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Home , Barbiturate overdose, Lithium toxicity, Paracetamol poisoning, Salicylate poisoning

Adult in Critical Care: Part II: Specific

Babak Mokhlesi, Jerrold B. Leikin, Patrick Murray and Thomas C. Corbridge

Chest 2003;123;897-922 DOI 10.1378/chest.123.3.897 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.org

CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder (http://www.chestjournal.org/misc/reprints.shtml). ISSN: 0012-3692.

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians critical care review Adult Toxicology in Critical Care* Part II: Specific Poisonings

Babak Mokhlesi, MD; Jerrold B. Leikin, MD; Patrick Murray, MD; and Thomas C. Corbridge, MD, FCCP

(CHEST 2003; 123:897–922) acetaminophen levels and six of them received N-.2 As these data show, the majority Key words: critical care; ICU; ; toxicology; toxidromes of exposures are not associated with significant mor- bidity or mortality; however, acetaminophen can Abbreviations: ABCs ϭ airway, breathing, circulation; CCB ϭ calcium-channel blocker; DNS ϭ delayed neuropsychiatric se- cause severe and fatal hepatic injury. quelae; FDA ϭ US Food and Drug Administration; GABA ϭ After oral ingestion, acetaminophen is rapidly ␥-aminobutyric acid; GHB ϭ␥-hydroxybutyrate; MAO ϭ mono- Ͻ amine oxidase; NAPQI ϭ n-acetyl-p-benzoquinonimine; SSRI ϭ absorbed, achieving peak plasma levels in 1h. selective re-uptake inhibitor Primarily, the liver metabolizes acetaminophen, but the metabolic path can vary based on age and blood levels. At therapeutic doses, the half-life is 2 to 4 h. Acetaminophen Ninety-five percent of the metabolites are nontoxic conjugates of glucuronide and sulfate. Glucuronida- cetaminophen () is the most com- tion is the primary route of acetaminophen metabo- A mon medicinal overdose reported to in- lism in adults. Sulfation is an additional important formation centers. Alone or in combination with pathway in young children. other drugs, it was implicated in 110,000 overdoses Acetaminophen is due to a metabolite, in the United States in 2000. Approximately 55,000 which constitutes only 5% of acetaminophen me- of these cases were treated in health-care facilities, tabolism. This metabolite, n-acetyl-p-benzoqui- 12,613 patients received N-acetylcysteine, 580 had nonimine (NAPQI), is produced by the hepatic 1 major liver damage, and 210 died. On a smaller cytochrome P-450 mixed-function oxidase enzyme 2 scale, Bond et al reported that of 137 patients system.3 At usual therapeutic doses, this metabo- presenting to an emergency department with acet- lite is rapidly detoxified by conjugating irreversibly aminophen ingestion, 92% had an acute ingestion with the sulfhydryl group of and ex- and 122 patients (89%) reported a single suprathera- creted by the kidneys as mercapturic acid and peutic ingestion. Twenty-five patients (18%) were conjugates. In overdose, the supply of hospitalized for treatment; of these, 18 patients were glutathione is depleted and NAPQI is not detoxi- treated with N-acetylcysteine based on the Rumack- fied. The toxic metabolite binds to macromole- Matthew nomogram. The remaining seven patients Ն cules of hepatocytes inducing centrilobular he- presented 18 h after ingestion with unmeasurable patic with periportal sparing.4 Local production of NAPQI makes the liver the primary *From the Division of Pulmonary and Critical Care Medicine (Dr. Mokhlesi), Cook County /Rush Medical College, target, but other organs can be affected (discussed Chicago; Evanston Northwestern Healthcare-OMEGA (Dr. later). The toxic threshold with the potential to Leiken), Chicago; Section of Nephrology (Dr. Murray), University produce liver damage is 150 mg/kg or 7.5 to 10 g of Chicago, Chicago; and Medical Intensive Care Unit (Dr. Cor- bridge), Northwestern University Medical School, Chicago, IL. in adults and 200 mg/kg in children (due to enhanced Manuscript received March 19, 2002; revision accepted July 12, sulfation).5–7 However, 4 to 6 g can cause injury 2002. in certain kinds of patients (see below). Reproduction of this article is prohibited without written permis- 5 sion from the American College of Chest Physicians (e-mail: There are four phases of acetaminophen toxicity. [email protected]). Common in the first 24 h, or phase 1, are anorexia, Correspondence to: Babak Mokhlesi, MD, Division of Pulmonary malaise, , diaphoresis, , and . and Critical Care Medicine, Cook County Hospital/Rush Medical College, 1900 West Polk St, Chicago, IL 60612; e-mail: Phase 2 occurs 24 to 48 h after untreated overdose. [email protected] Right-upper-quadrant pain and abnormalities of www.chestjournal.org CHEST / 123/3/MARCH, 2003 897

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians liver function test results, which occur even while of phase 1 improve, characterize this phase. If the patient progresses to phase 3 (48 to 96 h), symptoms of severe including encephalopathy, , and will ensue. Liver function abnormalities typically peak in this period, with extreme elevations in alanine aminotransferase, aspartate aminotransferase (Ն 10,000 IU/L), total , and prothrombin time. The rise in transaminases tends to be dispro- portionate to the rise in total bilirubin, which may help differentiate acetaminophen-induced hepato- toxicity from viral , biliary obstruction, or cholestatic . Rare phase 3 sequelae include hemorrhagic , myocardial necrosis, and acute renal failure. Acute renal failure represents acetaminophen-induced acute tubular necrosis.8 It rarely occurs in the absence of fulminant hepatic failure9; treatment with N-acetylcysteine may not prevent its occurrence.10 Phase 4 involves the period beyond the fourth day postingestion. During this period, the patient may die, fully recover (without ), or undergo emergent . Declining hepatic enzymes signal recovery or massive hepatocellular necrosis. A rising Figure 1. The Rumack-Matthew nomogram for predicting prothrombin time, ammonia measure, and bilirubin acetaminophen hepatotoxicity. This nomogram stratifies patients into three categories: probable hepatic toxicity, possible hepatic levels accompany the latter. If the patient recovers, toxicity, and no hepatic toxicity. It is based on the relationship significant improvement will be evident between day between acetaminophen level and time after ingestion. When this 5 and day 7 postingestion. relationship is known, N-acetylcysteine is indicated for acetamin- ophen levels above the lower line. N-acetylcysteine is also The modified Rumack-Matthew nomogram (Fig indicated if serum acetaminophen level is Ͼ 5 ␮g/mL with an 1) allows for stratification of patients into risk cate- unknown time of ingestion (but Ͻ 24 h) and if serum acetamin- gories based on the relationship between the serum ophen levels are not readily available. The nomogram should be used only in relation to a single acute ingestion. See text for 11 acetaminophen level and time after ingestion. The situations in which the nomogram may be of limited use. lower line of this nomogram defines plasma levels Reproduced with permission from Rumack and Matthew.11 25% below those expected to cause hepatotoxicity. Points below this line are not concerning for the development of hepatotoxicity; points between the lower line and a parallel middle line suggest a sorption phase. For extended-release preparation, possible risk for hepatotoxicity; points above the samples for serial acetaminophen levels should be middle line but below a parallel upper line represent drawn every 4 to 6 h postingestion and plotted on the probable risk; points above the upper line are high Rumack-Matthew nomogram. If any point is above risk. N-acetylcysteine is indicated for any acetamin- the lower line, an entire course of N-acetylcysteine is ophen level above the lower line (see below). indicated. N-acetylcysteine should also be adminis- There are several situations in which the Rumack- tered for any signs of hepatotoxicity despite low Matthew nomogram is of limited use. First, serum acetaminophen serum levels. Third, the nomogram acetaminophen levels obtained prior to 4 h postin- does not account for at-risk populations. Whereas 7.5 gestion are not interpretable because of ongoing to 10 g of acetaminophen are toxic in healthy adults, drug absorption and distribution; conversely, pa- 4to6gmaybeenough in chronic users, tients presenting late may have undetectable serum patients with induced cytochrome P-450 enzymes, concentrations despite having received a . malnourished individuals, and patients with depleted Second, in chronic ingestion or in overdose with an glutathione stores (as in recent sublethal acetamino- extended-release preparation, the nomogram is less phen ingestion).16,17 In these cases, N-acetylcysteine predictive of toxicity.12–15 Extended-release acet- should be considered even if the serum acetamino- aminophen preparations exhibit a longer elimination phen level falls below the lower nomogram line. half-life (up to 12 h compared to 2 to3hfor Fourth, accurate risk assessment requires an accu- immediate-release preparations), with a longer ab- rate time of ingestion, which is not always attainable.

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians A 1- to 2-h difference easily moves the borderline serum acetaminophen level was undetectable. Of the patient above or below the treatment line. A low 75 patients, 25 (33.3%) were treated for Ͻ 24 h. The threshold to treat is warranted in these situations. mean (Ϯ SD) duration of therapy was 31 Ϯ 16 h. Bond et al2 reported that the Rumack-Matthew The incidence of hepatotoxicity was low and compa- nomogram could not be used in almost half of all rable to that in patients treated in the standard way. patients hospitalized for treatment of acetaminophen Protocols using a 20-h IV course and a 48-h IV course ingestion, and an even higher proportion of those have also been shown to be safe and effective.27,28 with bad outcomes. The dose is prepared using the standard 10% (100 is reasonable if administered within mg/mL) or 20% (200 mg/mL) formulations diluted 60 min of ingestion.18 Activated charcoal is the to a 5% solution in juice. If vomiting interferes modality of choice for gastric decontamination. It with oral N-acetylcysteine use, the dose should be is unlikely that activated charcoal reduces the effi- repeated with an antiemetic such as metoclopra- cacy of oral N-acetylcysteine. Administration of N- mide or ondansetron.29,30 Occasionally, a nasogastric acetylcysteine 2 h apart from activated charcoal to tube may be necessary. IV administration of N- minimize interaction or increasing the dose of N- acetylcysteine, using the same dose and dosing acetylcysteine after activated charcoal seem to be schedule, may be beneficial in patients unable to unnecessary.19,20 Activated charcoal reduces the tolerate the oral preparation. Other indications for number of patients reaching toxic serum levels after IV N-acetylcysteine include pregnancy and late pre- ingesting Ͼ 10 g of acetaminophen and presenting sentation of acetaminophen overdose. Although within 24 h of ingestion. Activated charcoal can also IV administration is routinely used in Europe, the reduce the need for a full treatment course of US Food and Drug Administration (FDA) has not N-acetylcysteine and hospital stay.21 approved the IV formulation of N-acetylcysteine.31 All patients with possible or probable risk of There is no clear evidence that the oral route is hepatic toxicity based on the Rumack-Matthew no- superior to an IV route.32 When oral N-acetylcyste- mogram (ie, all patients with serum acetaminophen ine is administered IV, a micropore filter should be levels above the lower line) should receive N- used. Yip et al33 reported the IV use of oral N- acetylcysteine. N-acetylcysteine should also be ad- acetylcysteine in 76 patients. Only four patients ministered if the acetaminophen level is Ͼ 5 ␮g/mL acquired adverse reactions, and none were life- with an unknown time of ingestion (but Ͻ 24 h), threatening. Flushing requires no treatment. Urti- if there is evidence of hepatotoxicity or if a caria, angioedema, and respiratory symptoms are ␤ serum acetaminophen level is not available. N- treated with IV diphenhydramine and 2-agonist acetylcysteine can be discontinued if the initial bronchodilators. In case of a severe reaction, the plasma acetaminophen concentration is found to infusion should be stopped and resumed 1 h after di- be nontoxic. Importantly, N-acetylcysteine should phenhydramine has been administered. Anaphylac- be considered in at-risk patients (as noted earlier) toid reactions to the IV drug have been reported.34 even if levels are nontoxic. In the United States, acetaminophen-induced ful- N-acetylcysteine repletes glutathione, combines minant hepatic failure is one of the most common directly with NAPQI, and enhances sulfate conjuga- reasons for liver transplantation.35 Among patients tion of acetaminophen. N-acetylcysteine is virtually with acute fulminant hepatic failure who do not 100% effective when administered within the first 8 receive liver transplantation, survival is highest for to 10 h,22 although benefits may be seen for up to acetaminophen-induced fulminant hepatic failure 24 h after ingestion, even after the onset of fulminant (57%).36 In general, late presentation, grade 3 or 4 hepatic failure.23 These effects include a lower inci- , prothrombin time prolon- dence of hepatic encephalopathy and improved ox- gation, pH Ͻ 7.30, renal dysfunction, cerebral ygen transport and consumption in the setting of edema, and are indicators of poor outcome.37 fulminant hepatic failure.24,25 The usefulness of factors V and VIII as An initial oral loading dose of 140 mg/kg of predictors of outcome in acetaminophen-induced N-acetylcysteine is followed by a maintenance dose fulminant hepatic failure remains controversial.38,39 of 70 mg/kg q4h for 17 doses. Limited data support Investigators from King’s College Hospital Liver the safety and efficacy of a shorter treatment course in Unit demonstrated that an APACHE (acute physiol- certain cases. Woo and colleagues26 conducted a retro- ogy and chronic health evaluation) II score40 Ն 15 spective, observational case study of short course treat- provided an accurate risk of hospital mortality and ment in patients with acute overdose and acetamino- identified patients in need of transfer for possible phen levels in the toxic range. Study patients received transplantation in the setting of acetaminophen- an oral loading dose of 140 mg/kg N-acetylcysteine induced acute . Since intensivists are followed by 70 mg/kg N-acetylcysteine q4h until the more familiar with APACHE II than with specialist www.chestjournal.org CHEST / 123/3/MARCH, 2003 899

