Tylenol Overdose

 Introduction o acetaminophen most widely used analgesic-antipyretic in the United States. o Component of many other medications o Most common cause of acute liver failure in the United States o Acetaminophen accounts for more overdoses and overdose deaths each year in the United States than any other pharmaceutical agent.  More than 1200 cases of severe hepatic injury and 21 deaths were attributed to acetaminophen intoxication during 2003, accounting for 23 percent of all pharmaceutical-related deaths reported that year  Dosing o 325 to 1000 mg per dose in adults, given every 4 to 6 hours, with a maximum recommended daily dose of 4 g in adults.  Toxicity is unlikely from a single dose of less than 10 g for an adult o Toxicity is likely to occur with single ingestions greater than 12 g over a 24-hour period o Peak serum concentrations are reached within four hours following overdose  May be delayed beyond four hours when drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested, or following overdose of extended releases preparations.  Therapeutic serum concentrations range from 10 to 20 mcg/mL.  Elimination half-lives range from 2 to 4 hours for all acetaminophen preparations  Pathophysiology o At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates, which are then excreted in the urine o The remaining acetaminophen is metabolized via the hepatic cytochrome P450 into a toxic, highly reactive,

phenobarbital.  Examples: anticonvulsants (eg. carbamazepine.  Chronic alcohol ingestion increases CYP2E1 activity two-fold and depletes glutathione levels o Medications — Concomitant use of drugs that induce CYP2E1 enzymes can cause hepatotoxicity in the absence of overt acetaminophen overdose. independent risk factor for mortality following acetaminophen overdose. When hepatic glutathione stores are depleted and NAPQI begins to react with hepatocytes. isoniazid and rifampin)  trimethoprim-sulfamethoxazole and zidovudine may potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways  Herbal supplements may potentially amplify o Tobacco — Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism. and injury ensues – centrolubular necrosis  Factors influencing toxicity o Excessive intake of acetaminophen o Excessive cytochrome P450 activity o Decreased capacity for glucuronidation or sulfation o Depletion of glutathione stores o Acute alcohol ingestion  Acute alcohol NOT a risk factor  Protective by competing with APAP o Chronic alcohol ingestion — The role of chronic alcohol ingestion in acetaminophen-induced hepatotoxicity remains contentious. N-acetyl-pbenzoquinoneimine (NAPQI) o Appropriate acetaminophen doses produce a small amount of NAPQI which is rapidly conjugated with hepatic glutathione. and phenytoin) and antituberculosis drugs (eg.electrophilic intermediate. forming nontoxic cysteine and mercaptate compounds that are excreted in the urine o With toxic doses more acetaminophen is metabolized to NAPQI via the cytochrome P450 enzymes. and may worsen the outcome of an intentional overdose. o Pattern of use — Patients who accidentally poison .

even though the latter had ingested more acetaminophen [6]. hyperammonemia. hepatic coma.  Acute pancreatitis has been described in case reports o Stage III (72 to 96 hours)  LFT abnormalities peak from 72 to 96  Symptoms of stage I reappear along with jaundice. when the toxic effects of acetaminophen are already established. usually from multiorgan system failure. o Stage IV (4 days to 2 weeks)  Patients who survive stage III enter a recovery . o The accidental-overdose group had higher rates of severe hepatotoxicity. marked elevation in hepatic enzymes. fasting. prolonged PT or INR.5 to 24 hours)  nausea. and malaise or asymptomatic  Laboratory studies are typically normal. stage I symptoms usually resolve and patients appear to improve clinically while subclinical elevations and AST & ALT occur.  CLINICAL MANIFESTATIONS — o Stage I (0. chronic ethanol use) and are more likely to present late. and a bleeding diathesis. lactic acidosis. pallor.  Acute renal failure occurs in 25 percent of patients with significant hepatotoxicity and in more than 50 percent of those with frank hepatic failure  Death most commonly occurs in this stage.  Severe hepatotoxicity = ALT & AST levels that often exceed 10. diaphoresis.themselves with repeated excessive doses in an attempt to relieve pain or treat fever are more likely to have established risk factors for hepatotoxicity (eg.  CNS depression and AG acidosis usually due to coingestants. and death than those who attempted suicide. hypoglycemia. confusion. and a total bilirubin above 4. o Stage II (24 to 72 hours)  Initially.000 IU/L.0 mg/dL (primarily indirect). lethargy. vomiting.

