR on day 4, a peak prothrombin time of 180 seconds or more, and the combination of serum creatinine greater than 300 micromoles/Liter, PT greater than 100 seconds and grade III-IV encephalopathy have all shown strong correlations with fatal outcomes in patients with fulminant hepatic failure. Assuming a standard control PT of 15 seconds, then a peak International Normalized Ratio (INR) of approximately 12 or an INR greater than approximately 6.6 presumably have the same prognostic significance (Harrison et al, 1990a; O'Grady et al, 1988; O'Grady et al, 1989; Janes & Routledge, 1992; Vale, 1992; Mutimer et al, 1994).
f) The use of arterial lactate concentration may allow for earlier identification of patients at high risk of fatal acetaminophen induced liver failure and likely to benefit from listing early for liver transplantation.
g) Another study has seriously questioned the King's College lactate criteria for liver transplant. In a series of 40 patients who presented with acetaminophen-induced fulminant hepatic failure (FHF), 2 patients received transplants. Nine patients died overall: 1 who had received a transplant, 6 who arrived moribund or developed severe cerebral edema soon after presentation and transplantation was never feasible, and 2 died without transplantation. Non-transplant survival in patients who met one or both of the King's College lactate criteria (early lactate greater than 3.5 or post resuscitation lactate greater than 3) was 68% in these patients. In a series of 56 FHF patients from a related center, non-transplant survival in patients who met one or both of the King's College lactate criteria was 62%. The authors suggest that improvements in the management of FHF (particularly the prevention of cerebral edema) may make liver transplantation in acetaminophen-induced FHF necessary less often than previously believed (Gow et al, 2007).
h) A meta-analysis was conducted that compared the different prognostic criteria that were used to determine the need for liver transplantation in patients with fulminant hepatic failure secondary to acetaminophen poisoning. The criteria that was analyzed included King's criteria (pH less than 7.3 or a combination of prothrombin time (PT) of greater than 100 sec plus creatinine of greater than 300 mcmol/L plus encephalopathy grade 3 or greater), pH less than 7.3 only, PT greater than 100 sec only, PT greater than 100 sec plus creatinine greater than 300 mcmol/L plus encephalopathy grade 3 or greater, an increase in PT day 4, factor V of less than 10%, APACHE II score of greater than 15, and Gc-globulin less than 100 mg/L. Overall, in the meta-analysis, King's criteria had moderate sensitivity at 69% (range 55% to 100%), as compared with the other criteria analyzed, but it had high specificity at 92% (range 43% to 100%). Further analysis, utilizing Q values (a Q value of 1 reflects a perfect test and a Q value of 0.5 reflects an uninformative test) showed that the ability of the King's criteria to distinguish between patients requiring transplantation and those who do not seems limited, with a Q value of 0.61. However, using likelihood ratios, as an alternative method for evaluating the accuracies of diagnostic criteria (the greater the positive likelihood ratio and the lower the negative likelihood ratio, the better the criteria), the King's criteria had a positive:negative likelihood ratio of 12.33:0.29, indicating that it is a fairly accurate prognostic indicator. In comparison, the APACHE score greater than 15 criteria had a sensitivity of 81% and a specificity of 92% on the first day of patient's admission. The APACHE criteria also had the highest positive and lowest negative likelihood ratios of any criteria analyzed in the meta-analysis (16.4:0.19); however, the APACHE criteria was evaluated in only one study. Because there was only one study available, the authors concluded that further studies are needed to evaluate the efficacy of APACHE II score criteria, and in the interim, King's criteria should be used as the standard criteria, despite its moderate sensitivity (Bailey et al, 2003).
i) One study found a factor V concentration of less than 10% in patients with grade 3/4 encephalopathy and a factor VIII/factor V ratio greater than 30 to correlate with fatal outcome (Pereira et al, 1992). Another study found that, in a group of patients who did not all have grade 2 or 4 encephalopathy, these markers were not useful if measured less than 72 hours after overdose (Bradberry, 1994) (Bradberry et al, 1995).
j) In a retrospective study of 21 patients who underwent liver transplant for acetaminophen-induced liver failure 16 survived to 2 months and 5 did not. In survivors the time from ingestion to transplant was shorter (4 days vs. 6 days in non-survivors) and the pH at the time of transplant was higher (7.38 vs. 7.21 in non-survivors). A pH below 7.3 at transplantation had a sensitivity of 80% and a specificity of 94% for 2-month mortality (Devlin et al, 1995).
k) A model was developed, based on a prospective and validated study, to predict hepatic encephalopathy in acetaminophen overdose and to identify high-risk patients for early transfer to a liver intensive care unit/transplantation facility. The most accurate model for encephalopathy included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count x hours from overdose (chi-square=41.2; p less than 0.00001). Hepatic encephalopathy was not seen in patients treated within 18 hours after overdose (Schiodt et al, 1999).
l) A variety of biochemical markers (ie, hemoglobin, pyruvate, calcium, and phenylalanine levels) were identified which were combined to form a prognostic model that, when applied to patients at hospital admission, appeared to accurately predict the outcome of patients with fulminant hepatic failure. The prognostic tool was derived used a cohort of 97 patients and prospectively validated with a second cohort of 86 patients admitted to the Scottish Liver Transplant Unit for acetaminophen-induced fulminant hepatic failure. Hemoglobin, pyruvate, and phenylalanine levels were significantly lower in patients who either subsequently died or underwent transplantation compared with patients who spontaneously survived. This prognostic model of outcome in acetaminophen-induced fulminant hepatic failure appears to be as accurate a predictor as utilizing King's College Hospital criteria, but at an earlier stage of the patient's condition (Dabos et al, 2005).
m) PEDIATRIC PATIENTS: Based on a retrospective review of paracetamol-induced hepatotoxicity in pediatric patients, the following indicators were associated with a poor prognosis and a need for liver transplantation (Mahadevan et al, 2006):

