Pediatric Annals

Case Studies in Pediatric Toxicology

Shaun D Carstairs, MD; David A Tanen, MD, FACMT

Abstract

If irreversible hepatic damage occurs, fulminant liver failure usually is apparent 3 to 5 days after overdose. Patients usually die from acute respiratory distress syndrome (ARDS), cerebral edema, hemorrhage, or some combination of these.22 Patients who survive stage III progress to stage IV (4 days to 2 weeks after ingestion), during which time hepatic regeneration occurs; no hepatic fibrosis occurs. Laboratory studies usually normalize within 5 to 7 days after overdose, but may take longer in severely poisoned patients. Patients who survive regain normal hepatic function; there have been no reported cases of chronic liver dysfunction in survivors of acute acetaminophen poisoning.

Risk of significant ingestion is evaluated by obtaining a history of acetaminophen ingestion (or finding APAP on screening laboratory studies) and by determining the serum APAP concentration. The Rumack-Matthew nomogram23 (Figure) is used to determine the risk of hepatotoxicity after a single acute ingestion based on serum APAP levels and may be used as early as 4 hours post-ingestion. In general, toxicity can occur with a single acute dose of 7.5 g in adults or 150 mg/kg in children. Antidotal treatment with 7V-acetylcysteine (NAC) is indicated with a 4-hour APAP level of 150 mcg/mL. In chronic (multiple-dose) acetaminophen overdose, the nomogram cannot be applied; NAC should be administered.

Treatment

Initial management of acetaminophen overdose is the same as with nearly all poisoned patients. Airway, breathing, and circulation should be secured. Activated charcoal should be administered orally at a dose of 1 g/kg. If nausea and vomiting is present, anti-emetics should be considered. Laboratory studies that should be obtained include serum electrolytes, BUN, creatinine, liver function tests, and prothrombin time. An APAP level should be obtained at 4 hours post-ingestion (or on arrival if it has been greater than 4 hours since ingestion) and plotted on the Rumack-Matthew nomogram; if a toxic level of acetaminophen is present, the patient should be treated with NAC.

NAC prevents hepatotoxicity by serving as a precursor to glutathione; it is also thought to have some ability to reduce NAPQI directly. It is most effective in preventing hepatotoxicity if given within 8 hours of ingestion but should still be considered if a longer time has elapsed.24 If the patient is able to tolerate oral dosing, it should be given in a loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours for a total of 18 doses (72 hours).

NAC tastes and smells quite unpleasant, and consideration should be given to diluting it ( 1 :4) with juice or a carbonated beverage in order to increase palatability. Placing the diluted NAC in a cup with a lid and straw also helps to decrease the unpleasant smell and subsequent nausea. If nausea does occur, anti-emetic administration should be considered strongly; if the patient vomits the NAC dose within 1 hour of administration, the dose should be repeated. If vomiting persists, a nasogastric tube can be used. Shorter courses of oral NAC are being studied, and consultation with a toxicologist or poison center is highly recommended.

An intravenous formulation of NAC recently has been approved by the Food and Drug Administration (FDA). It should be considered in patients with severe vomiting, altered mental status, or severely ill patients. The medication is given in a loading dose of 150 mg/kg intravenously over 15 minutes, followed by 50 mg/kg in 500 ce D5W over 4 hours and then 100 mg/kg in 1,000 ce D5W over 16 hours, for a total treatment time of 20 hours, 15 minutes.25 Anaphylactoid reactions may occur with the intravenous formulation and should be treated by slowing or stopping the infusion and…

Poisonings are among the most common medical emergencies seen in children and account for a significant number of emergency department visits annually. While intentional exposures account for 10% to 15% percent of cases, the vast majority of cases (greater than 80%) are unintentional.

This article describes the pharmacology, presentation, and management of three specific toxicologie presentations: poisonous snake envenomation, methemoglobinemia,and acetaminophen overdose. Specific signs and symptoms, assessment procedures, and treatment options are discussed.