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians liver scores (ie, King’s criteria),41 this may expedite dial dysfunction with high- or low-pressure pulmo- appropriate transfers to liver units.42 nary edema. in this stage is caused by myo- cardial dysfunction or . Stage 3 (2 to 3 days) is dominated by acute renal failure due to acute tubular necrosis with an element of tubular obstruction from calcium oxalate precipitation.48–50 , , and isopropanol are Late (6 to 18 days) neurologic sequelae have also the most commonly ingested nonethanol alcohols. been described in survivors.51,52 Ethylene glycol is odorless and sweet tasting. Blue or Methanol is metabolized by alcohol dehydroge- green fluorescent dye is added to most products that nase to formaldehyde, which is converted by alde- contain ethylene glycol, such as antifreeze, de-icers, hyde dehydrogenase to formic acid. Formic acid is and industrial solvents. This explains the positive the primary responsible for metabolic derange- urinary fluorescence under a Wood lamp.43 How- ments and ocular disturbances. Intoxication can oc- ever, this method of detection is of limited useful- cur through oral ingestion, inhalation, or dermal ness.44 Methanol is also colorless and odorless but is absorption. Only 30 mL can cause significant mor- bitter tasting and highly volatile. Methanol is present bidity. Approximately 150 to 240 mL of 40% solution in many paint removers, duplicator fluid, gas-line can be lethal (lethal serum levels are 80 to 100 antifreeze, windshield washing fluid, and solid mg/dL). Methanol causes an initial period of head- canned fuel. Isopropanol is a colorless and bitter- ache, inebriation, , , and . As tasting alcohol that has the smell of acetone or formic acid accumulates (6 to 72 h), the anion gap alcohol. It is found in rubbing alcohol, skin lotions, elevates and visual symptoms become more pro- hair tonics, aftershave, deicers, and glass cleaners. All nounced. Visual loss or optic nerve swelling on three are weak by themselves; however, their funduscopy suggest methanol intoxication. Pancre- metabolites can be very toxic. atitis is an additional feature of methanol poison- Intoxication by nonethanol alcohols can present ing.53,54 Symptoms of ethylene glycol and methanol with signs and symptoms of inebriation and low or poisoning may be delayed if there is concomitant absent level. Ingestion history is important. ethanol consumption, which inhibits conversion of Metabolic with an elevated anion gap and/or these compounds to their toxic metabolites. presence of an elevated osmolal gap are cardinal The treatment of ethylene glycol and methanol features of methanol and ethylene glycol poisoning. poisoning is very similar.55 Inhibiting the formation However, serious intoxication can occur without of toxic metabolites by alcohol dehydrogenase and/or elevating the anion gap if there has been insufficient urgent dialytic removal of these alcohols and their time to form acid metabolites, or if the patient metabolites are the cornerstones of therapy. Sup- started with a low baseline anion gap. Nonethanol portive measures include gastric lavage in the first can also occur without an in- hour postingestion. Bicarbonate infusion may im- crease in osmolal gap (explained in detail last month prove , but buffer therapy has not in part I of this review).45–47 been shown to improve outcome. Hypocalcemia and Ethylene glycol is metabolized by alcohol dehy- hypoglycemia should be corrected. Thiamine (50 to drogenase to glycoaldehyde and glycolic acid, and 100 mg), folate (up to 50 mg), and pyridoxine (100 eventually to glyoxylic acid and oxalic acid. Accumu- mg) are usually administered. lation and precipitation of oxalic acid to calcium Inhibitors of alcohol dehydrogenase include fo- oxalate in the renal tubules produces calcium oxalate mepizole (4-methylpyrazole) and ethanol. Fomep- crystals and contributes to the development of acute izole is preferred because it does not exacerbate the tubular necrosis. Hypocalcemia (because of precipi- inebriated state or require blood monitoring.56,57 tation by oxalate) and myocardial dysfunction are The FDA has approved it for ethylene glycol and additional features of ethylene glycol poisoning. In- methanol poisoning. The protocol consists of a gestion of as little as 100 mL can be lethal in an adult 15 mg/kg IV loading dose followed by a 10 mg/kg IV patient. Significant toxicity is associated with serum bolus q12h. After 48 h, the bolus dose should be levels Ͼ 50 mg/dL. increased to 15 mg/kg q12h to account for enhanced Ethylene glycol poisoning has a triphasic clinical metabolism. For both ethylene glycol course: stage 1 (30 min to 12 h postingestion) and methanol, patients are treated until serum levels consists of inebriation, ataxia, , variable levels fall to Ͻ 20 mg/dL. can be performed of elevated anion gap metabolic acidosis with Kuss- concurrently with fomepizole if clinically indicated. maul breathing, elevated osmolal gap, crystalluria, In ethylene glycol poisoning, hemodialysis is indi- and hypocalcemia. causes or cated when serum ethylene glycol levels are death. Stage 2 (12 to 24 h) is dominated by myocar- Ͼ 50 mg/dL, when there is significant and refractory

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians metabolic acidosis, or when there is evidence of exert their toxicity via CNS stimu- end-organ damage. Dialysis is continued until ethyl- lation, peripheral release of catecholamines, inhibi- ene glycol levels are undetectable and metabolic tion of re-uptake of catecholamines, or inhibition of acidosis has resolved. In methanol poisoning, hemo- monoamine oxidase. They generally have a low dialysis is indicated if serum methanol levels are therapeutic index. In overdose, they cause confusion, Ͼ 50 mg/dL, a lethal dose of methanol has been , anxiety, agitation, and irritability. Additional ingested, there is significant and refractory metabolic features include mydriasis, tachyarrhythmias, myo- acidosis, or there is evidence of end-organ damage. cardial ischemia, hypertension, hyperreflexia, hyper- Dialysis is continued until acidosis has resolved and thermia, rhabdomyolysis, renal failure, coagulopathy, serum methanol levels are Ͻ 25 mg/dL. and seizures.62,63 Severe hepatotoxicity requiring Another inhibitor of alcohol dehydrogenase is liver transplantation has been reported with ecstasy ethanol (IV or orally). One protocol for therapeutic abuse.64,65 Death may result from , ethanol administration (maintaining a target serum arrhythmias, status epilepticus, intracranial hemor- level of 100 to 200 mg/dL) is as follows58: loading rhage, fulminant liver failure, or aspiration pneumo- dose, 0.6 g/kg ethanol IV; maintenance doses are, nitis.66 66 mg/kg/h ethanol by continuous IV infusion for Treatment is supportive, including maintenance of nonalcoholic patients, 154 mg/kg/h ethanol by con- the airway and mechanical ventilation if necessary. tinuous IV infusion for alcoholic patients, and double Hypertension generally responds to systemic vasodi- continuous infusion rate for patients receiving di- lation with phentolamine or nitroprusside. Tachyar- alysis. rythmias are best treated with esmolol or proprano- IV ethanol is supplied as a 10% solution in 5% lol. Agitation, violent behavior and should dextrose in water containing 10 g of ethanol per be treated with butyrophenones (ie, haloperidol or 100 mL of solution. Either dialysis bath supplemen- droperidol), , or phenothiazines. In tation with 200 mg/dL of ethanol or doubling the a randomized controlled trial of 146 agitated patients dose of IV ethanol infusion should maintain serum with methamphetamine toxicity, droperidol treat- ethanol levels in the target range during hemodialysis. ment led to a more rapid and profound sedation than Isopropanol is metabolized by alcohol dehydroge- lorazepam.67 If the rectal temperature exceeds 40°C, nase to acetone that is excreted through the kidneys active cooling measures may become necessary. The and breath.59 A combination of ketonemia (sweet- value of using a muscle relaxant such as dantrolene in smelling breath; ketones in the urine; and absence of this setting is debated, particularly since it has an elevated anion gap or metabolic acidosis), hem- potential side effects, including hepatitis.68–70 Acti- orrhagic gastritis, and an elevated osmolal gap sug- vated charcoal should be administered promptly with gests isopropyl alcohol consumption. A serum iso- a cathartic. Gastric lavage is useful if performed propanol level confirms the diagnosis. Supportive within1hofingestion. Dialysis and hemoperfusion measures are usually sufficient in the treatment of are not effective. these patients. Gastric lavage can be helpful if performed in the first hour postingestion. Hemodi- alysis is indicated when lethal doses have been ingested (150 to 240 mL of 40 to 70% solution) or when lethal serum levels are detected (400 mg/dL). Mild-to-moderate overdose presents Refractory shock or prolonged coma are other indi- with reduced level of consciousness, slurred speech, cations for dialysis.60 and ataxia. At high doses, barbiturates cause hypo- thermia, , bradycardia, flaccidity, hy- Amphetamines poreflexia, coma, and apnea. Patients with severe overdose may appear to be dead with absent EEG During the past decade, methamphetamine use activity. has increased rapidly in the United States, particu- Cardiovascular is caused by a combi- larly in inner-city areas.61 Common nation of decreased arterial tone and myocardial and amphetamine-like prescription drugs include depression, leading to a high filling pressure, low , , and pemo- cardiac output, and hypotensive state. Respiratory line, used primarily for narcolepsy and attention- depression with hypercapnia and hypoxemia are deficit disorder; and various anorectic common. In deep coma, the usual acid-base distur- used for weight loss, including diethylpropion and bance is a mixed respiratory and metabolic acidosis. phentermine. Illicit drugs include methamphet- Patients unresponsive to painful stimuli tend to be amine (“crank” or “ice”), and 3,4-methylenedioxy- significantly more acidemic and hypoxemic than methamphetamine (“ecstasy”). those who show some response to pain, a finding that www.chestjournal.org CHEST / 123/3/MARCH, 2003 901

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians is not explained by differences in alveolar ventila- forced , dialysis, or hemoperfusion. Fluma- tion.71 Hypoxemia may be aggravated by ventilation/ zenil is a specific antagonist that perfusion mismatch and/or increased capillary per- reverses sedation in postoperative patients and in meability with development of the ARDS, possibly intentional . Its effect on related to aspiration pneumonitis. reversal of respiratory depression remains controver- The diagnosis of is generally sial.78,79 Judicious use of provides useful made on clinical grounds and confirmed by routine diagnostic information, as it does not antagonize the urine toxicology screening. Blood levels correlate CNS effects of alcohol, barbiturates, tricyclic antide- with severity but rarely alter management.72 pressants, or narcotics. Although there are concerns Treatment of barbiturate overdose first involves regarding the precipitation of activity in the general supportive measures. There is no specific setting of mixed tricyclic antidepressant-benzodiaz- . Gastric lavage is useful in acute massive epine overdose,80,81 limited data suggest flumazenil overdose if performed within 60 min of ingestion.18 is safe and effective in this setting.82 Flumazenil Multidose activated charcoal decreases absorption could unmask seizures from any cause and increases and enhances elimination in life-threatening pheno- the incidence of death in a rat model of combined barbital overdose.73 Urine alkalinization (targeting a / poisoning.83 Flumazenil is not rec- urinary pH Ͼ 7.5) increases elimination of pheno- ommended in patients who use benzodiazepines barbital, but not other barbiturates, and care must be therapeutically to control seizures or raised intracra- taken not to cause by volume nial pressure.84 Addicted patients may acutely with- overload.50 Charcoal hemoperfusion is indicated draw after flumazenil administration. in severe poisoning characterized by prolonged coma The recommended initial dose of flumazenil is or refractory hypotension, but its role is dis- 0.2 mg (2 mL) IV over 30 s. A further 0.3-mg (3 mL) puted.74–76 If depressed mental status persists, other dose can be administered over 30 s if the desired conditions should be considered: head trauma with clinical effect is not seen within 30 s. Additional subdural or epidural hematoma, intracerebral hem- 0.5-mg doses can be administered over 30 s at 1-min orrhage, embolic stroke, abnormalities, intervals as needed to a total dose of 3 mg. Doses hypoxemia, hypothyroidism, liver or renal failure, Ͼ 3 mg are beneficial in a small number of pa- CNS infection, seizures, and significant alterations in tients.85 temperature. Patients should be monitored for re-sedation, par- ticularly in overdose cases and in patients receiving high-dose, long-term, or long-acting benzodiaz- Benzodiazepines epines. Re-sedation may occur within 1 to 2 h after administration, so repeat doses or continuous infu- Benzodiazepines are used for a variety of pur- sion (0.1 to 0.5 mg/h) may be required to maintain poses, such as , anxiolytics, muscle relax- therapeutic efficacy.86 However, continuous infusion ants, and . The half-life is dependent on the has not been shown to decrease complications.87 specific drug and can range from2htoseveral days. Patients with liver dysfunction require downward Because of widespread use, these drugs are fre- adjustment in dose.88 Patients with multidrug over- quently involved in drug overdoses, either as a single dose, significant comorbidities, advanced age, and agent or combined with other toxins. Confirmation re-sedation after initial response to flumazenil of exposure is rapidly available by urine toxicology should be admitted to an ICU. screening. Benzodiazepines enhance the inhibitory effects of ␥ the neurotransmitter -aminobutyric acid (GABA) ␤-Blockers causing generalized depression of the CNS. Symp- toms in overdose range from slurred speech and ␤-Blockers are competitive antagonists of ␤ recep- ␤ ␤ lethargy to and coma, depending tors. 1-Receptors are found in the heart; 2- on the dose and compound ingested. In general, receptors are found in bronchial tree and blood patients in coma from benzodiazepine poisoning are vessels. Some ␤-blockers (eg, acebutolol, betaxolol, hyporeflexic with small-to-midsized pupils that do pindolol, and propranolol) have myocardial membrane- not respond to administration. They do stabilizing activity that can cause QRS widening and respond to the cautious administration of flumazenil. decreased myocardial contractility. Treatment of benzodiazepine overdose consists of Clinical features of ␤-blocker overdose depend on initial supportive measures, gastric emptying if it can the drug type, amount and timing of overdose, be performed in the first hour postingestion, acti- co-ingestions, and comorbidities. The diagnosis is vated charcoal,77 and flumazenil. There is no role for usually established on clinical grounds; blood levels

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians are available but do not correlate closely with sever- Calcium-Channel Blockers ity of overdose.89 Factors associated with the risk of acquiring cardiovascular morbidity include co- Calcium-channel blockers (CCBs) selectively in- hibit the movement of calcium ions through ingestion of another cardioactive drug and a the membrane of cardiac and vascular smooth mus- ␤-blocker with myocardial membrane-stabilizing ac- cle during the slow inward phase of excitation- tivity (eg, acebutolol, betaxolol, pindolol, and pro- contraction. These agents can have varying degrees pranolol).90 The majority of patients (97%) acquire ␤ of cardiovascular effects. Verapamil is more of a -blocker toxicity within4hofingestion. Asymptom- negative inotrope; nifedipine has more vasodilatory atic patients with a normal ECG after 6 h generally effects. Verapamil and diltiazem depress the sinus 91 do not require intensive care monitoring. node and slow conduction through the atrioventric- ␤ Cardiovascular complications of -blocker toxicity ular node. The most common cardiovascular effect is include hypotension, bradycardia, atrioventricular hypotension, which generally occurs within6hof blocks of different degrees, and congestive heart CCB overdose (except with sustained-release prep- failure with or without pulmonary edema. Hypoten- arations in which toxicity may not be evident for sion is mainly due to decreased myocardial contrac- 12 h). This commonly follows a period of nausea and tility rather than bradycardia. Other manifestations vomiting. Hypotension is mainly secondary to pe- include bronchospasm, hypoglycemia, hyperkalemia, ripheral vasodilation as opposed to myocardial de- lethargy, stupor, coma, and seizures. Risk of seizure pression. Conduction abnormalities are worsened is highest with propranolol, particularly when the with concurrent ␤-blocker ingestion100 and existing QRS complex is Ͼ 100 ms.92 In a large retrospective cardiovascular disease. Lethargy, confusion, and review of 52,156 cases of ␤-blocker overdose, there coma have been attributed to CCB overdose. Sei- were 164 .93 Propranolol was responsible for zures are uncommon. Hyperglycemia from suppres- the greatest number of toxic exposures (44%) and sion of insulin secretion has also been reported. implicated as the primary cause of death in a dispro- Gastric lavage may be useful for up to 8 h after portionately higher percentage of fatalities (71%). ingestion of a sustained-release preparation. Whole- Fifty-nine percent of patients went into cardiac bowel irrigation has similarly been used for sustained- 101 arrest after reaching health-care personnel. release preparations. Multidose activated charcoal Treatment of ␤-blocker toxicity consists of initial and hemodialysis are not very helpful. However, char- supportive measures. Induced emesis is contraindi- coal hemoperfusion may have a role in verapamil 102 cated because of the risk of sudden cardiovascular overdose in the setting of hepatic dysfunction. collapse.92 Gastric lavage may help if the procedure Hypotension is treated first with fluids. However, can be undertaken within 60 min of ingestion. additional therapy is often required. Calcium glu- Activated charcoal can be used, but there is no clear conate (2 to 3 g total or 0.2 to 0.5 mL/kg of a 10% role for multidose activated charcoal.50 solution every 15 to 20 min to a total of four doses) 103,104 Cardiovascular manifestations are best treated is the preferred IV calcium agent. Glucagon, with combinations of fluid , vasopressor administered as a bolus of 5 to 10 mg IV over 1 min agents, atropine, transvenous pacing, and glucagon. followed by an infusion of 1 to 10 mg/h may decrease 95,105 Glucagon effectively reverses myocardial depression vasopressor requirements. Several investigators and bradycardia. Its positive inotropic and chrono- have reported successful reversal of refractory shock tropic effect is mediated through adenyl cyclase, in CCB toxicity with hyperinsulinemia-euglycemia which increases cyclic adenosine monophosphate therapy by continuous infusion of insulin at a rate of 106,107 and intracellular calcium influx.94 Improvements in 0.5 IU/kg/h. Larger trials are needed to con- bradycardia and hypotension are observed within a firm its safety and efficacy. few minutes and may preclude the need for high- 95 dose catecholamine infusion. Glucagon is adminis- tered as bolus of 5 to 10 mg IV over 1 min followed by an infusion of 1 to 10 mg/h. The diluent provided As a nonirritating, colorless, tasteless, and odorless by the manufacturer contains 2 mg of phenol per 1 gas, carbon monoxide is quite insidious. This gas mg of glucagon. In order to avoid phenol toxicity, is formed by incomplete combustion of carbon- dilution of glucagon in solution or dextrose is containing materials (complete oxidation produces recommended. Phenol toxicity can induce hypoten- carbon dioxide). Carbon monoxide poisoning occurs sion and arrhythmias.96–98 The use of an insulin- in the setting of smoke inhalation, attempted infusion for ␤-blocker toxicity may prove to from automobile exhaust, and poorly ventilated be superior to glucagon alone; this strategy is under burning charcoal or gas stoves. Carbon monoxide is investigation.99 also generated during hepatic metabolism of dichlo- www.chestjournal.org CHEST / 123/3/MARCH, 2003 903