a) RATE: 10 to 15 mL/kg/hr over 1 to 2 hours until a good urine flow is obtained (at least 3 to 6 mL/kg/hr).
b) Patients in shock may require more rapid fluid administration (Temple, 1981). MONITOR urine output and pH hourly.

a) STAGE ONE (alkaline plasma and urine): Although serum potassium may be normal, renal excretion of potassium and bicarbonate have occurred. This is because sodium or potassium must be excreted with bicarbonate.
b) STAGE TWO (plasma pH greater than 7.4 and urine pH less than 6.0): An acidic urine with alkaline plasma (paradoxical aciduria) may reflect renal intracellular hypokalemia before the plasma potassium level becomes depressed or the EKG shows changes.
c) STAGE THREE (acid plasma and urine): Total body potassium and bicarbonate depletion may be present, with evidence of decreased plasma potassium levels or EKG changes.
d) PRECAUTIONS

a) Forced diuresis, alkaline diuresis and urinary alkalinization without diuresis have all been shown to increase urinary salicylate excretion (Berg, 1977; Gordon et al, 1984; Prowse et al, 1970; Coppack & Higgins, 1984; Prescott et al, 1982). Alkalinization alone was at least as effective as forced alkaline diuresis in enhancing salicylate removal in one study (Prescott et al, 1982). Alkalinization of the urine (pH of 7.5 to 8) effectively enhances salicylate excretion, but may be difficult to achieve in severely poisoned patients because of depletion of total body potassium.
b) DOSE: A solution of D5W with 132 mEq/L of bicarbonate plus 30 to 40 mEq/L of KCl should be given at a rate of 2 to 3 mL/kg/hr to produce a urine flow of 2 to 3 mL/kg/hr. Monitor serum electrolytes and urine pH every 1 to 2 hours. Adjust potassium and bicarbonate administration as needed to maintain a urine pH of 7.5 to 8.
c) PRECAUTIONS: Alkaline diuresis is a potentially dangerous treatment and meticulous monitoring of urine output, pH, serum potassium, mental status, and pulmonary status must be performed. Additional potassium MAY be required if urine does not become sufficiently alkaline following the above regimen. An acidic urine with alkaline plasma may reflect intracellular hypokalemia before the plasma potassium level becomes depressed.
d) STUDY: A small comparison study of 9 healthy volunteers was conducted to determine the effectiveness of urinary alkalinization and multidose activated charcoal in salicylate elimination (Ruskosky et al, 1998). Urinary alkalinization shortened half-life by 48.4% (4.741 hours) compared to control (aspirin only administration) and 42.7% (3.767 hours) compared to the activated charcoal phase. Area under the curve was also statistically less for the urinary alkalinization group compared to the control or activated charcoal group.
e) PRECAUTIONS: Hypocalcemia (6.4 mg/dL) and tetany have developed with use of bicarbonate for urinary alkalinization treatment following salicylate poisoning; serum calcium was normal on admission (Fox, 1984).

a) ACETAZOLAMIDE: Diamox(R) and TROMETHAMINE (Tham) are NOT recommended as agents to alkalinize the urine due to their adverse effect on the metabolic acid-base balance.

a) SALICYLATES: Correct dehydration with 0.9% saline 10 to 20 mL/kg/hr over 1 to 2 hours until a good urine flow is obtained (at least 3 to 6 mL/kg/hr). In patients in whom urinary alkalinization is being considered, initial hydration may be with 10 to 20 mL/kg of D5W with 88 to 132 milliequivalents of bicarbonate added. Patients in shock may require more rapid fluid administration (Temple, 1981).
b) MONITOR urine output and pH hourly.
c) ACIDOSIS: Administer 1 to 2 mEq/kg NaHCO3 by intravenous bolus and begin urinary alkalinization. Monitor blood gases and urinary pH to guide frequency and quantity of administration. Patients with refractory acidosis, inability to maintain appropriate respiratory alkalosis, or acidemia should be treated with hemodialysis.

