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AUTHOR INFORMATION
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Section 1 of
10
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| Author:
Susan E Farrell, MD, Program Director, Instructor,
Department of Emergency Medicine, Harvard Medical School, Beth Israel
Deaconess Medical Center
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| Editor(s): Miguel C Fernandez, MD, Medical Director
of South Texas Poison Center, Associate Clinical Professor, Departments
of Emergency Medicine and Toxicology, University of Texas Health Science
Center at San Antonio; John T VanDeVoort, PharmD, DABAT,
Manager, Clinical Assistant Professor, Pharmacy Department, Regions
Hospital; Michael J Burns, MD, Instructor, Department
of Emergency Medicine, Harvard University Medical School, Beth Israel
Deaconess Medical Center; John Halamka, MD, Chief
Information Officer, CareGroup Healthcare System, Assistant Professor of
Medicine, Department of Emergency Medicine, Beth Israel Deaconess
Medical Center; Assistant Professor of Medicine, Harvard Medical School;
and Raymond J Roberge, MD, MPH, FAAEM, FACMT, Research
Director, Department of Emergency Medicine, Ohio Valley Medical Center;
Clinical Associate Professor, Department of Emergency Medicine,
University of Pittsburgh |
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INTRODUCTION
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Section 2 of
10 
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Background: Acetaminophen
is the most widely used pharmaceutical analgesic and antipyretic agent in
the United States and the world; it is contained in more than 100 products.
As such, acetaminophen is one of the most common pharmaceuticals associated
with both intentional and accidental poisoning.
Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen
also is known as paracetamol and N-acetyl-p-aminophenol (APAP). It
is found in the United States as 325-mg and 500-mg immediate-release tablets
and as a 650-mg extended-release preparation. Various children's chewable,
suspension, and elixir formulations of acetaminophen also are available.
Furthermore, acetaminophen is found as a component of combination drugs such
as propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg,
Percocet).
Pathophysiology: The maximum daily dose of APAP is 4 g
in adults and 90 mg/kg in children. The toxic dose of APAP after a single
acute ingestion is 150 mg/kg or approximately 7 g in adults, although the
at-risk dose may be lower in persons with alcoholism and other susceptible
individuals. When dosing recommendations are followed, the risk of
hepatotoxicity is extremely small.
Acetaminophen is rapidly absorbed from the stomach and small intestine
and metabolized by conjugation in the liver to nontoxic agents, which then
are eliminated in the urine.
In acute overdose or when maximum daily dose is exceeded over a prolonged
period, the normal pathways of metabolism become saturated. Excess APAP is
then metabolized in the liver via the mixed function oxidase P450 system to
a toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI
has an extremely short half-life and is rapidly conjugated with glutathione,
a sulfhydryl donor, and removed from the system. Under conditions of
excessive NAPQI formation or reduced glutathione stores, NAPQI is free to
covalently bind to vital proteins and the lipid bilayer of hepatocytes; this
results in hepatocellular death and subsequent centrilobular liver necrosis.
The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC
is theorized to work by a number of protective mechanisms. Early after
overdose, NAC prevents the formation and accumulation of NAPQI. NAC
increases glutathione stores, combines directly with NAPQI as a glutathione
substitute, and enhances sulfate conjugation. NAC also functions as an
anti-inflammatory and antioxidant and has positive inotropic and
vasodilating effects, which improve microcirculatory blood flow and oxygen
delivery to tissues. Vasodilating effects decrease morbidity and mortality
once hepatotoxicity is well established.
NAC is most effective when administered within 8 hours of ingestion. When
indicated, however, NAC should be administered regardless of time since the
overdose. Therapy with NAC has been shown to decrease mortality rates in
late-presenting patients with fulminant hepatic failure (in the absence of
acetaminophen in the serum).