ALT. single or repeated doses) o Time of the ingestion o Presence of coingestants o Existence of comorbid conditions that may predispose to the development of hepatic injury (eg.97]. anticonvulsant drug use. DIAGNOSIS  History should be obtained to elicit: o The dose o Intent of use (ie. toxic screening of blood and urine for other ingested drugs should be performed. serum total bilirubin level. alcohol use. AST.  Evaluation after acute overdose o The risk of toxicity is best predicted by relating the time of ingestion to the serum acetaminophen concentration. recent fasting). suicidal or not) o Pattern of use (eg. o The level should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC therapy o Serum concentrations drawn before 4 hours may not represent peak values.  chronic hepatic dysfunction is not a sequela of acetaminophen poisoning.  Additional laboratory tests o BUN and creatinine. amylase. Gilbert's disease.phase that usually begins by day 4 and is complete by 7 days after overdose [50]. . o After a single acute overdose of an immediate-release preparation. relates serum acetaminophen concentration to the time of ingestion as a predictor of hepatotoxicity. o The original nomogram. o In patients with intentional ingestions or unreliable histories. and should not be used [50. prothrombin time with INR. and urinalysis. based on large numbers of overdose patients not treated with antidote. a serum acetaminophen concentration should be drawn four and 24 hours after presentation.

4].7] and gastric lavage [8. unless endotracheal intubation is performed first. Probable hepatic toxicity = 60% percent incidence of severe hepatotoxicity (AST greater than 1000 IU/L) and a mortality rate of 5%  high hepatic toxicity = 90 percent incidence of severe hepatotoxicity and a mortality rate of up to 24%  As originally reported.9] limit the absorption of acetaminophen after simulated overdose and in clinical trials [2.  However. 1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known or suspected acetaminophen ingestion.  Acetylcysteine — o Serious hepatotoxicity is uncommon and death extremely rare if acetylcysteine is administered within . patients with serum acetaminophen concentrations below the "probable hepatic toxicity" line did not develop severe hepatotoxicity and no fatalities were reported o Insufficient experience following acute overdose of sustained-release acetaminophen products.  A number of studies using simulated overdose models have shown that AC reduces acetaminophen exposure [1].  Charcoal should be withheld in patients who are sedated and may not be able to protect their airway. so they are not routinely recommended [2. Several clinical trials have confirmed these findings:  Studies have shown that induced emesis [6. these therapies appear to be less effective than activated charcoal.6].  x  Treatment o GI DECONTAMINATION —  activated charcoal (AC). unless there are contraindications to its administration. Some authorities (including the manufacturer) recommend Treating same as for normal doses.

pancreatitis.  Next. acetylcysteine prevents acetaminophen-induced hepatic injury by restoring hepatic glutathione stores.  This treatment protocol provides a total of 300 mg/kg over 20 to 21 hours [15]. IV versus oral —  The best available data suggest that both routes are effective and differences are minimal. This is accomplished by initiating treatment within eight hours of an acute ingestion. The treatment period is often extended when patients have large ingestions or elevated serum transaminase activity.  The dose does not need to be adjusted if the patient has been treated with activated charcoal.  IV administration is favored for patients with any of the following:  Vomiting  Contraindications to oral administration (ie. either the oral or IV route is acceptable.25 mg/kg per hour IV.o o o o o eight hours following acetaminophen overdose [1012].  Finally. The key to effective treatment is to start therapy before the onset of alanine aminotransferase (ALT) elevation. give a dose of 70 mg/kg PO every four hours for a total of 17 doses. In most patients. administer a 16 hour infusion at 6. 20 hour IV protocol —  Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we recommend 60 minutes).  Next. bowel injury)  Hepatic failure  Patients who refuse oral administration  Patients with evidence of hepatic failure . administer a 4 hour infusion at 12. bowel ileus or obstruction. 72 hour oral protocol —  Give a loading dose of 140 mg/kg PO.5 mg/kg per hour IV.