POISONOUS SNAKE ENVENOMATION

Case Description

An 8-year-old boy is hiking with his father and sees what they believe to be a "baby rattlesnake" on the trail in front of them. The child reaches out to pet the snake and is bitten on the dorsum of the right hand. The patient begins to experience pain and swelling at the bite site nearly immediately, and his father takes him to a nearby clinic. The patient has one episode of emesis prior to arrival and complains of a metallic taste in his mouth on presentation. Vital signs are temperature 36.5 degrees C, blood pressure 125/85, pulse 110, and respiratory rate 20. Physical examination reveals significant swelling of the right upper extremity to the mid-forearm, with obvious myokymia (spontaneous, fine muscle contractions often observed as a quivering or rippling effect). Two puncture wounds are noted on the dorsum of the right hand with surrounding ecchymosis; no blebs are present Examination of the right axilla reveals significant tenderness.

Discussion

Approximately 2,000 venomous snakebites are reported to poison control centers in the United States each year. The true incidence is thought to be three to four times higher, with a mortality rate of about five per year, or less than 0.5%.1 Death due to a rattlesnake bite is rare; however, significant morbidity may occur without prompt treatment.

The vast majority of envenomations are due to pit vipers (including rattlesnakes, copperheads, and cottonmouths), with coral snakes making up much of the remainder. Victims usually are young males, and alcohol intoxication frequently plays a role in envenomations. Envenomations occur most frequently (more than 95%) on the extremities, with upper extremities being involved most often in adults and lower extremities most often in children.2

Crotalid venom is a complex mixture of metals, enzymes, and other substances with considerable biologic activity. Hemorrhagic toxins increase the permeability of capillary endothelial cells, which allows extravasation of blood and fluid into surrounding tissues. Many snake venoms contain enzymes that deplete plasma fibrinogen and fibrin levels, resulting in a laboratory picture of disseminated intravascular coagulation (DIC); however, clinical evidence of DIC is rare. Thrombocytopenia also is common, although the mechanisms by which it occurs are understood incompletely.3

Crotaline (pit viper) envenomations mainly produce local effects; patients usually present with pain and puncture wounds at the bite site, progressive swelling, ecchymosis, and occasionally hemorrhagic blebs. As the venom spreads through the lymphatic system, it can produce tender regional lymphadenopathy and lymphangitis. Systemic effects may also occur, such as nausea or vomiting, tachycardia, muscle fasciculations, perioral numbness, weakness, and dizziness. Patients occasionally complain of a minty or metallic taste in the mouth. Severe envenomations may cause tachypnea, respiratory distress, hypotension, or altered sensorium.4

It should be noted that approximately 25% of crotaline bites are "dry" and do not result in envenomation. These patients, however, may still present with autonomie reactions related to fear associated with a snakebite, such as tachycardia, nausea, and vomiting; care must be taken to distinguish these symptoms from those due to true envenomation.5 Patients suffering a suspected venomous snakebite who are undergoing pre-hospital transport should have the limb immobilized in a neutral position to reduce further venom spread through the lymphatics.6 Tourniquets, venom extractors, and ice immersion are not indicated and may cause more serious injury.

Treatment

On initial examination, airway, breathing, and circulation should be established. Intravenous access should be obtained, and isotonic crystalloid should be administered to prevent hypotension secondary to third-spacing. Circumferential measurements at several sites above and below the bite site should be obtained at baseline and serially every 15 to 20 minutes to assess for progression of edema. Baseline laboratory studies should include complete blood count, serum electrolytes, BUN, creatinine, PT/ PTT, fibrinogen, and urinalysis. Laboratory testing in patients with crotaline envenomations may reveal evidence of a significant coagulopathy, thrombocytopenia, or both. However, clinical experience has shown that bleeding is rarely a problem. Creatine phosphokinase may be measured in cases of suspected rhabdomyolysis.

Crotaline bites usually are associated with significant pain, and parenteral narcotic analgesia should be administered as appropriate; fentanyl is preferred because it is the least histaminergic narcotic medication. This may be important when treatment options may be affected by the appearance of an allergic reaction. The need for tetanus prophylaxis should also be assessed. Antibiotics or steroids are not routinely indicated.