Frequency:
- In the US: Acetaminophen is one of the most common
agents in overdose reported to the American Association of Poison Control
Centers. APAP toxicity is the most common cause of hepatic failure
requiring liver transplantation in the United States and Great Britain.
Mortality/Morbidity: The majority of patients with APAP
overdose survive with supportive care in conjunction with antidotal therapy.
If correctly treated in a timely manner, most patients do not suffer
significant sequelae.
- Case series report that fewer than 4% of patients who suffer severe
hepatotoxicity develop hepatic failure; fatalities or liver
transplantation occur in less than one half of these patients.
- Patients with malnutrition, AIDS, chronic ethanol abuse, or anorexia
nervosa may be at increased risk for morbidity because of deficient
glutathione stores and inadequate detoxification of NAPQI. Patients with
enhanced ability to make NAPQI because of induction of the P450 system,
specifically cyp2E1, may be at increased risk of morbidity; these patients
include those taking agents known to induce this enzyme activity, such as
rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or patients
with chronic ethanol abuse.
- Pediatric patients younger than 5 years appear to fare better than
adults after APAP poisoning, perhaps owing to a greater capacity to
conjugate acetaminophen, enhanced detoxification of NAPQI, or greater
glutathione stores. However, since no controlled studies have supported
any alternative pediatric therapy, treatment in children should not be
different than in adults.
History: The course of
acetaminophen toxicity generally is divided into 4 phases. Evidence of
end-organ (hepatic, renal) toxicity often is delayed 24-48 hours
postingestion.
- Because antidotal therapy is most efficacious when initiated within 8
hours postingestion, the clinician must attempt to obtain an accurate
history of the time(s) of ingestion, the quantity and formulation of
acetaminophen ingested, and any co-ingestants (eg, diphenhydramine, other
anticholinergic drugs, opioids), which may delay absorption.
- However, as a patient's history often is inaccurate, the serum
acetaminophen concentration is important for diagnosis and treatment, even
in the absence of symptoms.
- Decreasing symptoms of phase 1
- Right upper quadrant abdominal pain and rising liver enzymes (alanine
aminotransferase [ALT], aspartate aminotransferase [AST])
- Centrilobular hepatic necrosis with accompanying abdominal pain
- Jaundice
- Coagulopathy
- Hepatic encephalopathy
- Recurrence of nausea and vomiting
- Complete resolution of symptoms
- Complete resolution of organ failure
Physical: Physical examination findings vary, depending
on the phase of toxicity.
- Right upper quadrant abdominal tenderness
- Hypotension possibly due to volume loss
- Evidence of coagulopathy, including gastrointestinal (GI) bleeding
- Evidence of hepatic encephalopathy
Causes:
- Production of acetaminophen's toxic metabolite, NAPQI, in excess of an
adequate store of glutathione necessary to conjugate it, leads to NAPQI-induced
hepatocellular necrosis and hepatic failure.
- Additional mechanisms of acetaminophen-induced toxicity are postulated
as well.
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DIFFERENTIALS
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Section 4 of
10
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Gastritis and Peptic
Ulcer Disease
Gastroenteritis
Hepatitis
Pancreatitis
Toxicity, Mushroom -
Amatoxin
Other Problems to be Considered:
Vomiting of unclear etiology
Hepatic failure
Hepatorenal syndrome
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Continuing Education
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Patient Education |
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Click
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Lab Studies:
- Acetaminophen serum concentration
- A serum acetaminophen concentration drawn 4 or more hours after a
single ingestion may be plotted on the Rumack-Matthew nomogram as a
guide to recommended NAC therapy. Do not rely upon this nomogram
following multiple acetaminophen ingestions, multiple ingestions such as
those involving anticholinergics or opioids, extended release
formulations, or chronic ingestions. Note that the Rumack-Matthew
nomogram is a treatment nomogram and distinct from the Done nomogram,
which serves to predict the severity of toxicity in salicylate
poisoning.