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians romethane (methylene chloride), a component of moglobin.116,117 Venous blood can also be used to paint and varnish removers.108,109 Although there has predict carboxyhemoglobin levels.118 been a slight decline in deaths as a result of carbon The most essential treatment for carbon monoxide monoxide poisoning, it remains the most common poisoning is oxygen. Administration of 100% supple- cause of death by poisoning in the United States. Up mental oxygen decreases the half-life of carboxyhe- to 20% of all deaths due to this poisoning are moglobin from 5 to6honroom air to 40 to 90 min. considered to be accidental and unintentional in The addition of 4.5 to 4.8% carbon dioxide to a nature.110 nonrebreathing circuit while breathing oxygen allows Carbon monoxide binds to hemoglobin with an patients to maintain normocapnia while hyperventi- affinity that is 240 times greater than oxygen and lating and avoids the development of respiratory decreases oxyhemoglobin saturation and blood . In a study of seven healthy male volunteers, oxygen-carrying capacity. Its toxicity results from a this simple method decreased the half-life of car- combination of tissue hypoxia and direct inhibition of boxyhemoglobin from 78 Ϯ 24 to 31 Ϯ 6 min.119 cellular respiration through cytochrome oxidase This strategy requires further studying before rou- blockade. tine use. The severity of carbon monoxide poisoning de- Hyperbaric oxygen (2.8 atmospheres within6hof pends on the concentration of carbon monoxide, exposure) further decreases the half-life of carboxy- duration of exposure, and minute ventilation. Car- hemoglobin to 15 to 30 min. The role of hyperbaric boxyhemoglobin concentrations up to 5% are gener- oxygen in the management of carbon monoxide ally well tolerated. Mild exposures (carboxyhemoglo- poisoning has been debated, and reviewed.120 Evi- bin 5 to 10%) may result in and mild dence from available randomized controlled trials is dyspnea. These levels can be seen in heavy smokers insufficient to provide clear guidelines for the use of and commuters on polluted roads. Carboxyhemoglo- hyperbaric oxygen therapy in carbon monoxide poi- bin concentrations between 10% and 30% cause soning. There is no clear evidence that unselected headache, dizziness, weakness, dyspnea, irritability, use of hyperbaric oxygen decreases the frequency of nausea, and vomiting. These symptoms may be DNS at 1 month. Clearly, a multicenter, random- mistaken for the flu or food poisoning. Patients ized, double-blind controlled trial is needed to better with coronary artery disease are at risk for ischemia define the role of hyperbaric oxygen.121 We believe and infarction. Carboxyhemoglobin concentrations that patients with potentially life-threatening expo- Ͼ 50% result in coma, seizures, cardiovascular col- sures should receive at least one hyperbaric oxygen lapse, and death. It is important to note that carboxy- treatment (if hyperbaric capability is readily avail- hemoglobin levels do not always correlate well with able).122 clinical severity of carbon monoxide poisoning. Ten See addendum at the end of this text. to 30% of survivors acquire delayed neuropsychiatric sequelae (DNS).111–113 DNS has been described to occur from 3 to 240 days after apparent recovery. Its Cocaine variable manifestations include persistent vegetative state, Parkinsonism, short-term memory loss, behav- Cocaine may be snorted nasally, inhaled orally, or ioral changes, hearing loss, incontinence, and psy- used IV. “Body packers” swallow multiple wrapped chosis. There is no accurate way of predicting which packages of cocaine in an attempt to smuggle the patients will acquire DNS. At 1 year, 50 to 75% of drug across national boundaries; “body stuffers” patients with DNS experience a full recovery.113 swallow or conceal wrapped packets of cocaine in Clinicians must maintain a high index of suspicion various body cavities when law enforcement agents for carbon monoxide poisoning, especially during challenge them. Free-base cocaine, also known as cold weather. Important historical clues can aid in crack, is absorbed more rapidly and is more potent. the diagnosis. These include cohabitants with similar Toxic effects of cocaine arise from excessive CNS symptoms, use of heating devices other than a stimulation and inhibition of neuronal uptake of furnace, or problems with a forced-air heating sys- catecholamines. Onset and duration of symptoms tem.114,115 Carboxyhemoglobin levels are deter- depend on route of administration, dose, and patient mined by co-oximetry. Pulse oximetry cannot distin- tolerance. Smoking and IV use produce symptoms guish carboxyhemoglobin from oxyhemoglobin at the within 1 to 2 min; oral use delays onset of symptoms wavelengths that are commonly generated by stan- by 20 to 30 min. The half-life of cocaine is approxi- dard pulse oximeters. Pulse oximetry overestimates mately 60 min; however, its metabolites are detect- oxyhemoglobin by the amount of carboxyhemoglobin able in blood or urine for 24 to 36 h after ingestion. present; therefore, pulse oximetry results may be Cocaine is often mixed with other substances of “normal” despite high concentrations of carboxyhe- abuse including heroin (“speedball”), phencyclidine,

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians and alcohol. In the presence of ethanol, cocaine is tion.132 Surgical removal of retained packages may transesterified in the liver to cocaethylene. Cocaeth- be needed, particularly in patients with bowel ob- ylene is similar to cocaine, but lasts longer and is struction or package perforation.133 Endoscopic re- more toxic. moval is not recommended since packet rupture may Common CNS manifestations include euphoria, occur. Neither dialysis nor hemoperfusion effectively anxiety, agitation, psychosis, , and seizures. removes cocaine. Vasospasm, vasculitis, with car- Perhaps the most important treatment strategy in diac arrhythmias, and increased platelet aggregation is rapid treatment of agitation may provoke ischemic cerebral infarcts.123 Cardio- and hyperthermia. Active and passive patient cool- vascular manifestations of cocaine include chest ing, sedation with benzodiazepines, and muscle pa- pain, myocardial ischemia and infarction, sudden ralysis with nondepolarizing neuromuscular blockers death, arrhythmias, congestive heart failure, pulmo- may be necessary. Cocaine-associated chest pain nary hypertension, endocarditis, and aortic dissec- may be treated with nitrates and CCBs.134 ␤- tion.124 Currently, there are no clinical parameters Blockers administered alone should be avoided ␤ available to the physician that can reliably identify due to blockade of 2-mediated vasodilation and patients at very low risk for myocardial infarction, unopposed ␤-adrenergic stimulation. Propranolol mandating that all patients with cocaine-associated worsens outcome in an animal model; esmolol pro- chest pain be evaluated for myocardial infarction.125 duces an inconsistent antihypertensive response and Respiratory complications of cocaine include status may cause marked exacerbation of hypertension or asthmaticus, upper airway obstruction (stridor), hypotension135; and cocaine-induced coronary vaso- pulmonary hypertension, barotrauma, pulmonary constriction may be potentiated by ␤-adrenergic edema, and alveolar hemorrhage. The inhalation of blockade.124 Labetolol, which blocks both ␣- and crack cocaine can cause an acute pulmonary syn- ␤-adrenergic receptors, may reverse cocaine-induced drome characterized by dyspnea, diffuse infiltrates, hypertension, but not cocaine-induced coronary and hemoptysis.126 Severity ranges from mild respi- vasoconstriction.136,137 The combination of nitro- ratory distress to severe respiratory failure requiring prusside and a ␤-adrenergic blocking agent, or intubation and mechanical ventilatory support. An- phentolamine alone or in addition to a ␤-blocker other severe manifestation of cocaine abuse is rhab- may successfully treat myocardial ischemia and domyolysis with myoglobinuria.127 This in part may hypertension.138 reflect a direct toxic effect of cocaine on muscle. Treatment of respiratory complications is support- Patients may be hyperthermic on presentation, with ive.139 Inhaled bronchodilators and corticosteroids altered mental status, , muscle rigidity, generally improve cocaine-associated bronchospasm. disseminated intravascular coagulation, hepatic dys- Significant pneumothorax is treated with tube thora- function, and renal failure128 resembling neuroleptic costomy, and pneumomediastinum is watched ex- malignant syndrome.129 Other contributors to the pectantly. hyperthermic state include agitation and adrenergic stimulation causing vasoconstriction and ischemia. Cyanide Botulism has also been associated with skin wounds resulting from cocaine use.130 Cyanide is found in a variety of synthetic and Treatment of cocaine intoxication starts with the natural substances: plastics, glue removers, wool, “ABCs” (airway, breathing, circulation), followed by silks, nylons, various seeds, and plants. Poisoning immediate treatment of seizures, hyperthermia, and may occur through inhalation of hydrogen cyanide agitation if indicated. For orally ingested drug, acti- gas, a combustion byproduct of cyanide-containing vated charcoal should be administered to decrease products, sodium nitroprusside infusion, and very further drug absorption. Gastric lavage and ipecac- rarely absorption of cyanide-containing solutions or induced vomiting are not recommended because of gas through skin. Cyanide is a rapidly acting poison, the risk of seizures and subsequent aspiration. In particularly when it is inhaled. The mechanism of body packers (who are found frequently at toxicity involves the binding of cyanide to cellular near international airports), whole-bowel irrigation cytochrome oxidase and resultant interference with with a , electrolyte solution, 1 to 2 aerobic oxygen utilization. L/h, is a well tolerated, safe method of rapid elimi- Once ingested, cyanide is detoxified by enzymatic nation of drug packets from the GI tract.131 Contra- conversion to the less toxic, renally excreted metab- indications to whole-bowel irrigation include ileus, olite, thiocyanate. A small amount of cyanide is also

GI hemorrhage, and bowel perforation. Ideally, ac- detoxified by the vitamin B12 precursor, hydroxyco- tivated charcoal should be administered first, fol- balamin. This chelating agent binds cyanide to form lowed by the polyethylene glycol electrolyte solu- nontoxic cyanocobalamin. www.chestjournal.org CHEST / 123/3/MARCH, 2003 905

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians Early manifestations of poisoning include anxiety, thiocyanate toxicity, particularly in the setting of dyspnea, headache, confusion, tachycardia, and hy- renal insufficiency, but thiocyanate is readily dialyz- pertension. These are rapidly followed by stupor or able. Co-administration of with nitroprus- coma, seizures, fixed and dilated pupils, hypoventi- side (in a ratio of 1:10 thiosulfate to nitroprusside) lation, hypotension, bradycardia, heart block, ven- effectively eliminates the possibility of cyanide intox- tricular arrhythmias, and complete cardiopulmonary ication during nitroprusside infusion without altering collapse. the efficacy of nitroprusside.145 The diagnosis of is usually Hydroxycobalamin is a promising antidote capable made on clinical grounds, often in the setting of of reducing RBC and plasma cyanide concentrations. smoke inhalation where combined carbon monox- In healthy adult smokers, hydroxycobalamin,5gIV, ide and cyanide toxicity occurs. Blood cyanide decreased whole-blood cyanide levels by 59%.146 levels Ͼ 0.5 mg/L are considered toxic.140 Rapid The currently recommended dose of hydroxycobal- onset of coma, seizures, and cardiopulmonary dys- amin in acute cyanide poisoning is 4 to5gIV function in the presence of severe or administered as a one-time dose.147–149 However, the an elevated mixed venous oxyhemoglobin saturation FDA has not approved its use in the United States. (evidence of the blocking of aerobic oxygen utiliza- Gastric emptying is recommended for acute inges- tion) should increase the suspicion of cyanide poi- tions, followed by activated charcoal. Induced emesis soning.141 Funduscopic examination or direct exam- is not recommended because of the risk of rapid ination of venous blood can demonstrate this cyanide-induced deterioration in clinical status and “arteriolization” of venous blood. The bitter almond subsequent risk of aspiration. There is no role for scent of hydrogen cyanide gas may also be present. hemodialysis or hemoperfusion except to clear high Treatment of cyanide poisoning tends to be effec- levels of thiocyanate. tive if started early. Oxygen, decontamination, ni- trites, and are the main therapeu- tic modalities. Oxygen therapy at 100% fraction of Cyclic Antidepressants inspired oxygen either by face-mask or endotracheal tube should be instituted immediately. Hyperbaric The American Association of Poison Control Cen- oxygen is as of yet unproved in cyanide poisoning.142 ters has recently reported that antidepressants were Amyl and sodium nitrites induce formation of met- second only to analgesics as a cause of overdose- hemoglobin. Cyanide has a high affinity for the ferric related death. Sixty-nine percent of antidepressant iron contained in methemoglobin, thereby rendering fatalities were secondary to tricyclic antidepres- methemoglobin an effective scavenger of unbound sants.1 Cyclic antidepressants (including the tricy- cyanide. is administered by inhalation of clics, tetracyclics, bicyclics, and monocyclics) are crushable pearls, which are inhaled for 15 to 30 s among the most commonly encountered causes with 30 s of rest between inhalations. One pearl lasts of self-poisoning. Tricyclic antidepressants include approximately 2 to 3 min. This therapy induces a 5% amitriptyline, desipramine, doxepin, imipramine, methemoglobenemia and can be used in spontane- nortriptyline, protriptyline, and amoxapine. These ously breathing patients or in patients receiving drugs are used for depression, chronic pain syn- ventilatory support until administration of sodium dromes, obsessive-compulsive disorder, panic and nitrite. is administered IV at a dose of phobic disorders, eating disorders, migraines, insom- 300 mg over 3 min to convert more hemoglobin to nia, and peripheral neuropathies. The development methemoglobin. Half this dose may be repeated of newer and safer antidepressants, such as the after2hifthere is persistent toxicity, and a tolerable selective serotonin re-uptake inhibitors (SSRIs) has degree of methemoglobinemia. Usually, methemo- caused a decline in use of cyclic antidepressants. globin levels remain Ͻ 20% and the reduction of Compared to SSRI overdose, tricyclic antidepressant total oxygen-carrying capacity by the combination overdoses are more likely to cause severe toxicity, of carboxyhemoglobin and methemoglobin is admission to the ICU, and death.150,151 In overdose, Ͻ 21%.143 should be avoided as a these drugs mainly affect the CNS and cardiovascu- treatment of methemoglobinemia because it will lar system. Anticholinergic effects and inhibition of release free cyanide. neural re-uptake of norepinephrine and/or serotonin Sodium thiosulfate acts as a sulfur donor to rho- are responsible for CNS toxicity. Cardiovascular denase and other sulfur transferases and thereby manifestations stem from anticholinergic effects, in- enhances conversion of cyanide to thiocyanate.144 hibition of neural uptake of norepinephrine or sero- The dose is 12.5 g (50 mL of a 25% solution) IV over tonin, peripheral ␣-adrenergic blockade, and mem- 10 min. Half this dose may be repeated after2hfor brane depressant effects. persistent toxicity. Sodium thiosulfate may result in The clinical presentation may be divided into