In patients with crotaline bites, consideration should be given to treatment with FabAV antivenom. Indications for use are not defined concretely but generally include progressive edema, hypotension, or laboratory evidence of worsening coagulopathy.7 The initial dose of FabAV (for children or adults) is 4 to 6 vials reconstituted into 250 cc of normal saline. The infusion should be started slowly and titrated to 250 cc/hr. Although FabAV is sheep-derived, it is the Fab fragment of the antibody molecule that induces fewer anaphylactoid reactions than similar whole antibody antivenoms. If evidence of an anaphylactoid reaction occurs during the administration of the antivenom, the infusion should be stopped immediately, and antihistamines, epinephrine, or both should be administered as necessary. Once the symptoms have abated, the antivenom may be restarted at a slower rate and run to completion.

Patients may require additional vials of antivenom to establish initial control, defined as cessation of progression of signs and symptoms, or to treat recurrence, which can occur hours to days after the envenomation.8 Increased compartment pressures from crotaline bites are uncommon and usually respond to administration of antivenom. Fasciotomy is rarely indicated;9 indeed, animal models have demonstrated an increase in myonecrosis after treatment of venom-induced compartment syndrome with fasciotomy.10

Patients requiring administration of antivenom should be admitted to a closely monitored setting (eg, intensive care unit). Patients with crotaline bites who have minimal clinical signs or symptoms should be observed for a minimum of 8 hours, as clinical venom effects may be delayed by several hours. However, patients who continue to have no significant clinical or laboratory abnormalities at the end of this period are unlikely to develop any significant effects and may be discharged.

METHEMOGLOBINEMIA

Case Description

A 2-year-old boy presents with his parents after swallowing a chicken bone, which the parents think lodged in the patient's throat. The treating physician sprays benzocaine into the oropharynx in preparation for a nasopharyngeal endoscopy, and the child receives midazolam 1 mg intravenously for sedation. During the procedure, his oxygen saturation, which had been 1 00%, is observed to fall to 88%; the child also begins to exhibit central cyanosis. Supplemental oxygen via face mask fails to improve his status. Vital signs are temperature 37.1 degrees C, blood pressure 80/50, pulse 125, and respiratory rate 30. Blood drawn from the patient's peripheral IV is chocolate brown in appearance. Co-oximetry reveals a methemoglobin level of 42%.

Discussion

Methemoglobinemia is a rare but potentially life-threatening condition that is produced under conditions of oxygen stress when the iron moiety within hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state. This results in a decreased capability of hemoglobin to transport oxygen, leading to tissue hypoxemia, metabolic acidosis, and even death. Most commonly, methemoglobinemia is acquired (usually from exposure to an oxidizing substance), but it also can be dietary, genetic, or idiopathic in etiology.

Physiologic methemoglobin (MHb) levels are normally maintained at approximately one percent at any given time. There are a variety of mechanisms the body uses to reduce methemoglobin; the most important of these in normal homeostasis is NADH-cytochrome bs reductase, an enzyme that accounts for approximately 99% of daily MHb reduction. Glutathione and ascorbic acid each account for a small fraction of in vivo MHb reduction. Another enzyme that can reduce MHb is NADPH-MHb reductase. This enzyme plays a negligible role in reducing MHb under normal physiologic conditions, but its activity can be enhanced chemically and may be used in the treatment of methemoglobinemia.

Table

TABLE.Signs and Symptoms Associated With Methemoglobin (MHb) Concentrations

TABLE.

Signs and Symptoms Associated With Methemoglobin (MHb) Concentrations

Methemoglobinemia typically is caused by either ingestion of, inhalation of, or dermal exposure to an oxidizing agent. Common agents include nitrates, phenazopyridine, dapsone, and local anesthetics (such as benzocaine or prilocaine). The Sidebar (see page 975) lists a number of common substances that can cause methemoglobinemia.