- Determine serum acetaminophen concentration in any intentional
overdose because the history of acetaminophen ingestion may not be
elicited, and manifestations of toxicity may not become evident until
after treatment should have been initiated. (See
Special Concerns for information regarding extended-relief
acetaminophen.)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
begin to rise within 24 hours postingestion and peak at 48-72 hours.
- Severe toxicity can be defined as AST or ALT greater than 1000 IU/L.
- Measures of hepatic function
- Prothrombin time (PT) and bilirubin
- Electrolytes and creatinine
- Look for anion gap acidosis to help rule out co-ingestion, metabolic
disorder from vomiting, or liver failure (if subacute ingestion).
- Renal failure has been shown to coexist with or, rarely, be
independent of liver toxicity in overdose. One study indicated that this
is more likely to occur in alcoholic persons. Renal failure usually is
not observed acutely but rather within 2-3 days of overdose.
- Human chorionic gonadotropin (HCG) in females of childbearing age
- Acetaminophen crosses the placenta, and the fetal liver is able to
elaborate NAPQI by 14 weeks of gestation.
- Delay in treating pregnant patients with antidotal therapy is
associated with fetal demise.
- A type and crossmatch should be drawn for the treatment of active
bleeding in the face of coagulopathy.
- Urinalysis: Proteinuria and hematuria may be seen with acute tubular
necrosis (ATN), usually in conjunction with hepatic failure.
- Poor prognosis is associated with an arterial pH less than 7.30
(which fails to correct with fluid administration) and serum creatinine
greater than 3.4 mg/dL.
- An arterial blood gas (ABG) should be drawn in patients with
clinical or laboratory evidences of toxic overdose or altered mental
status.
Imaging Studies:
- CT scan may reveal cerebral edema in patients with late presentation
and encephalopathy.
- Consider in patients with altered mental status.
- Ultrasound may reveal mild hepatic enlargement in late presentation.
- If clinically indicated, this is usually an inpatient procedure.
Procedures:
- Gastric lavage is controversial and has no proven efficacy in
isolated acetaminophen overdose.
- Consider in early presentation (<1 h) following a multidrug
ingestion with altered mental status or hemodynamic compromise.
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TREATMENT |
Section 6 of
10
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Prehospital Care: Stabilize
immediate life-threatening conditions and initiate supportive care.
Emergency Department Care:
- Supportive therapy, including IV fluids, oxygen, and cardiac monitor
- Oral activated charcoal avidly adsorbs acetaminophen and should be
administered if the patient presents within 1-2 hours of ingestion or
later, especially if a GI motility-inhibiting co-ingestant may have been
involved.
- Administer oral activated charcoal if the time of ingestion is
unknown, the patient ingested extended-relief acetaminophen, or
possibility of a drug co-ingestion exists.
- Administer N-acetylcysteine, if indicated.
- Assess for evidence of other life-threatening co-ingestions.
Consultations:
- Medical toxicologist, available through consultation with a regional
poison control center
- This consultation is recommended if using IV NAC.
- Consultation with a medical toxicologist also is recommended for
patients who have a complicated or late presentation, hepatic or renal
dysfunction, or a history of potentially toxic co-ingestants.
- If fulminant hepatic failure is present, consult a hepatologist and
transplant surgeon.
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MEDICATION
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Section 7 of
10
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Agents used in the treatment of acetaminophen
poisoning include activated charcoal, N-acetylcysteine, and
antiemetics.
Drug Category: GI decontaminants --
Emergency treatment in poisoning caused by drugs and chemicals. Network of
pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of
charcoal. Does not dissolve in water.