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians anticholingeric effects, cardiovascular effects, and followed closely for 48 to 72 h.156 After initial seizures. Anticholinergic manifestations include my- stabilization, gastric lavage (within2hofingestion) driasis, blurred vision, , dry skin and mucous followed by activated charcoal is the preferred membranes, lethargy, delirium, coma, tachycardia, method of gastric decontamination. Emesis should ileus, myoclonus, and urinary retention. These ef- not be induced because of the possibility of abrupt fects are commonly summarized by the phrase: “hot deterioration in mental status and seizures leading to as a hare, dry as a bone, red as a beet, mad as a high risk of aspiration. Activated charcoal can be hatter.” administered without gastric lavage157; there is no Cardiovascular toxicity consists of sinus tachycar- role for multidose activated charcoal,73 particularly dia with prolongation of the QRS, QTc, and PR since anticholinergic-induced ileus increases the risk intervals. Occasionally, sinus tachycardia with QRS of charcoal-induced bowel obstruction. Because of prolongation is difficult to distinguish from ventric- high lipid solubility and protein binding, dialysis and ular tachycardia, which also occurs in cyclic antide- hemoperfusion are not effective. pressant overdose. Torsades des pointes is relatively Lidocaine is the drug of choice in cyclic antide- rare. Importantly, a limb-lead QRS interval longer than 0.10 s has been shown to predict seizures and pressant overdose complicated by refractory ven- QRS duration Ͼ 0.16 s has been associated with tricular arrhythmias. Support for the use of phe- ventricular arrhythmias.152 The degree of interrater nytoin comes largely from anectodal reports. agreement in the measurement of QRS interval is Based on the available data, we do not recommend adequate enough to make this measurement a useful this drug for either prophylaxis or treatment in part of the overall assessment of toxicity.153 Although cyclic antidepressant overdose.158,159 Bretylium the ECG can neither unequivocally rule in nor rule can exacerbate hypotension. Class 1a antiarrhyth- out impending toxicity, it is a valuable bedside tool in mics (eg, procainamide) can add to cardiac toxicity combination with other clinical data gathered during and should be avoided in the setting of ventricular patient assessment.154 A maximal limb-lead QRS arrhythmias. Temporary ventricular pacing may be duration Ͻ 0.1 s is rarely associated with seizures or required in high-grade blocks. ventricular arrhythmias. Various forms of atrioven- Hypotension tends to be refractory to fluid resus- tricular block may accompany cyclic antidepressant citation. Many patients will require vasopressor sup- overdose. Right bundle-branch block is common. port with a drug such as norepinephrine.160–162 Hypotension is mainly due to venodilation and a Pulmonary edema, both cardiogenic and noncardio- direct drug effect on myocardial contractility. Sei- genic, has been reported.163,164 Although a pulmo- zures may be short-lived and self-limited, or pro- nary artery catheter may help direct therapy, there is longed and refractory to treatment. Neurologic de- concern regarding the arrhythmogenic potential of terioration may be abrupt and unpredictable. right-heart catheterization in this setting. Metabolic acidosis from seizures or arrhythmias pro- Diazepam, lorazepam, and can be motes unbinding of the drug from proteins and used for the treatment of seizures. should contributes to increased toxicity.155 be reserved for refractory cases. Paralysis or deep The diagnosis of cyclic antidepressant overdose sedation with propofol may be indicated for refrac- depends on a compatible history and clinical features tory seizures (as may be seen in amoxapine overdose) with a high index of suspicion. Cyclic antidepressant 165 overdose should be considered in all patients with to control temperature and muscle breakdown. QRS prolongation. Confirmation of exposure is avail- Continuous EEG monitoring is required to guide able by urine toxicology screening. Blood levels are antiseizure medications during paralysis. 166,167 not generally followed because of the reliability of Experimental therapies include glucagon the QRS duration to predict severity. and monoclonal antibodies to tricyclics.168–170 Phy- Treatment of cyclic antidepressant overdose in- sostigmine should not be used in cyclic antidepres- volves initial supportive measures aimed at identify- sant overdose because of the potential for seizures ing and treating life-threatening problems. Serum and asystole. alkalinization remains the mainstay of therapy. Pa- Lethality from cyclic antidepressant overdose lies tients should immediately receive sodium bicarbon- primarily in their cardiac toxicity and tends to occur ate (1 to 2 mEq/kg IV) when there is widening of the in the first 24 h of arrival. Most patients acquire QRS interval to decrease the fraction of free drug. symptoms within the first 6 h after ingestion.171 should be continued until there Patients with altered mental status, seizures, hypo- is narrowing of the QRS interval or serum pH tension, metabolic acidosis, and cardiac arrhythmias exceeds 7.55. is an alternate strat- require ICU monitoring. Patients should remain in egy in intubated patients. The ECG should be the ICU up to 12 h after discontinuation of all www.chestjournal.org CHEST / 123/3/MARCH, 2003 907

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians therapeutic interventions, and should be asymptom- assault, it may be important to document GHB atic and demonstrate a normal ECG and arterial pH ingestion. Specialized laboratories can detect GHB before transfer.172,173 in both urine and blood by gas -mass spectroscopy.186,187 GHB can also be detected by hair analysis.188 ␥-Hydroxybutyrate ␥ -Hydroxybutyrate (GHB), also known as liquid ecstasy, liquid G, date-rape drug,orfantasy, has become a popular drug of abuse among young Lithium is a monovalent cation used for treatment individuals. In the 1980s, the drug was promoted to of bipolar affective disorders. It is rapidly absorbed bodybuilders as a growth hormone stimulator and through the GI tract. There is virtually no protein muscle-bulking agent. Recreationally, it was claimed binding and a small volume of distribution (0.66 to to cause euphoria without a and to increase 0.8 L/kg). Lithium is eliminated by glomerular filtra- sensuality and disinhibition. In 1990, GHB was tion; 80% of excreted lithium undergoes tubular banned outside of clinical trials approved by the reabsorption; even more is reabsorbed in states of FDA. However, products such as Revivarant (Philips . The elimination half-life, which is ap- Pharmatech; Largo, FL) containing a precursor of proximately 18 h in healthy adults, is prolonged in GHB (␥-butyrolactone) continued to be available the elderly or in patients receiving long-term ther- until a recent ban by the federal government.174,175 apy.189 Volume depletion and renal insufficiency are GHB is derived from GABA, and is thought to common precipitants of lithium overdose. Deliber- function as an inhibitory transmitter through specific ate acute lithium overdose by ingestion with suicidal brain receptors for GHB and possibly through intent also commonly occurs.190 Chronic use can GABA receptors.176 Experimentally, GHB increases result in nephrogenic diabetes insipidus, renal insuf- stage IV of nonrapid eye movement sleep (slow-wave ficiency, hypothyroidism, and leukocytosis. deep sleep).177 In controlled clinical trials of narco- Lithium has a low therapeutic index (target range, leptics, it decreases cataplexy, sleep paralysis, hypna- 0.5 to 1.25 mEq/L). Most cases of intoxication are gogic , and daytime sleep attacks.178,179 associated with levels Ͼ 1.5 mEq/L and are due to Clinical manifestations of GHB depend on the unintentional overdose during chronic therapy. Se- dose ingested. Regular use has been shown to pro- rum levels following acute lithium ingestion corre- duce tolerance and dependence. Abrupt discontinu- late poorly with intracellular lithium levels and clin- ation can produce withdrawal delirium and psycho- ical symptoms. A closer correlation exists between sis.180,181 Low doses of GHB can induce a state of serum levels and clinical symptoms in chronic and euphoria. Emesis, , symptomatic brady- acute-on-chronic intoxications. Severe toxicity may cardia, hypotension, and respiratory acidosis on ar- occur at a lower serum level in chronic lithium terial blood gas analysis have all been described.182 ingestion than in acute intoxication. Relatively mild Higher doses can result in deep coma and death.183 intoxications (levels Ͻ 2.5 mEq/L) cause tremor, Treatment of GHB poisoning is mainly supportive. ataxia, , choreoathetosis, photophobia, and It is important to keep in mind that patients may lethargy. At higher levels of intoxication (2.5 to 3.5 have co-ingested other drugs of abuse, especially mEq/L), agitation, fascicular twitching, confusion, ethanol and amphetamines.182 Mechanical ventila- nausea, vomiting, , and signs of cerebellar tion may be necessary for a short period of time; dysfunction may predominate. Severe toxicity (Ͼ 3.5 most patients regain consciousness spontaneously mEq/L) is characterized by worsening neurologic within5hofingestion.182 Naloxone is not helpful. dysfunction (seizures, coma), and cardiovascular in- Yates and Viera184 described the use of physostig- stability (sinus bradycardia, hypotension). Decreased mine, 2 mg IV, in the emergency department to serum anion gap (Ͻ 6 mEq/L) is an interesting reverse coma in two patients with GHB overdose. consequence of severely elevated lithium levels and Both patients awoke in Ͻ 5 min after the adminis- may be an important clue to the diagnosis. tration of a single dose of . The use of With adequate therapy, morbidity and mortality of physostigmine to reverse coma in GHB overdose is lithium intoxication remains low.191 Treatment con- controversial since rapid recovery is the norm sists of supportive care including seizure control and and there are risks, particularly when there is co- use of vasopressors for hypotension refractory to ingestion of a cyclic antidepressant.185 fluids. Gastric lavage is the preferred method of Laboratory diagnosis of GHB ingestion is a chal- gastric decontamination. Lithium is adsorbed poorly lenge. Normal toxicology screens do not include by activated charcoal; therefore, it is not indicated in GHB. However, in cases of drug-facilitated sexual the absence of co-ingestions. Sodium polystyrene

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians sulfonate (Kayexalate; Sanofi-Synthelabo; New York, Table 1—Selected Drugs/Toxins Associated With NY) does bind to lithium and may decrease its Acquired Methemoglobinemia 192 193 absorption, but may also cause . Acetanilid Multiple doses of sodium polystyrene sulfonate may Amyl nitrite result in GI dialysis and further lower serum lithium Butyl nitrite levels, but this therapy is unproven in human sub- Bromates jects.194 Whole-bowel irrigation with polyethylene Aniline dyes Benzocaine glycol has also been used to successfully decrease Bupivacaine absorption of sustained-release lithium in normal Chlorates volunteers.195 Enhancement of elimination with sa- Chloroquine line solution diuresis and forced alkaline diuresis are Dapsone not very effective and can be dangerous.196,197 Flutamide Herbicides Lithium is the prototypical dialyzable intoxicant Isobutyl nitrite because of its low molecular weight, lack of protein Isosorbide dinitrate binding, water solubility, low volume of distribution, Lidocaine and prolonged half-life. Indications for hemodialysis Loxosceles gaucho include the following: (1) serum levels Ͼ 3.5 mEq/L Methyl nitrite Ͼ Metoclopramide in an acute ingestion; (2) serum levels 2.5 mEq/L Nitric oxide in chronic ingestion, symptomatic patients, or pa- Nitroethane tients with renal insufficiency; and (3) serum levels Nitrobenzene Ͻ 2.5 mEq/L but following a large ingestion, so that Nitroglycerin rising levels are anticipated.198 After hemodialysis, Nitroprusside Pesticides drug levels may increase as the drug redistributes Petrol octane booster 199 requiring repeat dialysis. Four hours of hemodi- Phenacetin alysis should reduce serum lithium concentrations by Phenazopyridine approximately 1 mEq/L. Continuous arteriovenous Potassium ferricyanide or venovenous hemofiltration/hemodialysis may also Prilocaine 200,201 Primaquine be considered. Pyridium Plus (Warner Chilcott, Inc.; Rockaway, NJ) Silver nitrate Sodium chloride Sodium nitrite Methemoglobinemia Sulfonamides Methemoglobin is formed by oxidation of circu- ϩ lating hemoglobin. Contrary to reduced (Fe2 )he- ϩ moglobin, methemoglobin (Fe3 ) is incapable of binding and transporting oxygen. Under normal cir- methemoglobinemia (Ͻ 15% of the total hemoglo- cumstances, a small amount of methemoglobin is bin), patients generally remain asymptomatic despite formed by auto-oxidation. Reduced cytochrome b5 evidence of cyanosis. One possible exception is the reacts with circulating methemoglobin to restore patient with critical coronary artery disease who may hemoglobin and oxidized cytochrome b5; the RBC acquire angina or myocardial infarction in the pres- enzyme reduced nicotinamide adenine dinucleotide- ence of mild functional anemia. Higher methemo- cytochrome b5 reductase (methemoglobin reduc- globin concentrations result in dyspnea, headache, tase) regenerates reduced cytochrome b5 and and weakness. Severe methemoglobinemia (Ͼ 60%) thereby ensures insignificant concentrations of met- is associated with confusion, seizures, and death. hemoglobin in circulating blood.202 Arterial blood gases with co-oximetry are capable Methemoglobinemia arises from a variety of etiol- of measuring the absorption of four or more wave- ogies including hereditary, dietary or drug-induced, lengths, enabling it to directly measure levels of and idiopathic.203 Acquired methemoglobinemia, oxyhemoglobin, reduced hemoglobin, carboxyhemo- which can be severe and life threatening, generally globin, and methemoglobin. Pulse oximetry, how- occurs in the setting of oxidant drugs or toxin ever, estimates oxygen saturation by emitting a red exposure (Table 1). light (wavelength of 660 nm) absorbed mainly by A 50% concentration of methemoglobin decreases reduced hemoglobin and an infrared light (wave- hemoglobin concentration in half. In addition, met- length of 940 nm) absorbed by oxyhemoglobin.204 hemoglobinemia shifts the oxyhemoglobin dissocia- Methemoglobin absorbs equally at both wave- tion curve to the left, thereby interfering with off- lengths. At high methemoglobin levels (35%), the loading of oxygen in peripheral tissues. In mild oxygen saturation by pulse oximeter tends to regress www.chestjournal.org CHEST / 123/3/MARCH, 2003 909