a) Serial serum salicylate levels should normally decline with therapy. If they remain relatively unchanged or increase, this may indicate a possible mass (concretion) of aspirin in the stomach.
b) Surgical removal of the mass may be necessary, but enteric coated tablets sometimes can be disintegrated by using an isotonic sodium bicarbonate lavage with a pH of 8.5.
c) Infusion via a nasogastric tube of 300 mL/30 min of this solution alternated with continuous suction for 30 min for 24 hours resulted in the removal of 80 enteric-coated aspirin tablets in a patient with gastric outlet obstruction (Sogge et al, 1977).

a) Hemodialysis may be indicated if acute lung injury develops, as alkaline diuresis may be hazardous in this setting.
b) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
c) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
d) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
e) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
f) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
g) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
h) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

a) VENTILATION/MONITORING: Employ controlled hyperventilation, maintaining an arterial CO2 tension of 25 to 30 mmHg (Woster & LeBlanc, 1990). Monitor cardiovascular function, renal function, and serum electrolytes carefully (Heinemeyer, 1987).
b) OSMOTIC DIURETICS:
c) DEXAMETHASONE: There is controversy in the literature as to whether dexamethasone is an effective treatment for cerebral edema that is induced by other mechanisms than malignancy, and as to the appropriate dose.

1) Late hemoperfusion is not likely to be of benefit since the toxic metabolites are intrahepatic and are not likely to be removed by hemoperfusion.

a) IMPORTANT NOTE - Hydrolysis of one gram of benorilate yields approximately 600 milligrams salicylate and 400 milligrams acetaminophen (Hanks, 1985).

a) The usual adult dose of benorilate in the treatment of pain due to metastatic bone cancer is 2 to 4 grams orally twice a day (Hanks, 1985).
b) For the prophylactic reduction of postoperative dental pain, benorilate 4 grams given orally immediately before third molar extraction has been moderately effective (Moore et al, 1989).
c) In primary dysmenorrhea, benorilate 1500 milligrams orally 3 times a day is effective and well tolerated (Prasad, 1980).
d) Benorilate is effective in the treatment of symptoms associated with musculoskeletal diseases.

a) This should be titrated to produce a serum salicylate concentration of approximately 25 to 30 milligrams/deciliter (Powell & Ansell, 1974; Makela et al, 1979).

1) The patients' mean age (57.8 years vs 41.1 years (p less than 0.02))
2) Unconscious on admission (5/7 vs 7/90, (p less than 0.001))
3) Arterial hydrogen ion concentration on admission (57 vs 36 nanomoles/liter (p less than 0.001))
4) Mean arterial partial pressure of oxygen on admission (10.8 vs 13.3 kilopascals, (p less than 0.01))
5) Mean plasma potassium concentration on admission (4.9 vs 4.3 millimoles/liter, (p less than 0.05))
6) Coingestants in this study included alcohol (37), benzodiazepines (11), codeine phosphate (3), acetaminophen (2), and mianserin (2).

1) The age-weight relationship is the result of the average of the 50th percentile weight for boys and girls at the given age (Behrman & Vaughn, 1983).
2) Example of dosage units are: 120 mg tablet, 120 mg wafer, 120 mg suppository, 120 mg/5 mL elixir, and 120 mg/2.5 mL solution

1) An 18-month-old toddler (11 kg) was estimated to have ingested 45 mL of a solution of acetaminophen containing 120 mg/2.5 mL by history. Is this child above or below the 200 mg/kg threshold?
2) Find 11 kg under weight column, read across to 120 mg dosage form = 18 dosage units. Eighteen dosage units x 2.5 mL/dosage unit = 45 mL

1) Of 417 pediatric acetaminophen overdoses, 55 (13%) had toxic plasma concentrations, resulting in hepatotoxicity (SGOT greater than 1,000 units/liter) in 3 (5.5%).
2) COMPARISON TO ADULTS: A comparison with 639 adult cases showed toxic concentrations in 23.2% and hepatotoxicity in 29% of those. It is suggested that the increased glutathione turnover rate in children results in greater detoxification of acetaminophen (Rumack, 1984).

1) ACUTE INGESTION

a) BENORILATE SERUM LEVEL -
b) ACETAMINOPHEN -

a) 1255 mg/kg (RTECS, 2002)

a) 1551 mg/kg (RTECS, 2002)

a) 1830 mg/kg (RTECS, 2002)

a) 3500 mg/kg (RTECS, 2002)

1) The exact etiology is unclear but may result from excessive accumulation of carbon dioxide in the CNS (Smith, 1968), decreased brain glucose concentration (Thurston et al, 1970), or a direct toxic effect.

1) They found that in alert patients with systemic acidosis, the pH of the cerebrospinal fluid was nearly normal but was in the far acid range in those patients in coma. Correction of the systemic acidosis with sodium bicarbonate was demonstrated to correct the cerebrospinal fluid acidosis resulting in an increased mental alertness.