Drug Name
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Activated charcoal (Liqui-Char) --
DOC for patients presenting within 1-2 h postingestion or in cases where
co-ingestants may delay gastric emptying or gut motility. Expect minimal
benefit if administered >4 h postingestion. |
| Adult Dose |
1 g/kg PO or 10 times the amount of
drug ingested |
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity;
poisoning or overdosage of mineral acids and alkalies; unprotected
airway with absent gag reflex |
| Interactions |
May inactivate ipecac syrup if used
concomitantly; effectiveness of other medications decreases with
coadministration; do not mix with sherbet, milk, or ice cream (decreases
adsorptive properties) |
| Pregnancy |
C - Safety for use during pregnancy
has not been established. |
| Precautions |
Not very effective in poisonings of
ethanol, methanol, and iron salts; induce emesis before administering
activated charcoal; after emesis with ipecac, patient may not tolerate
activated charcoal for 1-2 h; can administer in early stages of gastric
lavage; without sorbitol, gastric lavage returns are black; adverse
effects include nausea, vomiting, and aspiration if the airway is not
secure; monitor for bowel sounds to minimize risk of charcoal ileus |
Drug Category: Antidote -- May provide
substrate for conjugation with the toxic metabolite of acetaminophen.
Administer all doses, even if acetaminophen level has dropped below toxic
range.
Drug Name
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N-acetylcysteine (Mucomyst)
-- DOC for prevention and treatment of acetaminophen-induced
hepatotoxicity. Approved by the FDA for PO administration but is also
administered IV, especially when PO NAC is not tolerated due to
refractory vomiting. For maximum hepatoprotective effect, administer
within 8-24 h of acetaminophen ingestion. When given PO, dilute in
chilled juice or cola to a 5% solution. May be dripped slowly via
nasogastric tube if severe nausea threatens administration. Repeat dose
if vomiting occurs within 1 h of NAC administration. When administered
IV, infuse over 1 h through a 0.2 micron Millipore pyrogen filter. |
| Adult Dose |
140 mg/kg PO loading dose, followed
by 70 mg/kg q4h for 17 additional doses (total 1330 mg/kg over 72 h)
140 mg/kg IV loading dose, followed by 70 mg/kg q4h for 12 doses (total
980 mg/kg over 48 h); infuse over 1 h through a micropore filter
(consult with a regional poison center and/or medical toxicologist)
Some centers use a 20-h treatment protocol (consult regional poison
center and/or medical toxicologist) |
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity |
| Interactions |
None reported |
| Pregnancy |
A - Safe in pregnancy |
| Precautions |
Adverse effects associated with PO
NAC include nausea and vomiting, probably induced by its foul "rotten
egg" odor and, rarely, clinically insignificant sulfhemoglobinemia; only
1 case of an anaphylactoid reaction following PO NAC has been reported;
IV NAC may cause various degrees of infusion rate-dependent erythema at
infusion site, urticaria, fever, and bronchospasm (anaphylactoid
reaction); respond to antihistamines and epinephrine; may be limited by
slowing the infusion rate |
Drug Category: Antiemetics -- Emesis
frequently is associated with acetaminophen toxicity and is a common
consequence of activated charcoal and NAC administration. For these reasons,
antiemetic therapy often is necessary to allow successful administration of
NAC.
Antiemetics that do not decrease gastric motility or significantly alter
mental status are the DOC; anticholinergic drugs, such as prochlorperazine (Compazine)
are not considered beneficial, in part because of their propensity to cause
both of these effects. Phenothiazines also may add to the toxicity
associated with other anticholinergic drugs, which are often in APAP-containing
formulations.