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians toward 85% and plateaus at that level despite further curs early in the course of acute overdose and may increments in methemoglobin levels. Thus, if the also be caused by treatment of overdose with nalox- actual oxygen saturation by co-oximetry is Ͼ 85%, one. In a retrospective review of 27 patients present- the pulse oximeter would be underestimating it; if it ing to the emergency department with heroin-in- is Ͻ 85% by co-oximetry, it would be overestimating duced noncardiogenic pulmonary edema, only a oxygen saturation.205 Therefore, pulse oximetry may third of patients required mechanical ventilation and become unreliable in this setting, registering falsely all patients but one were extubated at 24 h.211 high in patients with severe methemoglobinemia and Inhaled heroin can trigger status asthmaticus.212,213 falsely low with mild methemoglobinemia. In addi- poisoning can also cause hypotension, bra- tion, methylene blue can also cause false elevation in dycardia, decreased gut motility, rhabdomyolysis, methemoglobin levels measured by co-oximetry and muscle flaccidity, hypothermia, and seizures. Sei- pulse oximetry.206 “Chocolate colored” venous blood zures are most common with propoxyphene214 and that does not change color on exposure to air is meperidine. Particularly implicated in lowering the another clue to methemoglobinemia.207 seizure threshold is the meperidine metabolite, Treatment of methemoglobinemia involves gen- eral supportive measures and removal of the inciting normeperidine, which can cause seizures in the 215 drug or toxin. The preferred mode of gastric decon- therapeutic dosing range, particularly if there is 216 tamination is gastric lavage followed by activated renal insufficiency. Seizures unresponsive to nal- charcoal. Methylene blue, a dye capable of reversing oxone may be treated with IV diazepam or loraz- drug/toxin-induced methemoglobinemia by increas- epam. Ongoing seizures suggest either body packing ing conversion of methemoglobin to hemoglobin, or body stuffing of heroin, or a secondary process. should be considered in symptomatic patients. A Examination during classically dose of 1 to 2 mg/kg (0.1 to 0.2 mL/kg of a 1% reveals small, pinpoint-sized pupils that respond to solution) IV administered over 5 min generally re- naloxone administration. Lack of miosis does not rule sults in a significant reduction in methemoglobin out opioid poisoning as coexisting toxins or comor- level within 30 to 60 min. A repeat dose of methylene bidities such as anoxic brain injury may influence blue may be administered after 60 min if needed. pupil size. Additional repeat doses may be required in patients The majority of opioid-related deaths are due to who have received a long-acting oxidant drug such as IV heroin, which is seven times more toxic than dapsone; however, excessive doses of methylene blue morphine.217 Most deaths occur in chronic abusers may paradoxically increase oxidant stress and methe- 20 to 40 years old.218 Up to a third of fatalities have moglobinemia. Contraindications to methylene blue experienced a nonfatal overdose in the prior year. include glucose-6-phosphate dehydrogenase defi- A minority of deaths (17%) occurs in first-time ciency (where methylene blue may cause hemolytic users.219 Co-ingestion of other toxic agents is anemia), renal failure (due to renal excretion of the common.220 antidote), and reversal of nitrite-induced methemo- The diagnosis of opioid toxicity and overdose is globinemia during treatment of cyanide poisoning. often made on clinical grounds. Investigators in Los Failure to respond to methylene blue suggests Angeles have proposed that clinical criteria can cytochrome b5 reductase deficiency, glucose-6- diagnose opioid toxicity as accurately as response to phosphate dehydrogenase deficiency, or sulfhemo- naloxone in patients with acute alteration of mental globinemia. Additional therapies of possible value in status. The combination of Glasgow coma scale score severe conditions include exchange transfusion and of Յ 12 with respirations Յ 12 breaths/min, miotic hyperbaric oxygen.208 pupils, or circumstantial evidence of drug use, had a sensitivity of 92% and specificity of 76% for diagnos- ing opiate overdose.221 The excellent performance of this clinical criterion may not be reproducible in all cities. Rapid response to naloxone corroborates opi- Opioid stimulation of opiate receptors induces a oid exposure; however, not every patient who re- generalized depression of the CNS. The severity of sponds to naloxone has an opiate overdose—and not overdose depends on dose, drug type, and patient every patient with a heroin overdose responds to tolerance. Symptoms range from lethargy to respira- naloxone. Naloxone is obviously helpful in opioid tory arrest and coma. Respiratory failure can arise overdose, but its indiscriminate use should be dis- through a number of mechanisms: alveolar hypoven- couraged.222 Opioid exposure is confirmed by urine tilation, aspiration pneumonitis, and noncardiogenic toxicology screening; however, certain opioids such pulmonary edema (which occurs by unknown mech- as fentanyl are not detected by routine urine toxicol- anisms).209,210 Noncardiogenic pulmonary edema oc- ogy screening.223 Blood toxicology screening is more

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians sensitive and may confirm opioid intoxication in rare toxicity through inhibition of acetylcholinesterase. instances when the urine toxicology screen result is Organophosphates are irreversible inhibitors of ace- false-negative.224 tylcholinesterase; carbamate inhibition of acetylcho- Treatment of opioid overdose involves initial sup- linesterase is reversible. The accumulation of acetyl- portive measures (ABCs). In cases of oral ingestion, choline at the synapses gives rise to the cholinergic gastric lavage should be attempted after ensuring syndrome. Carbamates do not produce CNS toxicity adequate airway protection. Since opioids decrease due to poor penetration of the CNS. gut motility, the usefulness of gastric lavage may Most intoxications occur through the GI tract. extend to several hours postingestion.18 Activated However, insecticides can also be absorbed through charcoal should follow gastric lavage. Small-bowel the skin, conjunctiva, and respiratory tract. Organo- obstruction after activated charcoal has been de- phosphates are typically lipophilic and rapidly ab- scribed.225 There is no role for forced diuresis, sorbed.231 In the United States, most exposures are dialysis, or hemoperfusion. accidental, but in some developing countries, or- Naloxone, a specific with no ganophosphates are commonly used for suicide.232 opioid agonist properties, can reverse opioid- Poisoning has occurred through contaminated induced sedation, hypotension, and respiratory de- food233; emergency department personnel have also pression. It is administered IV at an initial dose of 0.2 been inadvertently poisoned through contact with to 0.4 mg. Endotracheal use has also been de- poisoned patients.234 scribed.226 A lower initial dose (0.1 to 0.2 mg) should Signs and symptoms of acute toxicity occur within be administered to patients with opioid dependence the first 12 to 24 h after exposure.235 Symptoms can to avoid acute withdrawal, or if there are concerns be nonspecific, but commonly include weakness, regarding concurrent overdose. If nalox- blurred vision, nausea, vomiting, headache, abdom- one does not produce a clinical response after 2 to 3 inal pain, and dizziness. Signs include miosis (85% of min, an additional 1 to 2 mg IV may be administered patients), vomiting (58%), salivation (58%), respira- to a total dose of 10 mg. In general, a lack of tory distress (48%), depressed mental status (42%), response to 10 mg of naloxone is required to exclude and muscle fasciculations (40%).236 In one large opioid toxicity, although doses Ͼ 10 mg may be study, tachycardia occurred more often than brady- required to antagonize the effects of propoxyphene, cardia.237 Other cardiac complications include non- diphenoxylate, methadone, and pentazocine.227 Opi- cardiogenic pulmonary edema, arrhythmias, and oid antagonism typically occurs within minutes of conduction abnormalities. An odor of garlic in the naloxone administration and lasts for 45 to 90 min. breath or sweat may be noted. Repeat boluses may be needed every 20 to 60 min to Clinical features of organophosphate poisoning maintain an adequate clinical response. Alterna- can be secondary to overstimulation of muscarinic, tively, a continuous naloxone infusion may be used nicotinic, and central receptors. Muscarinic over- (0.4 to 0.8 mg/h). Severe side effects to naloxone are stimulation tends to be sustained and is character- rare, but pulmonary edema and seizures have been ized by SLUDGE (Salivation, Lacrimation, Urina- reported.228–230 Noncardiogenic pulmonary edema, tion, Diarrhea, GI cramps, and Emesis), blurred which tends to occur in the first few hours after acute vision, miosis, bradycardia, and wheezing. Nicotinic overdose, may be difficult to distinguish from aspi- overstimulation is more transient and presents with ration pneumonitis with ARDS217; however, im- muscular weakness and fasciculations, which can provement is generally more rapid in opioid-induced progress to paresis and paralysis, hypertension, and pulmonary edema. Supplemental oxygen and me- tachycardia. Organophosphates, as opposed to car- chanical ventilation with positive end-expiratory bamates, can penetrate the blood brain barrier and pressure may be required to achieve adequate arte- overstimulate central receptors inducing anxiety, rial oxygen saturation.209 Since central venous pres- confusion, seizures, psychosis, and ataxia. sure is low, diuresis may aggravate hypotension. The diagnosis of organophosphate poisoning is aided by measurement of cholinesterase activity in the blood. The two principal cholinesterases are Organophosphates and Carbamate RBC cholinersterase (also called acetylcholinester- Insecticides ase), which is present in RBC and nerve endings, and pseudocholinesterase, which is found primarily in Most insecticides used in the United States are liver and serum. Both are inhibited by organophos- organophosphates (also used as warfare nerve phates and carbamates, and although clinical toxicity agents) or carbamates. The use of these compounds is due primarily to their action on acetylcholinester- has increased because of their rapid degradability ase, pseudocholinesterase is more readily quantified. in the environment. Both compounds exert their When measured, acetylcholinesterase is considered www.chestjournal.org CHEST / 123/3/MARCH, 2003 911

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians more specific. A falsely low pseudocholinesterase reversible nature of enzyme inhibition. may be seen in patients with liver disease, anemia, or reactivates phosphorylated cholinesterase enzyme . It may also represent a genetic variant and protects the enzyme from further inhibition. (familial succinylcholine sensitivity). Normal levels of Administration prior to irreversible inactivation of enzyme activity do not exclude poisoning because cholinesterase is crucial, preferably within the first of wide variations in normal levels. In the absence of 6 h of poisoning. Pralidoxime is still effective in the baseline plasma acetylcholinesterase levels, use of first 24 to 48 h after exposure, especially when highly sequential postexposure plasma acetylcholinesterase lipophilic organophosphates have accumulated in fat levels can be helpful in confirming the diagnosis of and are gradually released. After this critical period organophosphate exposure.238 Typically in severe of time, restoration of cholinesterase function re- poisoning, levels are Ͻ 20% to 50%. However, the quires regeneration of the enzyme, a process that plasma acetylcholinesterase level may not correlate may take weeks to complete. The antimuscarinic with severity of intoxication.239 Because of these effects of pralidoxime allow for faster atropinization limitations, the diagnosis of organophosphate and with lower doses of atropine. The initial dose of carbamate poisoning remains primarily a clinical pralidoxime is 1 to2gIVover approximately 10 to one. 20 min. Clinical response should be evident in During initial patient stabilization, special atten- Ͻ 30 min. In cases where there is no improvement in tion should be paid to the respiratory status. Bron- muscle fasciculations or weakness, the same dose can choconstriction, excess secretions, muscle weakness, be repeated in 1 h. A continuous infusion is then and altered mental status increase the risk of respi- administered at a rate of 200 to 500 mg/h, titrated to ratory failure. In agricultural exposures, it is ex- achieve the desired effect. Continuous infusion of tremely important to remove all contaminated cloth- pralidoxime may be necessary for Ͼ 24 h depending ing and cleanse the hair and skin thoroughly to on the half-life and lipid solubility of the poison, after decrease skin absorption. Health-care workers must which the dose may be gradually reduced and take precautions to protect themselves from acciden- stopped while the patient is observed for signs of tal exposure by wearing protective gloves and recurrent muscle weakness. gowns.234 Activated charcoal is indicated to limit Serious complications of organophosphates and further drug absorption. Gastric lavage may be use- carbamates include respiratory failure, ventricular ful if done immediately postingestion. arrhythmias, CNS depression, and seizures. On av- Symptomatic patients should receive atropine im- erage, most patients will require 5 to 14 days of mediately. Treatment should not await results of intensive care monitoring. Recovery from carbamate acetylcholinesterase or pseudocholinesterase levels. poisoning is quicker than recovery from organophos- Atropine competitively blocks acetylcholine at mus- phates. Between 60% and 70% of patients will carinic receptors but has no effect on nicotinic require mechanical ventilation. Mortality has been receptors. Thus atropine should not increase heart reported between 15% to 36%.241,242 rate significantly. Atropine crosses the blood-brain barrier and can cause CNS toxicity. Effects can be difficult to distinguish from organophosphate poi- Phencyclidine soning. In this situation, substituting atropine with an anticholinergic that does not cross the blood-brain Phencyclidine or “angel dust” has variable anticho- barrier (such as glycopyrrolate) allows for further linergic, opioid, dopaminergic, CNS-stimulant, and anticholinergic administration without CNS ef- ␣-adrenergic effects. It can be smoked, snorted, fects.240 The dose of atropine required to achieve ingested orally, or injected IV. Phencyclidine is atropinization (mydriasis, dry mouth, increased heart frequently combined with other co-ingestants such rate) varies considerably, depending on the severity as ethanol, marijuana, and lysergic acid diethyl- of poisoning. Doses of up to 40 mg/d are not amide. uncommon. If atropinization occurs after 1 to 2 mg McCarron et al243 evaluated 1,000 patients pre- of atropine, the diagnosis of acetylcholinesterase senting with acute phencyclidine intoxication. The inhibitor poisoning should be questioned. The initial incidence of violence was 35%, bizarre behavior was dose of atropine is 2 mg IV (6 mg IV for life- noted in 29% of cases, and agitation was seen in 34% threatening cases) followed by 2 mg every 15 min of cases. Only 46% of patients were alert and until adequate atropinization has occurred. oriented; the others demonstrated alterations in Pralidoxime reverses muscarinic and nicotinic ef- mental status ranging from lethargy to coma. Nys- fects of organophosphate poisoning. In carbamate tagmus (which may be vertical and horizontal) and poisoning, pralidoxime is generally not needed be- hypertension occurred in only 57% of cases. Grand cause of rapid resolution of symptoms and the mal seizures, muscle rigidity, dystonic reactions, or