 Duration of treatment — o Acute ingestion with treatment started when ALT is NOT elevated or within eight hours of ingestion Administer IV or oral acetylcysteine for a minimum of 20 hours (some authors suggest longer treatment when the oral route is used) [29]. unless more severe signs develop.  If a patient vomits within 60 minutes of an oral dose of acetylcysteine.  Patients who develop urticaria or angioedema should have the infusion stopped and be treated with diphenhydramine (1 mg/kg IV up to 50 mg).21].  It is reasonable to administer an antiemetic to nauseated patients or patients who have vomited prior to giving oral acetylcysteine.  Adverse reactions — o Anaphylactoid reaction — Prospective studies suggest that between 10 and 20 percent of patients treated with IV acetylcysteine develop an anaphylactoid reaction [20.  Patients who develop hypotension or respiratory symptoms after IV acetylcysteine therapy will generally tolerate oral acetylcysteine. The infusion can be restarted once symptoms resolve.25 mg/kg per hour and obtain a serum acetaminophen concentration and . continue treatment with acetylcysteine at 6. o If the serum ALT is elevated OR if the serum acetaminophen concentration is detectable. the dose should be repeated.  Patients who experience only flushing do not require intervention and the infusion can be continued. o Vomiting  Approximately 33 percent of subjects treated with oral acetylcysteine develop nausea and vomiting [23]. 
 
 o Check the serum ALT and acetaminophen concentrations as the patient is approaching the end of the protocol (approximately 18 hours after starting treatment).require IV therapy.

 We suggest measuring the ALT and INR every 12 hours for any patient who develops ALT elevation. also measure the international normalized ratio (INR). maternal overdose causes fetal exposure and there are case reports of fetal and neonatal death from hepatic necrosis following maternal overdose [32. If the ALT is elevated. or encephalopathy.ALT measurement every 12 hours thereafter. Treatment of the pregnant patient — The essential elements of treating acetaminophen overdose do not differ significantly in the pregnant patient. Many toxicologists prefer to give acetylcysteine intravenously to pregnant patients to reduce the risk of vomiting and ensure more rapid delivery to the fetus. 
 
 o Treatment can be stopped when the serum acetaminophen concentration is undetectable. coagulopathy (ie.34]. the ALT is clearly decreasing or in the normal range. glucose.  If the patient develops an ALT greater than 1000 IU/L. then the serum bicarbonate.  Side effects — o Both therapeutic serum concentrations of . cardiac monitor) may be indicated based upon the patient's clinical condition if a significant coingestion is known or suspected or other problems arise.33].  Since acetaminophen crosses the placenta. Monitoring during treatment —  We suggest measuring the ALT prior to stopping acetylcysteine and continuing treatment if the ALT is abnormal. and creatinine should also be measured every 12 hours. and the INR is less than two. ICU admission. most cases of pregnant women with an acetaminophen overdose are uneventful [32. as some patients will develop liver injury during the treatment period.  Closer monitoring (eg.  We also suggest remeasuring the serum acetaminophen concentration prior to stopping acetylcysteine to verify that the level is undetectable.5). INR >1. Nevertheless.

. occur between 4 and 20 hours post ingestion. These elevations are usually mild (INR should not be greater than 1. and resolve as treatment is continued [46].acetylcysteine and high concentrations of acetaminophen can elevate the INR.5).

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