Infants are at greatest risk of developing acquired methemoglobinemia because their levels of NADH-cytochrome b5 reductase typically are only 50% to 60% of adult levels and do not reach normal adult levels until approximately age 4 months. Systemic acidosis can also produce methemoglobinemia in infants, commonly as a result of infection (typically diarrhea), dehydration, or both.11

Oxidizing agents can act either directly or indirectly. Direct oxidizing agents react directly with hemoglobin to create MHb. Indirect oxidizing agents are actually strong reducing agents that create O2* (a free radical) from oxygen or H2O2 from water, both of which subsequently oxidize hemoglobin to MHb.

Congenital methemoglobinemia may be due to either a deficiency in the NADHcytochrome b5 reductase system or by an abnormal hemoglobin molecule (also known as hemoglobin M) resulting in an altered structure that increases the risk of oxidation of the iron moiety of the heme. Patients with these conditions typically present shortly after birth with cyanosis. Patients with G6PD deficiency are not at increased risk for developing methemoglobinemia, but if methemoglobinemia is present, treatment may be complicated by the lack of NADPH available.

MHb leads to a decrease in tissue oxygénation through two mechanisms. First, MHb levels greater than 2% lead to a functional anemia with less heme available to carry oxygen to the tissues (ie, diminished oxygen-carrying capacity). Second, the ferric heme groups impair the unloading of oxygen by the ferrous heme, producing a leftward shift in the oxyhemoglobin dissociation curve.12

Clinical effects often correlate with the level of methemoglobinemia (Table). Levels below 20% usually are asymptomatic. Levels above 70% can cause circulatory collapse and death. Cyanosis in the absence of MHb typically requires 5 g/dL of reduced hemoglobin; however, in patients with methemoglobinemia, only 1.5 g/dL of the oxidized heme moiety produces noticeable discoloration. Therefore, in the nonanemic patient, 10% to 20% methemoglobinemia produces asymptomatic cyanosis.

Hemolysis also may be observed in cases of methemoglobinemia and is thought to occur secondary to the oxidative stress on the red blood cells rather than any direct effect from the formation of MHb. The degree and clinical significance of the hemolysis that may be seen can vary widely and usually is delayed 12 to 24 hours after drug exposure.

Arterial blood gas analysis and pulse oximetry can be falsely normal or nearnormal in patients with methemoglobinemia and cannot be relied on to confirm or exclude its presence. Co-oximetry of arterial or venous blood can directly measure the presence of methemoglobin, carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin13 and should be used whenever possible to confirm the presence of methemoglobinemia if suspected.

Blood containing more than 15% methemoglobin appears "chocolate" brown when placed on white filter paper. This test can help distinguish between MHb and deoxyhemoglobin, which normally brightens after exposure to atmospheric oxygen. Other diagnostic tests that should be obtained include complete blood count (CBC), Heinz body stain and plasma-free hemoglobin (looking for evidence of hemolysis), and electrocardiogram (for evidence of cardiac ischemia).

Treatment

Initial treatment of patients with methemoglobinemia includes airway, breathing, and circulation assessment (ABCs), as well as supplemental oxygen to maximize the oxygen-carrying capacity of normal hemoglobin. The mainstay of treatment is methylene blue. Methylene blue acts as a cofactor and is reduced by NADPH-MHb reductase to leukomethylene blue; this substance in turn reduces Fe3+ back to Fe2+. Indications for methylene blue treatment include significant symptoms, such as dyspnea or chest pain, MHb levels above 30%, electrocardiogram changes, and metabolic acidosis. It typically is infused at a dose of 1 to 2 mg/kg intravenously over 5 minutes. Response usually is seen within 15 minutes. This may be repeated hourly to a maximum dose of 7 mg/kg.