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians athetosis were rare. Diaphoresis, hypersalivation, Chadds Ford, PA), and Pepto-Bismol (bismuth sub- bronchospasm, and urinary retention occurred in salicylate; Proctor and Gamble Pharmaceuticals; Ͻ 5% of cases. Twenty-eight cases (2.8%) were apneic, Cincinnati, OH). Ingestion of topical products con- and 3 cases (0.3%) presented in . Hypo- taining salicylates such as Ben-Gay (Pfizer; New glycemia and elevated serum creatine phosphoki- York, NY), (keratolytic), and oil of nase, uric acid, and aspartate aminotransferase/ wintergreen or (one teaspoon con- alanine aminotransferase were common. Rhabdo- tains 7,000 mg of salicylate) can cause salicylate myolysis can complicate phencyclidine intoxication toxicity.250,251 244 and cause acute renal failure. Hypertensive cri- The incidence of has been 245 sis and intracranial and subarachnoid hemorrhage declining in the pediatric population because of 246,247 have been reported. reliance on alternative analgesics and the use of The diagnosis of phencyclidine intoxication should child-resistant containers. Improvements in packag- be considered in patients with fluctuating behavior, ing and package size restrictions have reduced the signs of sympathomimetic overstimulation, and ver- likelihood of severe intentional poisonings in tical nystagmus. The finding of pinpoint pupils in an 252,253 agitated patient suggests phencyclidine toxicity. adults. Phencyclidine exposure is confirmed by qualitative Once ingested, acetylsalicylic acid or is urine toxicology screening; drug levels do not corre- rapidly converted to salicylic acid, its active moiety. late with the severity of clinical findings.243 Salicylic acid is readily absorbed from the stomach Treatment of phencyclidine intoxication starts and small bowel. At therapeutic doses, salicylic acid with initial supportive measures. There is no role for is metabolized by the liver and eliminated in 2 to 3 h. emesis or gastric lavage. Activated charcoal is useful. Therapeutic serum levels are 10 to 30 mg/dL. Although urine acidification and diuretics may en- Chronic ingestion can increase the half-life to hance drug elimination,248 they may also exacerbate Ͼ 20 h.254 myoglobinuric renal failure and are therefore not Clinical features of aspirin intoxication occur in recommended. Because of its large volume of distri- most people with serum levels Ͼ 40 mg/dL; in bution, dialytic therapies are not effective in phen- chronic intoxication, severe poisoning occurs at cyclidine intoxication. lower serum levels (particularly in elderly patients). Violent psychotic behavior may require physical At toxic levels, salicylates are metabolic that restraints to ensure patient and staff safety. Haloper- affect a multitude of organ systems by uncoupling idol appears to be the drug of choice to treat oxidative phosphorylation and interfering with the phencyclidine psychosis.249 Adding a benzodiazepine Krebs cycle.255 (eg, lorazepam, 1 mg) to each dose of haloperidol Minor intoxication causes , vertigo, nausea, may expedite control of the difficult patient. Other vomiting, and diarrhea. Significant ingestions in causes of agitation should be considered in patients adults result in or a mixed with phencyclidine overdose who do not seem to metabolic acidosis and respiratory alkalosis (unless respond. co-ingestion of a CNS depressant causes respiratory Severe hypertension that does not respond to acidosis).256,257 Respiratory alkalosis occurs through calming strategies should be treated with nitroprus- direct central stimulation. Uncoupling of oxidative side or labetolol. ␤-Blockers alone should be avoided phosphorylation leads to accumulation of organic because of the risk of unopposed ␣ activity worsen- acids (including lactic acid and ketoacids) and a ing hypertension and increasing the risk of cerebro- metabolic acidosis with an elevated anion gap. Sali- vascular accidents. cylic acid itself contributes only minimally to the measured anion gap (3 mEq/L with a 50 mg/dL level). Salicylates Other effects include noncardiogenic pulmonary edema, mental status changes, seizures, coma, GI Salicylates are common ingredients in a variety of bleeding, liver and renal failure, hypoglycemia (in- prescription and nonprescription preparations. The cluding low cerebrospinal fluid glucose), and most common is acetylsalicylic acid or aspirin. Other death.258 Thisted et al259 described the clinical find- medications containing salicylates include Soma ings in 177 consecutive admissions to an ICU with Compound, (Wallace Lab; Cranbury, NJ) Norgesic acute salicylate poisoning. Neurologic abnormalities (3M Pharmaceuticals; St. Paul, MN), Darvon occurred in 61% of patients, acid-base disturbances Compound-65 (Eli Lilly; Indianapolis, IN), Trilisate in 50%, pulmonary complications in 43%, coagula- (Choline magnesium trisalicylate; Purdue Frederick; tion disorders in 38%, fever in 20%, and circulatory Norwalk, CT), Percodan (Endo Pharmaceuticals; disorders such as hypotension in 14%. In a 2-year www.chestjournal.org CHEST / 123/3/MARCH, 2003 913

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians review of salicylate deaths in Ontario, 31.4% of the SSRIs () patients were dead on arrival.260 ICU mortality of severe salicylate poisoning has been reported to be With the increased use of SSRIs, psychiatrists, 15%.259 emergency department physicians, and intensivists The lethal adult dose is approximately 10 to 30 g or should expect to see increasing numbers of patients 269 150 mg/kg (Ն 35 tablets). Lethality correlates poorly with serotonin syndrome. The increased use of with serum levels. A critical review of the commonly these medications reflects their relatively nontoxic used Done nomogram254 has revealed that is of no drug profile compared to other antidepressants (such value in the assessment of acute or chronic salicyl- as the tricyclics and monoamine oxidase inhibi- 270 ism.261 Its use may be misleading when there is an tors). The list of SSRIs and noncyclic serotonin- incorrect time of ingestion, ingestion of more than a ergic antidepressants has been growing rapidly in the last decade: , paroxetine, , fluvox- single dose, use of enteric-coated preparations,262 or amine, citalopram, trazodone, nefazodone, and ven- long-term use of salicylates. Elderly patients are lafaxine. Although SSRIs and selective monoamine particularly at risk for unintentional poisoning; a high oxidase (MAO) inhibitor antidepressants are rela- index of suspicion is thus required to avoid delays in tively nontoxic when taken alone, combinations of 263 diagnosis that may contribute to higher mortality. MAO inhibitors or tryptophan and either SSRIs or Patients with chronic intoxication commonly pre- tricyclic antidepressants with serotomimetic effects 264 sent with CNS injury, noncardiogenic pulmonary may result in serotonin syndrome and death.271 edema,265 or isolated elevation of the prothrombin Thus, in general, SSRI antidepressants should not be time. combined with MAO inhibitor antidepressants or Optimal management of a salicylate poisoning de- other agents that have serotomimetic effects.272,273 pends on whether the exposure is acute or chronic. Other serotomimetic agents associated with this Gastric lavage and activated charcoal (1 g/kg) are useful syndrome include 3,4-methylenedioxy-methamphet- for acute ingestions but not in cases of chronic salicyl- amine, dextromethorphan, and meperidine.274 The ism. The use of multidose activated charcoal to en- presumed pathophysiologic mechanism involves hance elimination is controversial.266 Empiric adminis- brainstem and spinal cord activation of the 1A form tration of dextrose helps avoid low cerebrospinal fluid of serotonin (5-hydroxytryptamine) receptor. glucose levels. Because of the long half-life of some of these Administration of bicarbonate to raise plasma drugs, toxic combination therapy may not be appar- pH to between 7.45 and 7.5 induces urinary ent for days to weeks. Many of the newer antide- alkalinization, which in turn increases renal clear- pressants are associated with a risk for clinically ance. Raising urinary pH from 6.1 to 8.1 results in significant drug interactions, in part due to cyto- 275,276 an Ͼ 18-fold increase in renal clearance by pre- chrome P450 inhibition. venting nonionic tubular back-diffusion.267 This Clinical manifestations can be mild, moderate, or 277 decreases the half-life of salicylates from 20 to severe. The most frequent features are changes in mental status, restlessness, myoclonus, hyperreflexia, 24htoϽ 8 h. Care must be taken to avoid diaphoresis, shivering, tremor, flushing, fever, nau- hypokalemia, which prevents excretion of alkaline sea, and diarrhea. In severe cases, disseminated urine by promoting distal tubular potassium reab- intravascular coagulation, convulsions, coma, muscle sorption in exchange for hydrogen ion. Urinary rigidity, myoclonus, autonomic instability, orthostatic alkalinization must be used with caution in the hypotension, and rhabdomyolysis can occur.272 Other presence of alkalemia due to salicylate-induced findings include hyponatremia and syndrome of in- hyperventilation. Forced diuresis does not appear appropriate antidiuretic hormone secretion.278,279 to increase the efficacy of urinary alkalinization Fortunately, recovery is usually seen within 1 day and may precipitate volume overload. Repetitive and death is rare. determination of serum salicylate levels should be The diagnosis of serotonin syndrome should be obtained to confirm a declining level. considered in any patient with compatible clinical Salicylates can be removed by hemodialysis. Indi- features, particularly if there is a history of depres- cations for hemodialysis include a serum level Ͼ 120 sion and use of serotonergic drugs. Additionally, it is mg/dL acutely, or Ͼ 100 mg/dL 6 h postingestion, important to consider serotonin syndrome in any refractory acidosis, coma or seizures, noncardiogenic agitated patient presenting to the emergency depart- pulmonary edema, volume overload, and renal fail- ment.280 Blood and urine assays are currently not ure.268 In chronic overdose, hemodialysis may be readily available and are not included in routine necessary for a symptomatic patient with a serum toxicology screening panels. salicylate level Ͼ 60 mg/dL. Treatment of serotonin syndrome starts with dis-

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians continuation of the suspected serotonergic agent and nificant enterohepatic circulation, multidose acti- institution of supportive measures. The ABCs of vated charcoal (without sorbitol) can enhance elim- basic life support should be addressed sequentially. ination.73 Theophylline levels should be monitored Gastric lavage should be considered in patients with every 2 to3htoensure decreasing values. early acute ingestion (within 1 h). Activated charcoal Seizures should be treated with benzodiazepines. should be administered. Dialysis and hemoperfusion Refractory seizures are an indication for phenobar- are not effective. Further data are needed to address bital. Phenytoin can worsen theophylline-induced the safety and efficacy of serotonin antagonists such seizures and should be avoided.290,293,294 Supraven- 281 ␤ as methysergide and cyproheptadine. There are tricular tachyarrhythmias are best controlled by 1- anecdotal reports of success with these agents.282 cardioselective ␤-blockers (metoprolol, esmolol). Chlorpromazine, diphenhydramine, and benzodiaz- ␤-Blockers must be used with extreme caution in epines have also been used in the treatment of this patients with obstructive airways disease and should condition.283,284 not be used if active bronchospasm is present. ␤ Hypotension secondary to 2-adrenergic stimulation should be treated with fluids and phenylephrine. ␤ Theophylline Nonselective -blockers such as propranolol or es- molol have been used to treat cases of refractory Theophylline is a dimethylxanthine bronchodilator hypotension.295–297 Lidocaine and other standard used in the management of patients with obstructive agents are suitable for ventricular arrhythmias. CCBs lung disease. Despite declining use, it remains an may be useful in the management of sustained important cause of intoxication with significant mor- supraventricular .298–300 Aggressive elec- bidity and mortality.285 The reasons for toxicity in- trolyte repletion may be required, but consider that clude the following: narrow and low therapeutic low serum potassium levels may be secondary to index, patient and physician dosing errors, and con- intracellular shift, not total body potassium deficit. ditions that decrease drug clearance (ie, drug inter- Nausea may be refractory to agents other than actions, smoking cessation, and the development of ondansetron.301,302 congestive heart failure or hepatic dysfunction).286 Patients presenting with life-threatening condi- Mild toxicity can occur within the therapeutic range. tions such as refractory seizures, hypotension, or Significant toxicity generally occurs with plasma lev- unstable arrhythmias are candidates for extracorpo- els Ͼ 25 mg/L. Intoxication may result from either real drug removal. Other indications for extracorpo- an acute ingestion or chronic use. For the same real drug removal are the following: a plasma level plasma level, chronic intoxication causes more severe Ͼ 100 mg/L 2 h after an acute ingestion (after initial clinical sequelae due to larger total body stores of charcoal therapy), a plasma level Ͼ 50 mg/L in drug.285,287,288 chronic ingestion, and a 2-h level Ͼ 35 mg/L associ- Clinical features of theophylline toxicity are clas- ated with clinical instability or high risk of adverse sified into neurologic, cardiovascular, and metabolic outcome and/or prolonged intoxication. High-risk categories.289 Seizures can occur in chronic intoxica- characteristics include the following: chronic intoxi- tions at serum levels of 35 to 70 mg/L; in acute cation, intolerance of oral charcoal or intractable intoxication, seizures are less likely unless serum emesis, impaired theophylline metabolism (conges- levels exceed 80 to 100 mg/L.285,290 Uncontrolled tive heart failure, , severe hypoxemia), in- seizures may occur and lead to hyperthermia and creased susceptibility to cardiovascular toxicity and rhabdomyolysis. Tachyarrhythmias (both supraven- seizures, or respiratory failure. Charcoal hemoperfu- tricular and ventricular) can occur at theophylline sion is the extracorporeal removal procedure of levels of 20 to 30 mg/L. However, at these serum choice. It is twice as effective as dialysis, which levels, the need for antiarrhythmic therapy is uncom- remains an acceptable alternative.303 Sequential and mon.291 Cardiovascular collapse can occur at levels simultaneous “in-series” hemodialysis and hemoper- Ͼ 50 mg/L. Metabolic abnormalities are common fusion has also been described.304,305 Other tech- and include hypokalemia, hypomagnesemia, hyper- niques such as plasmapheresis and exchange trans- glycemia, hypophosphatemia, hypercalcemia, and re- fusion have been successfully used in pediatric and spiratory alkalosis.292 neonatal patients. The preferred mode of gastric decontamination is gastric lavage followed by activated charcoal for Addendum ingestions Ͼ 50 mg/kg. Gastric lavage may be useful Since the submission of this manuscript, a large, double-bind, for several hours after ingestion of sustained-release randomized, controlled trial of hyperbaric oxygen treatment vs preparations. Because of high risk of seizure, emesis normobaric oxygen treatment in carbon monoxide poisoning has is contraindicated. Since theophylline undergoes sig- been published. Weaver et al306 demonstrated that three hyper- www.chestjournal.org CHEST / 123/3/MARCH, 2003 915