Drug Name
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Metoclopramide (Reglan) --
Functions as antiemetic by blocking dopamine receptors in the
chemoreceptor trigger zone of CNS. Is generally DOC due to lower cost
than ondansetron (Zofran). |
| Adult Dose |
10-20 mg IV, not to exceed 1 mg/kg;
not to exceed 3 mg/kg/d divided prn |
| Pediatric Dose |
1-2 mg/kg total dose |
| Contraindications |
Documented hypersensitivity |
| Interactions |
May antagonize effects of
metoclopramide; opiate analgesics may increase metoclopramide toxicity
in CNS |
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
| Precautions |
Caution in history of mental
illness and Parkinson disease; adverse effects include drowsiness,
hypotension, and acute dystonia, especially at high doses; may increase
frequency of seizure in individuals with epilepsy |
Drug Name
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Ondansetron (Zofran) -- Selective
5-HT3–receptor antagonist that blocks serotonin both peripherally and
centrally. Considered potentially more effective than metoclopramide; in
addition, adverse effects are less common. |
| Adult Dose |
0.15 mg/kg or 8 mg IV q8h, not to
exceed 3 doses |
| Pediatric Dose |
0.15 mg/kg IV q 8h, not to exceed 3
doses |
| Contraindications |
Documented hypersensitivity |
| Interactions |
Although cytochrome P-450 inducers
(barbiturates, rifampin, carbamazepine, and phenytoin) may potentially
change half-life and clearance of ondansetron, dosage adjustment is not
usually required |
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
| Precautions |
Medication is to be administered
for prevention of nausea and vomiting, not for rescue of nausea and
vomiting |
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FOLLOW-UP |
Section 8 of
10
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Further Inpatient Care:
- Admit patients for NAC therapy if they have an acetaminophen level
associated with potential toxicity, as suggested by the Rumack-Matthew
treatment nomogram.
- Unless coexisting toxicologic, medical, or psychiatric issues are
present, patients with acetaminophen toxicity may be admitted and treated
on a general medical floor.
- Admit patients to an ICU setting if they show signs of significant
hepatotoxicity; hepatic failure; or other potentially life-threatening,
coexisting, toxicologic, or medical issues.
Further Outpatient Care:
- Patients who do not have a suggestive history or acetaminophen level
associated with potential toxicity, as determined by the Rumack-Matthew
nomogram, may be discharged or transferred for psychiatric evaluation if
indicated.
Transfer:
- Transfer patients with fulminant hepatic failure to a facility capable
of intensive care monitoring and evaluation for potential transplantation.
Patient Education:
- Advise patients of the potential risk associated with the
inappropriate use of acetaminophen, which commonly is considered an
innocuous over-the-counter drug.
- Educate parents of the proper acetaminophen dosing for children and
the danger associated with misusing various acetaminophen preparations (eg,
infant suspension vs pediatric elixir, pediatric vs adult suppositories).
Because infant suspension (drops) is a more concentrated formulation than
the elixir (100 mg/mL vs 32 mg/mL), this can be a potential source of
therapeutic error. Parents always should be given clear dose and
formulation instructions.
- Educate patients of the increased potential for renal toxicity
associated with concurrent acetaminophen and NSAID analgesic use or
chronic alcoholism.
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MISCELLANEOUS
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Section 9 of
10
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Medical/Legal Pitfalls:
- NAC-activated charcoal interaction
- In vitro studies have shown that NAC is adsorbed to activated
charcoal and the administration of activated charcoal reduced total NAC
absorption by 39% in human volunteers, as measured by serum NAC levels.
Prospective evaluation of patients treated with activated charcoal and
NAC, however, indicated no adverse outcome associated with this
treatment.
- Despite binding to NAC, activated charcoal adsorbs acetaminophen
more avidly. Therefore, although charcoal may decrease the
bioavailability of NAC, this decrease is clinically inconsequential.
- Finally, activated charcoal administration may prevent significant
acetaminophen absorption and obviate the need for NAC.
- Super-loading doses of NAC have shown to be of no greater clinical
benefit than the current recommended loading dose.
- Administer activated charcoal and draw a 4-hour serum acetaminophen
concentration if the patient presents within 1-2 hours of ingestion,
presents later after co-ingestion with a substance that could delay
systemic absorption, or the history is unclear.
- Draw an acetaminophen level if the patient presents later than 4
hours after ingestion. Administer NAC if presentation is close to 8
hours postingestion or if the acetaminophen level will not be available
within 8 hours postingestion.