Methylene blue should be used with caution in patients presenting with methemoglobinemia who are G6PD-deficient; these patients may not produce enough NADPH for méthylène blue to be effective. Additionally, treatment of G6PD-deficient patients with méthylène blue, an oxidizing agent itself, has been associated with hemolytic anemia.14 Other treatment modalities that may be considered in these patients include exchange transfusion and hyperbaric oxygen therapy. Several other reducing agents, including N-acetylcysteine and sodium thiosulfate, have been tried without success in the treatment of methemoglobinemia and thus cannot be recommended. 15'16

Caution should also be exercised in the treatment of methemoglobinemia due to certain long-acting substances such as dapsone, which has an elimination half-life of approximately 30 hours. Patients who have ingested these substances can experience "rebound" methemoglobinemia after treatment with méthylène blue and may require multiple repeat doses.

ACETAMINOPHEN OVERDOSE

Case Description

A 4-year-old girl presents with her parents after they found that she had ingested a 120 mL bottle of children's acetaminophen. The parents report that the patient has not experienced any vomiting. She is seen by the physician approximately 1 hour postingestion. Vital signs are temperature 36.3 degrees C, blood pressure 92/50, pulse 90, and respiratory rate 20. Physical examination is unremarkable.

Discussion

Acetaminophen (N-acetyl-p-aminophenol or APAP) was first synthesized in the mid-1800s17 but did not go on sale in the United States until 1955. It is by far the most commonly used analgesic/ antipyretic; it is available in many preparations, both alone and in combination with other pain relievers (eg, propoxyphene, oxycodone, hydrocodone). As a result, overdose and toxicity are fairly common. Poison control centers in the US receive more than 100,000 calls annually resulting from acetaminophen exposures, and acetaminophen overdose produces more hospitalizations than overdose of any other medication.18

Acetaminophen produces its effects by central inhibition of prostaglandin synthetase. Although it is a potent analgesic and antipyretic, it possesses almost no anti-inflammatory properties. Absorption is rapid, with peak levels occurring within 30 to 45 minutes for oral preparations19 but much longer (108 to 288 minutes) for rectal administration. Bioavailability ranges from 30% to 40% for rectal formulations and 60% to 98% for oral formulations. Normal pediatrie dosage is 15 mg/kg every 6 hours (up to 1 g), with a maximum daily dosage of 4 g.

The vast majority (85% to 95%) of absorbed acetaminophen is eliminated through hepatic conjugation pathways to yield nontoxic glucuronide or sulfate metabolites. The remainder (5% to 15%) is oxidized by various enzymes in the cytochrome P450 system to produce the potentially toxic metabolite 7V-acetylp-benzoquinoneimine (NAPQI). If not eliminated, NAPQI can bind covalently to critical cell proteins in the hepatocyte, triggering a cascade of events that eventually leads to cell death.20

In the liver, glutathione (GSH) combines quickly with NAPQI, detoxifying it and allowing it to be excreted in the urine. With the administration of therapeutic amounts of acetaminophen, GSH supply far exceeds that which is necessary to detoxify NAPQI. However, when potentially toxic doses of acetaminophen are ingested, the glucuronidation and sulfation elimination pathways become saturated and GSH supply is depleted rapidly, resulting in free NAPQI. It is this free NAPQI that produces the clinical effects of overdose.

The clinical effects of acetaminophen poisoning may be divided into four stages. In stage I, which typically occurs 30 minutes to 24 hours after ingestion, patients may experience nausea, vomiting, anorexia, and malaise; however, they may be asymptomatic. In stage ?, which occurs 24 to 72 hours after ingestion, the signs and symptoms seen in stage I lessen, but right upper quadrant pain may be present as liver injury becomes evident. During this stage, aspartate aminotransferase (AST) levels elevate, which may be the most sensitive indicator of the onset of hepatotoxicity.

During stage III, which occurs 72 to 96 hours post-ingestion, liver injury peaks. Clinical presentation may vary from asymptomatic to fulminant hepatic failure with encephalopathy and coma. Patients may become coagulopathic from the loss of synthesis of coagulation factors, and jaundice may be evident due to elevated bilirubin. Renal failure may occur, which is believed to be due to renal P450 formation of NAPQI,21 and anuria may be present. Liver biopsy, if performed, shows evidence of centrilobular necrosis. This is because most oxidative drug metabolism is located in the centrilobular regions (zone III) of the liver; as NAPQI is produced through oxidation, this zone is affected most profoundly.