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians baric oxygen treatment sessions (2 to 3 atmospheres at intervals N-acetylcysteine in the treatment of acetaminophen over- of 6 to 12 h) within a 24-h period of exposure significantly dose: analysis of the national multicenter study (1976–1985). reduced DNS both at 6 weeks and 12 months. N Engl J Med 1988; 319:1557–1562 23 Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303:1026– References 1029 1 Litovitz TL, Klein-Schawrtz W, White S, et al. 2000 annual 24 Harrison PM, Wendon JA, Gimson AE, et al. Improvement report of the American Association of Poison Control Cen- by acetylcysteine of hemodynamics and oxygen transport in ters toxic exposure surveillance system. Am J Emerg Med fulminant hepatic failure. N Engl J Med 1991; 324:1852– 2001; 19:337–395 1857 2 Bond GR, Lite LK. Population-based incidence and out- 25 Harrison PM, Keays R, Bray GP, et al. Improved outcome of come of acetaminophen poisoning by type of ingestion. Acad paracetamol-induced fulminant hepatic failure by late ad- Emerg Med 1999; 6:1115–1120 ministration of acetylcysteine. Lancet 1990; 335:1572–1573 3 Corcoran GB, Mitchell JR, Vaishnav YN, et al. Evidence that 26 Woo OF, Mueller PD, Olson KR, et al. Shorter duration of acetaminophen and N-hydroxyacetaminophen form a com- oral N-acetylcysteine therapy for acute acetaminophen over- mon arylating intermediate, N-acetyl-p-benzoquinoneimine. dose. Ann Emerg Med 2000; 35:363–368 Mol Pharmacol 1980; 18:536–542 27 Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous 4 Kunkel DB. Updating acetaminophen toxicity. Emerg Med N-acetylcysteine: the treatment of choice for paracetamol 1985; 17:111–125 poisoning. BMJ 1979; 2:1097–1100 5 Rumack BH. Acetaminophen poisoning. Am J Med 1983; 28 Smilkstein MJ, Bronstein AC, Linden C, et al. Acetamino- 75:104–112 phen overdose: a 48-h intravenous N-acetylcysteine treat- 6 Rumack BH. Acetaminophen overdose in children and ment protocol. Ann Emerg Med 1991; 20:1058–1063 adolescents. Pediatr Clin North Am 1986; 33:691–701 29 Scharman EJ. Use of ondansetron and other antiemetics in 7 Rumack BH. Acetaminophen overdose in young children. the management of toxic acetaminophen ingestions. J Toxi- Am J Dis Child 1984; 138:428–433 col Clin Toxicol 1998; 36:19–25 8 McBride PV, Rumack BH. Acetaminophen intoxication. 30 Wright RO, Anderson AC, Lesko SL, et al. Effect of Semin Dial 1992; 5:292–298 metoclopramide dose on preventing emesis after oral ad- 9 Eguia L, Materson BJ. Acetaminophen-related acute renal ministration of N-acetylcysteine for acetaminophen over- failure without fulminant liver failure. Pharmacotherapy dose. J Toxicol Clin Toxicol 1999; 37:35–42 1997; 17:363–370 31 Amirzadeh A, McCotter C. The intravenous use of oral 10 Jones AF, Vale JA. and the . acetylcysteine (Mucomyst) for the treatment of acetamino- J Clin Pharm Ther 1993; 18:5–8 phen overdose. Arch Intern Med 2002; 162:96–97 11 Rumack BH, Matthew M. Acetaminophen poisoning and 32 Buckley NA, Whyte IM, O’Connell DL, et al. Oral or toxicity. Pediatrics 1975; 55:871–876 intravenous N-acetylcysteine: which is the treatment of 12 Graudins A, Aaron CK, Linden CH. Overdose of extended- choice for acetaminophen (paracetamol) poisoning? J Toxi- release acetaminophen [letter]. N Engl J Med 1995; 333:196 col Clin Toxicol 1999; 37:759–767 13 Bizovi K, Keys N, Rivas J, et al. Tylenol ER, late rise of 33 Yip L, Dart RC, Hurlbut KM. Intravenous administration of APAP level after overdose [abstract]. J Toxicol Clin Toxicol oral N-acetylcysteine. Crit Care Med 1998; 26:40–43 1995; 33:510 34 Bailey B, McGuigan MA. Management of anaphylactoid 14 Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic reactions to intravenous N-acetylcysteine. Ann Emerg Med comparison of acetaminophen products (Tylenol Extended 1998; 31:710–715 Relief vs regular Tylenol). Acad Emerg Med 1996; 3:740–744 35 Ostapowicz G, Lee WM. Acute hepatic failure: a Western 15 Stork CM, Rees S, Howland MA, et al. Pharmacokinetics of perspective. J Gastroenterol Hepatol 2000; 15:480–488 extended relief vs regular release Tylenol in a simulated 36 Schiodt FV, Atillasoy E, Shakil AO, et al. Etiology and human overdose. J Toxicol Clin Toxicol 1996; 34:157–162 outcome for 295 patients with in the 16 Whitcomb DC, Block GD. Association of acetaminophen United States. Liver Transpl Surg 1999; 5:29–34 with and ethanol abuse. JAMA 1994; 272:1845–1850 37 Mutimer DJ, Ayres RC, Neuberger JM, et al. Serious 17 Schiodt FV, Rochling FA, Casey DL, et al. Acetaminophen paracetamol poisoning and the results of liver transplanta- toxicity in an urban county hospital. N Engl J Med 1997; tion. Gut 1994; 35:809–814 16:1112–1117 38 Pereira LM, Langley PG, Hayllar KM, et al. Coagulation 18 Vale JA. American Academy of Clinical Toxicology, Euro- factor V, and VIII/V ratio as predictors of outcome in pean Association of Poison Centres and Clinical Toxicolo- paracetamol induced fulminant hepatic failure: relation to gists. Position statement: gastric lavage. J Toxicol Clin other prognostic indicators. Gut 1992; 33:98–102 Toxicol 1997; 35:711–719 39 Izumi S, Langley PG, Wendon J, et al. Coagulation factor V 19 Spiller HA, Krenzelok EP, Grande GA, et al. A prospective levels as a prognostic indicator in fulminant hepatic failure. evaluation of the effect of activated charcoal before oral 1996; 23:1507–1511 N-acetylcysteine in acetaminophen overdose. Ann Emerg 40 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a Med 1994; 23:519–523 severity of disease classification system. Crit Care Med 1985; 20 Brent J. Are activated charcoal–N-acetylcysteine interac- 13:818–829 tions of clinical significance? Ann Emerg Med 1993; 22: 41 O’Grady JG, Alexander GJM, Hallayar KM, et al. Early 1860–1861 indicators of in fulminant hepatic failure. Gastro- 21 Buckley NA, Whyte IM, O’Connell DL, et al. Activated enterology 1989; 97:439–445 charcoal reduces the need for N-acetylcysteine treatment 42 Mitchell I, Bihari D, Chang R, et al. Earlier identification of after acetaminophen (paracetamol) overdose. J Toxicol Clin patients at risk from acetaminophen-induced acute liver Toxicol 1999; 37:753–757 failure. Crit Care Med 1998; 26:279–284 22 Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral 43 Winter ML, Ellis MD, Snodgrass WR. Urine fluorescence

916 Critical Care Review

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians using a Wood’s lamp to detect the antifreeze additive 66 Byard RW, Gilbert J, James R, et al. Amphetamine deriva- sodium fluorescein: a qualitative adjunctive test in suspected tive fatalities in South Australia: is “Ecstasy” the culprit? ethylene glycol ingestions. Ann Emerg Med 1990; 19:663– Am J Forensic Med Pathol 1998; 19:261–265 667 67 Richards JR, Derlet RW, Duncan DR. Methamphetamine 44 Wallace KL, Suchard JR, Curry SC, et al. Diagnostic use of toxicity: treatment with a benzodiazepine vs a butyrophe- physicians’ detection of urine fluorescence in a simulated none. Eur J Emerg Med 1997; 4:130–135 ingestion of sodium fluorescein-containing antifreeze. Ann 68 Jones AL, Volans G. Management of self poisoning. BMJ Emerg Med 2001; 38:49–54 1999; 319:1414–1417 45 Hoffman RS, Smilkstein MJ, Howland MA, et al. Osmolal 69 Denborough MA, Hopkinson KC. Dantrolene and “ecstasy.” gaps revisited: normal values and limitations. J Toxicol Clin Med J Aust 1997; 166:165–166 Toxicol 1993; 31:81–93 70 Watson JD, Ferguson C, Hinds CJ, et al. Exertional heat 46 Walker JA, Schwartzbard A, Krauss EA, et al. The missing stroke caused by amphetamine analogues: does dantrolene gap: a pitfall in the diagnosis of alcohol intoxication by have a place? Anaesthesia 1993; 48:1057–1060 osmometry. Arch Intern Med 1986; 146:1843–1844 71 Sutherland GR, Park J, Proudfoot AT. Ventilation and 47 Ammar KA, Heckerling PS. Ethylene glycol poisoning with acid-base changes in deep coma due to barbiturate or a normal anion gap caused by concurrent ethanol ingestion: tricyclic antidepressant poisoning. Clin Toxicol 1977; 11: importance of the osmolal gap. Am J Kidney Dis 1996; 403–12 27:130–133 72 Mahoney JD, Gross PL, Stern TA, et al. Quantitative serum 48 Gabow PA. Ethylene glycol intoxication. Am J Kidney Dis toxic screening in the management of suspected drug over- 1988; 11:277–279 dose. Am J Emerg Med 1990; 8:16–22 49 Wine H, Savitt D, Abuelo JG. Ethylene glycol intoxication. 73 Vale JA, Krenzelok EP, Barceloux GD, et al. Position Semin Dial 1994; 7:338–345 statement and practice guidelines on the use of multi-dose 50 Krenzelok EP, Leikin JB. Approach to a poisoned patient. activated charcoal in the treatment of acute poisoning. Dis Mon 1996; 42:509–608 American Academy of Clinical Toxicology/European Asso- 51 Palmer BF, Eigenbrodt EH, Henrich WL. Cranial nerve ciation of Poisons Centres and Clinical Toxicologists. J deficit: a clue to the diagnosis of ethylene glycol poisoning. Toxicol Clin Toxicol 1999; 37:731–751 Am J Med 1989; 87:91–92 74 Lorch JA, Garella S. Hemoperfusion to treat intoxications. 52 Mallya KB, Mendis T, Guberman A. Bilateral facial paralysis Ann Intern Med 1979; 91:301–304 following ethylene glycol toxicity. Can J Neurol Sci 1986; 75 Lindberg MC, Cunningham A, Lindberg NH. Acute phe- 13:340–341 nobarbital intoxication. South Med J 1992; 85:803–807 53 Kruse JA. Methanol poisoning. Intensive Care Med 1992; 76 Jacobsen D, Wiik-Larsen E, Dahl T, et al. Pharmacokinetic 18:391–397 evaluation of haemoperfusion in phenobarbital poisoning. 54 Hantson P, Mahieu P. Pancreatic injury following acute Eur J Clin Pharmacol 1984; 26:109–112 methanol poisoning. J Toxicol Clin Toxicol 2000; 38:297–303 77 Bouget J, Breurec JY, Baert A, et al. Value of charcoal by 55 Brent J. Current management of ethylene glycol poisoning. oral route in patients admitted to emergency department for Drugs 2001; 61:979–988 voluntary absorption of benzodiazepines. J Toxicol Clin Exp 56 Brent J, McMartin K, Phillips S, et al. Fomepizole for the 1989; 9:287–289 treatment of ethylene glycol poisoning. N Engl J Med 1999; 78 Gross JB, Blouin RT, Zandsberg S, et al. Effect of flumazenil 340:832–838 on ventilatory drive during sedation with midazolam and 57 Brent J, McMartin K, Phillips S, et al. Fomepizole for the alfentanil. Anesthesiology 1996; 85:713–720 treatment of methanol poisoning. N Engl J Med 2001; 79 Shalansky SJ, Naumann TL, Englander FA. Effect of fluma- 344:424–429 zenil on benzodiazepine-induced respiratory depression. 58 McCoy HG, Cipolle RJ, Ehlers SM, et al. Severe methanol Clin Pharm 1993; 12:483–487 poisoning: application of a pharmacokinetic model for eth- 80 Longmire AW, Seger DL. Topics in clinical pharmacology: anol therapy and hemodialysis. Am J Med 1979; 67:804–807 flumazenil, a benzodiazepine antagonist. Am J Med Sci 59 Pappas AA, Ackerman BH, Olsen KM, et al. Isopropanol 1993; 306:49–52 ingestion: a report of six episodes with isopropanol and 81 Mordel A, Winkler E, Almog S, et al. Seizures after fluma- acetone serum concentration time data. J Toxicol Clin zenil administration in a case of combined benzodiazepine Toxicol 1991; 29:11–21 and tricyclic antidepressant overdose. Crit Care Med 1992; 60 Lacouture PG, Wason S, Abrams A, et al. Acute isopropyl 20:1733–1734 alcohol intoxication: diagnosis and management. Am J Med 82 Weinbroum A, Rudick V, Sorkine P, et al. Use of flumazenil 1983; 75:680–686 in the treatment of : a double-blind and open 61 Richards JR, Bretz SW, Johnson EB, et al. Methamphet- clinical study in 110 patients. Crit Care Med 1996; 24:199– amine abuse and emergency department utilization. West 206 J Med 1999; 170:198–202 83 Derlet RW, Albertson TE. Flumazenil induces seizures and 62 Lan KC, Lin YF, Yu FC, et al. Clinical manifestations and death in mixed cocaine-diazepam intoxications. Ann Emerg prognostic features of acute methamphetamine intoxication. Med 1994; 23:494–498 J Formos Med Assoc 1998; 97:528–533 84 Treatment of benzodiazepine overdose with flumazenil: The 63 Richards JR, Johnson EB, Stark RW, et al. Methamphet- Flumazenil in Benzodiazepine Intoxication Multicenter amine abuse and rhabdomyolysis in the ED: a 5-year study. Study Group. Clin Ther 1992; 14:978–995 Am J Emerg Med 1999; 17:681–685 85 Spivey WH, Roberts JR, Derlet RW. A clinical trial of 64 Jones AL, Simpson KJ. Mechanisms and management of escalating doses of flumazenil for reversal of suspected hepatotoxicity in ecstasy (MDMA) and amphetamine intox- benzodiazepine overdose in the emergency department. ications. Aliment Pharmacol Ther 1999; 12:129–133 Ann Emerg Med 1993; 22:1813–1821 65 Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 86 Weinbroum A, Halpern P, Geller E. The use of flumazenil 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet in the management of acute drug poisoning: a review. 1992; 340:384–387 Intensive Care Med 1991; 17:S32–S38 www.chestjournal.org CHEST / 123/3/MARCH, 2003 917