- NAC may be staggered with activated charcoal if multiple doses of
activated charcoal are necessary for treatment of a co-ingestant.
- For greatest efficacy, administer NAC within 8 hours of ingestion;
however, a later presentation should not preclude its administration if
the history or presentation suggests potential toxicity. Failure to
administer NAC because of late presentation could be considered
medically and legally risky.
- Failure to consider and evaluate for possible co-ingestants or to
consider the effects of decreased GI motility on absorption of APAP; the
treatment nomogram does not pertain to these situations. Therefore, in
the absence of good data on multidrug or co-ingestions involving APAP,
administer NAC as early as possible and consult the regional poison
control center for guidance on a treatment regimen.
Special Concerns:
- If a patient presents with ingestion of supratherapeutic doses of
acetaminophen over hours or days, evaluate for presence of
hepatotoxicity and unmetabolized acetaminophen.
- Begin NAC therapy if the patient has elevated AST and ALT and a
measurable acetaminophen concentration.
- Consult the regional poison control center for guidance on a
treatment regimen.
- If a patient presents 8-24 hours or longer postingestion, evaluate
for ongoing hepatotoxicity and initiate NAC therapy if indicated.
- NAC administration in cases of hepatic failure has been associated
with decreased incidence of cerebral edema and improved survival.
- Extended-relief acetaminophen (Tylenol ER)
- The Tylenol ER preparation became available in 1995. The tablet is
composed of acetaminophen 325 mg in immediate release form with a matrix
of acetaminophen 325 mg formulated for slow release. Some alteration of
the elimination kinetics of this preparation may affect the ability of
the Rumack-Matthew nomogram to guide treatment. Several studies show
that eliminations of extended and immediate-release acetaminophen are
nearly identical after 4 hours. However, some case reports have
documented acetaminophen levels falling above the treatment nomogram
line as late as 11-14 hours postingestion of the extended-release
preparation.
- Check 4-, 6-, and 8-hour acetaminophen concentration levels. Begin
NAC therapy if any level crosses above the nomogram treatment line. If
the 6-hour level is greater than the 4-hour level, begin NAC therapy.
More prolonged monitoring of levels may be necessary if the patient has
food in the stomach or co-ingestants that delay gastric emptying.
Consult the regional poison control center for guidance in evaluation
and treatment regimen.
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BIBLIOGRAPHY
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Section 10 of
10
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- Anker AL, Smilkstein MJ: Acetaminophen. Concepts and controversies.
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- Bizovi KE, Aks SE, Paloucek F, et al: Late increase in acetaminophen
concentration after overdose of Tylenol Extended Relief. Ann Emerg Med
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- Chamberlain JM, Gorman RL, Oderda GM, et al: Use of activated charcoal
in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?
Ann Emerg Med 1993 Sep; 22(9): 1398-402[Medline].
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charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med
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Winchester J, Fletcher J, eds. Clinical Management of Poisoning and Drug
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- Smilkstein MJ: A new loading dose for N-acetylcysteine? The answer is
no. Ann Emerg Med 1994 Sep; 24(3): 538-9[Medline].
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| NOTE:
|
| Medicine is a constantly
changing science and not all therapies are clearly established. New
research changes drug and treatment therapies daily. The authors,
editors, and publisher of this journal have used their best efforts to
provide information that is up-to-date and accurate and is generally
accepted within medical standards at the time of publication. However,
as medical science is constantly changing and human error is always
possible, the authors, editors, and publisher or any other party
involved with the publication of this article do not warrant the
information in this article is accurate or complete, nor are they
responsible for omissions or errors in the article or for the results of
using this information. The reader should confirm the information in
this article from other sources prior to use. In particular, all drug
doses, indications, and contraindications should be confirmed in the
package insert. FULL
DISCLAIMER |
Toxicity, Acetaminophen excerpt
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