Figure. Rumack-Matthew nomogram.23

Figure. Rumack-Matthew nomogram.23

If irreversible hepatic damage occurs, fulminant liver failure usually is apparent 3 to 5 days after overdose. Patients usually die from acute respiratory distress syndrome (ARDS), cerebral edema, hemorrhage, or some combination of these.22 Patients who survive stage III progress to stage IV (4 days to 2 weeks after ingestion), during which time hepatic regeneration occurs; no hepatic fibrosis occurs. Laboratory studies usually normalize within 5 to 7 days after overdose, but may take longer in severely poisoned patients. Patients who survive regain normal hepatic function; there have been no reported cases of chronic liver dysfunction in survivors of acute acetaminophen poisoning.

Risk of significant ingestion is evaluated by obtaining a history of acetaminophen ingestion (or finding APAP on screening laboratory studies) and by determining the serum APAP concentration. The Rumack-Matthew nomogram23 (Figure) is used to determine the risk of hepatotoxicity after a single acute ingestion based on serum APAP levels and may be used as early as 4 hours post-ingestion. In general, toxicity can occur with a single acute dose of 7.5 g in adults or 150 mg/kg in children. Antidotal treatment with 7V-acetylcysteine (NAC) is indicated with a 4-hour APAP level of 150 mcg/mL. In chronic (multiple-dose) acetaminophen overdose, the nomogram cannot be applied; NAC should be administered.

Treatment

Initial management of acetaminophen overdose is the same as with nearly all poisoned patients. Airway, breathing, and circulation should be secured. Activated charcoal should be administered orally at a dose of 1 g/kg. If nausea and vomiting is present, anti-emetics should be considered. Laboratory studies that should be obtained include serum electrolytes, BUN, creatinine, liver function tests, and prothrombin time. An APAP level should be obtained at 4 hours post-ingestion (or on arrival if it has been greater than 4 hours since ingestion) and plotted on the Rumack-Matthew nomogram; if a toxic level of acetaminophen is present, the patient should be treated with NAC.

NAC prevents hepatotoxicity by serving as a precursor to glutathione; it is also thought to have some ability to reduce NAPQI directly. It is most effective in preventing hepatotoxicity if given within 8 hours of ingestion but should still be considered if a longer time has elapsed.24 If the patient is able to tolerate oral dosing, it should be given in a loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours for a total of 18 doses (72 hours).

NAC tastes and smells quite unpleasant, and consideration should be given to diluting it ( 1 :4) with juice or a carbonated beverage in order to increase palatability. Placing the diluted NAC in a cup with a lid and straw also helps to decrease the unpleasant smell and subsequent nausea. If nausea does occur, anti-emetic administration should be considered strongly; if the patient vomits the NAC dose within 1 hour of administration, the dose should be repeated. If vomiting persists, a nasogastric tube can be used. Shorter courses of oral NAC are being studied, and consultation with a toxicologist or poison center is highly recommended.

An intravenous formulation of NAC recently has been approved by the Food and Drug Administration (FDA). It should be considered in patients with severe vomiting, altered mental status, or severely ill patients. The medication is given in a loading dose of 150 mg/kg intravenously over 15 minutes, followed by 50 mg/kg in 500 ce D5W over 4 hours and then 100 mg/kg in 1,000 ce D5W over 16 hours, for a total treatment time of 20 hours, 15 minutes.25 Anaphylactoid reactions may occur with the intravenous formulation and should be treated by slowing or stopping the infusion and administering antihistamines, epinephrine, or both as necessary.26'28

All patients with toxic ingestions of acetaminophen should be admitted, and those with evidence of severe hepatotoxicity or encephalopathy require intensive care admission.

SUMMARY

Intentional and unintentional poisonings are encountered commonly in the pediatrie population. Providers should be familiar both with the general approach to the poisoned child and with specific interventions required for certain toxic exposures.

REFERENCES

1. Langley RL, Morrow WE. Deaths resulting from animal attacks in the United States. Wilderness Environ Med. 1997; 8(1):8-16.

2. Tanen DA, Runa AM, Graeme KA, Curry SC. Epidemiology and hospital course of rattlesnake envenomations cared for at a tertiary referral center in central Arizona. Acad Emerg Med. 2001;8(2):177-182.

3. Holstege CP, Miller MB, Wermuth M, Furbee B, Curry SC. Crotalid snake envenomation. Crit Care Clin. 1997;13(4):889-921.

4. Tanen DA, Runa AM, Graeme KA, Curry SC, Rschione MA. Rattlesnake envenomations: unusual case presentations. Arch Int Med. 2001;161(3):474479.

5. Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med. 2002;347(5): 347-356.

6. Bush SP, Green SM, Laack TA, et al. Pressure immobilization delays mortality and increases intracompartmental pressure after artificial intramuscular rattlesnake envenomation in a porcine model. Ann Emerg Med. 2004;44(6): 599-604.

7. Yip L. Rational use of Crotalidae polyvalent immune Fab (ovine) in the management of crotaline bite. Ann Emerg Med. 2002;39(6): 648-650.

8. Dart RC, McNally J. Efficacy, safety, and use of snake antivenoms in the United States. Ann EmergMed. 2001;37(2):181-188.

9. Hall EL. Role of surgical intervention in the management of crotaline snake envenomation. Ann Emerg Med. 2001;37(2): 175-180.

10. Tanen DA, Danish DC, Grice GA, Riffenburgh RH, Clark RF. Fasciotomy worsens the amount of myonecrosis in a porcine model of crotaline envenomation. Ann Emerg Med. 2004;44(2):99-104.

11. WrightRO,LewanderWJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999; 34(5):646-656.

12. Darling RC, Roughton FJW. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol. 1942 Aug;137:56-68.

13. Matthews PJ. Co-oximetry. Respir Care Clin NorthAm. 1995;l(l):47-68.

14. Rosen PJ, Johnson C, McGehee WG, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6 -phosphate dehydrogenase deficiency. Ann Intern Med. 1971;75(l):83-86.

15. Tanen DA, LoVecchìo F, Curry SC. Failure of intravenous N-acetylcysteine to reduce methemoglobin produced by sodium nitrite in volunteers. A randomized controlled trial. Ann Emerg Med. 2000;35(4): 369-373.

16. Matteucci MJ, Reed WJ, Tañen DA. Sodium thiosulfate fails to reduce nitrite-induced methemoglobinemia in vitro. Acad Emerg Med. 2003;10(4):299-302.

17. Morse HN. A new method of synthesis for acetaminophen [in German]. Berichte der Deutschen Chemischen Gesellschaft. 1878;ll:232-233.

18. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004; 22(5): 335-404.

19. DivollM,GreenblattDJ,EmeerB,Abemethy DR. Effect of food on acetaminophen absorption in young and elderly subjects. J CUn Pharmacol. 1982;22(ll-12):571-576.

20. Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. ?. Role of covalent binding in vivo. J Pharmacol ExpTher. 1973;187(1):195-202.

21. Breen K, Wandscheer JC, Peignoux M, Pessayre D. hi situ formation of the acetaminophen metabolite covalently bound in kidneys and lung: Supportive evidence provided by total hepatectomy. Biochem Pharmacol. 1982;31(1):115-116.

22. Makin AJ, Williams R. The current management of paracetamol overdosage. Br J Clin Prac. 1994;48(3): 144-148.

23. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6): 87 1-876.

24. Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br MedJ. 1979;2(6198): 1097-1 100.

25. Acetadote® prescribing information. Available at: http://www.acetadote.com/prescribe. pdf. Accessed June 8, 2005.

26. Dawson AH, Henry DA, McEwen J. Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust. 1989;150(6):329-331.

27. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous Nacetylcysteine. Ann Emerg Med. 1998;31(6): 710-715.

28. Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med. 2005;45(4):409-413.

TABLE.

Signs and Symptoms Associated With Methemoglobin (MHb) Concentrations

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