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians 87 Chern CH, Chern TL, Wang LM, et al. Continuous fluma- spray paint inhalation. Acad Emerg Med 1998; 5:84–86 zenil infusion in preventing complications arising from 110 Cobb N, Etzel RA. Unintentional carbon monoxide related severe benzodiazepine intoxication. Am J Emerg Med 1998; deaths in the United States. JAMA 1991; 266:659–663 16:238–241 111 Hart IK, Kennedy PGE, Adams JH, et al. Neurological 88 Hoffman EJ, Warren EW. Flumazenil: a benzodiazepine manifestation of carbon monoxide poisoning. Postgrad Med antagonist. Clin Pharm 1993; 12:641–656 J 1988; 64:213–216 89 Love JN. Beta-blocker toxicity: a clinical diagnosis. Am J 112 Sawa GM, Watson CPM, Terbrugge K, et al. Delayed Emerg Med 1994; 12:356–357 encephalopathy following carbon monoxide intoxication. 90 Love JN, Howell JM, Litovitz TL, et al. Acute beta blocker Can J Neurol Sci 1981; 8:77–79 overdose: factors associated with the development of cardio- 113 Choi IS. Delayed neurologic sequelae in carbon monoxide vascular morbidity. J Toxicol Clin Toxicol 2000; 38:275–281 intoxication. Arch Neurol 1983; 40:433–435 91 Love JN. Beta blocker toxicity after overdose: when do 114 Heckerling PS, Leikin JB, Maturen A, et al. Predictors of symptoms develop in adults? J Emerg Med 1994; 12:799– carbon monoxide poisoning in patients with headache and 802 dizziness. Ann Intern Med 1987; 107:174–176 92 Reith DM, Dawson AH, Epid D, et al. Relative toxicity of 115 Heckerling PS, Leikin JB, Maturen A. Occult carbon mon- beta blockers in overdose. J Toxicol Clin Toxicol 1996; oxide poisoning: validation of a prediction model. Am J Med 34:273–278 1988; 84:251–256 93 Love JN, Litovitz TL, Howell JM, et al. Characterization of 116 Buckley RG, Aks SE, Eshom JL, et al. The pulse oximetry fatal beta blocker ingestion: a review of the American gap in carbon monoxide intoxication. Ann Emerg Med 1994; Association of Poison Control Centers data from 1985 to 24:252–255 1995. J Toxicol Clin Toxicol 1997; 35:353–359 117 Hampson NB. Pulse oximetry in severe carbon monoxide 94 Lipski JI, Kaminsky D, Donoso E, et al. Electrophysiological poisoning. Chest 1998; 114:1036–1041 effects of glucagon on the normal canine heart. Am J Physiol 118 Touger M, Gallagher EJ, Tyrell J. Relationship between 1972; 222:1107–1112 venous and arterial carboxyhemoglobin levels in patients 95 Love JN, Sachdeva DK, Bessman ES, et al. A potential role with suspected carbon monoxide poisoning. Ann Emerg for glucagon in the treatment of drug-induced symptomatic Med 1995; 25:481–483 bradycardia. Chest 1998; 114:323–326 119 Takeuchi A, Vesely A, Rucker J, et al. A simple “new” 96 Critchley JA, Ungar A. The management of acute poisoning method to accelerate clearance of carbon monoxide. Am J due to ␤-adrenoceptor antagonists. Med Toxicol Adverse Respir Crit Care Med 2000; 161:1816–1819 Drug Exp 1989; 4:32–45 120 Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. 97 Zamponi GW, French RJ. Arrhythmias during phenol ther- N Engl J Med 1996; 334:1642–1648 apies: a specific action on cardiac sodium channels [letter]. 121 Juurlink DN, Stanbrook MB, McGuigan MA. Hyperbaric Circulation 1994; 89:914 oxygen for carbon monoxide poisoning (CD-ROM). Co- 98 Bentur Y, Shoshani O, Tabak A, et al. Prolonged elimination chrane Database Syst Rev 2000; 2:CD002041 half-life of phenol after dermal exposure. J Toxicol Clin 122 Thom SR, Taber RL, Mendiguren II, et al. Delayed neuro- Toxicol 1998; 36:707–711 psychologic sequelae after carbon monoxide poisoning: pre- 99 Kerns W, Schroeder D, Williams C, et al. Insulin improves vention by treatment with hyperbaric oxygen. Ann Emerg survival in a canine model of acute beta-blocker toxicity. Ann Med 1995; 25:474–480 Emerg Med 1997; 29:748–757 123 Daras M, Tuchman AJ, Koppel BS, et al. Neurovascular 100 Kerns W, Kline J, Ford MD. Beta-blocker and calcium complications of cocaine. Acta Neurol Scand 1994; 90:124– channel blocker toxicity. Emerg Med Clin North Am 1994; 129 12:365–390 124 Lange RA, Hillis LD. Medical progress: cardiovascular 101 Buckley N, Dawson AH, Howarth D, et al. Slow release complications of cocaine use. N Engl J Med 2001; 345:351– verapamil poisoning: use of polyethylene glycol whole-bowel 358 lavage and high-dose calcium. Med J Aust 1993; 158:202– 125 Hollander JE, Hoffman RS, Gennis P, et al. Prospective 204 multicenter evaluation of cocaine-associated chest pain. 102 Rosansky SJ. Verapamil toxicity: treatment with hemoperfu- Cocaine Associated Chest Pain (COCHPA) Study Group. sion. Ann Intern Med 1991; 114:340–341 Acad Emerg Med 1994; 1:330–339 103 Kenny J. Treating overdose with calcium channel blockers. 126 Albertson TE, Walby WF, Derlet RW. Stimulant-induced BMJ 1994; 308:992–993 pulmonary toxicity. Chest 1995; 108:1140–1149 104 Luscher TF, Noll G, Sturmer T, et al. in 127 Roth D, Alarcon FJ, Fernandez JA, et al. Acute rhabdomy- severe verapamil intoxication. N Engl J Med 1994; 330:718– olysis associated with cocaine intoxication. N Engl J Med 720 1988; 319:673–677 105 Papadopoulos J, O’Neil MG. Utilization of a glucagon 128 Bakir AA, Dunea G. Renal disease in the inner city. Semin infusion in the management of a massive nifedipine over- Nephrol 2001; 21:334–345 dose. J Emerg Med 2000; 18:453–455 129 Daras M, Kakkouras L, Tuchman AJ, et al. Rhabdomyolysis 106 Yuan TH, Kerns WP, Tomaszewski CA, et al. Insulin- and hyperthermia after cocaine abuse: a variant of the glucose as adjunctive therapy for severe calcium channel neuroleptic malignant syndrome? Acta Neurol Scand 1995; antagonist poisoning. J Toxicol Clin Toxicol 1999; 37:463– 92:161–165 474 130 MacDonald KL, Rutherford GW, Friedman SM, et al. 107 Boyer EW, Shannon M. Treatment of calcium-channel- Botulism and botulism-like illness in chronic drug abusers. blocker intoxication with insulin infusion. N Engl J Med Ann Intern Med 1985; 102:616–618 2001; 344:1721–1722 131 Hoffman RS, Smilkstein MJ, Goldfrank LR. Whole bowel 108 Mahmud M, Kales SN. Methylene chloride poisoning in a irrigation and the cocaine body-packer: a new approach to a cabinet worker. Environ Health Perspect 1999; 107:769– common problem. Am J Emerg Med 1990; 8:523–527 772 132 Makosiej FJ, Hoffman RS, Howland MA, et al. An in vitro 109 Nager EC, O’Connor RE. Carbon monoxide poisoning from evaluation of cocaine hydrochloride adsorption by activated

918 Critical Care Review

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians charcoal and desorption upon addition of polyethylene sants. N Engl J Med 1985; 313:474–479 glycol electrolyte lavage solution. J Toxicol Clin Toxicol 153 Buckley NA, O’Connell DL, Whyte IM, et al. Interrater 1993; 31:381–395 agreement in the measurement of QRS interval in tricyclic 133 Glass JM, Scott HJ. “Surgical mules”: the smuggling of drugs antidepressant overdose: implications for monitoring and in the . J R Soc Med 1995; 88:450–453 research. Ann Emerg Med 1996; 28:515–519 134 Brogan WC, Lange RA, Kim AS, et al. Alleviation of 154 Harrigan RA, Brady WJ. ECG abnormalities in tricyclic cocaine-induced coronary vasoconstriction by nitroglycerin. antidepressant ingestion. Am J Emerg Med 1999; 17:387– J Am Coll Card 1991; 18:581–586 393 135 Sand IC, Brody SL, Wrenn KD, et al. Experience with 155 Taboulet P, Michard F, Muszynski J, et al. Cardiovascular esmolol for the treatment of cocaine-associated cardiovas- repercussions of seizures during cyclic antidepressant poi- cular complications. Am J Emerg Med 1991; 9:161–163 soning. J Toxicol Clin Toxicol 1995; 33:205–211 136 Boehrer JD, Moliterno DJ, Willard JE, et al. Influence of 156 Stern TA, O’Gara PT, Mulley AG, et al. Complications after labetalol on cocaine-induced coronary vasoconstriction in overdose with tricyclic antidepressants. Crit Care Med 1985; humans. Am J Med 1993; 94:608–610 13:672–674 137 Sofuoglu M, Brown S, Babb DA, et al. Effects of labetalol 157 Bosse GM, Barefoot JA, Pfeifer MP, et al. Comparison of treatment on the physiological and subjective response to three methods of gut decontamination in tricyclic antide- smoked cocaine. Pharmacol Biochem Behav 2000; 65:255– pressant overdose. J Emerg Med 1995; 13:203–209 259 158 Mayron R, Ruiz E. Phenytoin: does it reverse tricyclic- 138 Hollander JE, Carter WA, Hoffman RS. Use of phentol- antidepressant-induced cardiac conduction abnormalities? amine for cocaine-induced myocardial ischemia [letter]. Ann Emerg Med 1986; 15:876–880 N Engl J Med 1992; 327:361 159 Callaham M, Schumaker H, Pentel P. Phenytoin prophylaxis 139 Forrester JM, Steele AW, Waldron JA, et al. Crack lung: an of cardiotoxicity in experimental amitriptyline poisoning. acute pulmonary syndrome with a spectrum of clinical and J Pharmacol Exp Ther 1988; 245:216–220 histopathologic findings. Am Rev Respir Dis 1990; 142:462– 160 Merigian KS, Hedges JR, Kaplan LA, et al. Plasma catechol- 467 amine levels in cyclic antidepressant overdose. J Toxicol Clin 140 Blanc PD. Cyanide. In: Olson KR, ed. Poisonings and drug Toxicol 1991; 29:177–190 overdose. 3rd ed. Stamford, CT: Appleton and Lange, 1999; 161 Buchman AL, Dauer J, Geiderman J, et al. The use of 150–152 vasoactive agents in the treatment of refractory hypotension 141 Yeh MM, Becker CE, Arieff AI. Is measurement of venous seen in tricyclic antidepressant overdose. J Clin Psychophar- oxygen saturation useful in the diagnosis of cyanide poison- macol 1990; 10:409–413 ing? Am J Med 1992; 93:582–583 162 Teba L, Schiebel F, Dedhia HV, et al. Beneficial effect of 142 Litovitz TL, Larkin RF, Myers RA. Cyanide poisoning norepinephrine in the treatment of circulatory shock caused treated with hyperbaric oxygen. Am J Emerg Med 1983; by tricyclic antidepressant overdose. Am J Emerg Med 1988; 1:94–101 6:566–568 143 Kirk MA, Gerace R, Kulig KW. Cyanide and methemoglo- 163 Zuckerman GB, Conway EE. Pulmonary complications bin kinetics in smoke inhalation victims treated with the following tricyclic antidepressant overdose in an adolescent. cyanide antidote kit. Ann Emerg Med 1993; 22:1413–1418 Ann Pharmacother 1993; 27:572–574 144 Robin ED, McCauley R. Nitroprusside-related cyanide poi- 164 Shannon M, Lovejoy FH. Pulmonary consequences of se- soning: time (long past due) for urgent, effective interven- vere tricyclic antidepressant ingestion. J Toxicol Clin Toxicol tions. Chest 1992; 102:1842–1845 1987; 25:443–461 145 Hall VA, Guest JM. Sodium nitroprusside-induced cyanide 165 Merigian KS, Browning RG, Leeper KV. Successful treat- intoxication and prevention with sodium thiosulfate prophy- ment of amoxapine-induced refractory status epilepticus laxis. Am J Crit Care 1992; 1:19–25 with propofol (Diprivan). Acad Emerg Med 1995; 2:128– 146 Forsyth JC, Mueller PD, Becker CE, et al. Hydroxocobal- 133 amin as a cyanide antidote: safety, efficacy and pharmaco- 166 Sener EK, Gabe S, Henry JA. Response to glucagon in kinetics in heavily smoking normal volunteers. J Toxicol Clin imipramine overdose. J Toxicol Clin Toxicol 1995; 33:51–53 Toxicol 1993; 31:277–294 167 Sensky PR, Olczak SA. High-dose intravenous glucagon in 147 Sauer SW, Keim ME. : improved public severe tricyclic poisoning. Postgrad Med J 1999; 75:611–612 health readiness for cyanide disasters. Ann Emerg Med 168 Pentel PR, Keyler DE. Drug-specific antibodies as 2001; 37:635–641 for tricyclic antidepressant overdose. Toxicol Lett 1995; 148 Houeto P, Borron SW, Sandouk P, et al. Pharmacokinetics 8283:801–806 of hydroxocobalamin in smoke inhalation victims. J Toxicol 169 Shelver WL, Keyler DE, Lin G, et al. Effects of recombi- Clin Toxicol 1996; 34:397–404 nant drug-specific single chain antibody Fv fragment on [3 149 Houeto P, Hoffman JR, Imbert M, et al. Relation of blood h]-desipramine distribution in rats. Biochem Pharmacol cyanide to plasma cyanocobalamin concentration after a 1996; 51:531–537 fixed dose of hydroxocobalamin in cyanide poisoning. Lancet 170 Heard K, O’Malley GF, Dart RC. Treatment of amitripty- 1995; 346:605–608 line poisoning with ovine antibody to tricyclic antidepres- 150 Phillips S, Brent J, Kulig K, et al. Fluoxetine vs tricyclic sants. Lancet 1999; 354:1614–1615 antidepressants: a prospective multicenter study of antide- 171 Callaham M, Kassel D. Epidemiology of fatal tricyclic pressant drug overdoses. J Emerg Med 1997; 15:439–445 antidepressant ingestion: implications for management. Ann 151 Bosch TM, van der Werf TS, Uges DR, et al. Antidepres- Emerg Med 1985; 14:1–9 sants self-poisoning and ICU admissions in a university 172 Callaham M. Admission criteria for tricyclic antidepressant hospital in The Netherlands. Pharm World Sci 2000; 22: ingestion. West J Med 1982; 137:425–429 92–95 173 Tokarski GF, Young MJ. Criteria for admitting patients with 152 Boehnert MT, Lovejoy FH. Value of the QRS duration vs tricyclic antidepressant overdose. J Emerg Med 1988; the serum drug level in predicting seizures and ventricular 6:121–124 arrhythmias after an acute overdose of tricyclic antidepres- 174 Adverse events associated with ingestion of ␥-butyrolactone: www.chestjournal.org CHEST / 123/3/MARCH, 2003 919

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians Minnesota, New Mexico, and Texas, 1998–1999. MMWR cases and review of 100 cases from the literature.QJMed Morb Mortal Wkly Rep 1999; 48:137–140 1978; 186:123–144 175 Placement of ␥-butyrolactone in list I of the Controlled 197 Scharman EJ. Methods used to decrease lithium absorption Substances Act (21 U.S.C. 802(34)). Drug Enforcement or enhance elimination. J Toxicol Clin Toxicol 1997; 35:601– Administration, Justice. Final rule. Federal Register 2000; 608 65:1645–1647 198 Jaeger A, Sauder P, Kopferschmitt T, et al. When should 176 Tunnicliff G. Sites of action of ␥-hydroxybutyrate (GHB): a dialysis be performed in lithium poisoning? Clin Toxicol neuroactive drug with abuse potential. Toxicol Clin Toxicol 1993; 31:429–447 1997; 35:581–590 199 Clendeninn NJ, Pond SM, Kaysen G, et al. Potential pitfalls 177 Van Cauter E, Plat L, Scharf MB, et al. Simultaneous in the evaluation of the usefulness of hemodialysis for the stimulation of slow-wave sleep and growth hormone secre- removal of lithium. J Toxicol Clin Toxicol 1982; 19:341–352 tion by ␥-hydroxybutyrate in normal young men. J Clin 200 Beckmann U, Oakley PW, Dawson AH, et al. Efficacy of Invest 1997; 100:745–753 continuous venovenous hemodialysis in the treatment of 178 Lammers GJ, Arends J, Declerck AC, et al. Gammahydroxy- severe . J Toxicol Clin Toxicol 2001; 39:393– butyrate and narcolepsy: a double-blind placebo-controlled 397 study. Sleep 1993; 16:216–220 201 Leblanc M, Raymond M, Bonnardeaux A, et al. Lithium 179 Scharf MB, Lai AA, Branigan B, et al. Pharmacokinetics of poisoning treated by high-performance continuous arterio- gammahydroxybutyrate (GHB) in narcoleptic patients. venous and venovenous hemodiafiltration. Am J Kidney Dis Sleep 1998; 21:507–514 1996; 27:365–372 180 Miotto K, Darakjian J, Basch J, et al. ␥-Hydroxybutyric acid: 202 Mansouri A, Lurie AA. Concise review: methemoglobin- patterns of use, effects and withdrawal. Am J Addict 2001; emia. Am J Hematol 1993; 42:7–12 10:232–241 203 Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: 181 Dyer JE, Roth B, Hyma BA. ␥-Hydroxybutyrate withdrawal etiology, pharmacology, and clinical management. Ann syndrome. Ann Emerg Med 2001; 37:147–153 Emerg Med 1999; 34:646–656 182 Chin RL, Sporer KA, Cullison B, et al. Clinical course of 204 Tremper KK, Barker SJ. Pulse oximetry. Anesthesiology ␥-hydroxybutyrate overdose. Ann Emerg Med 1998; 31: 1989; 70:98–108 716–722 205 Barker SJ, Tremper KK, Hyatt J. Effects of methemoglo- 183 Davis LG. Fatalities attributed to GHB and related com- binemia on pulse oximetry and mixed venous oximetry. pounds [letter]. South Med J 1999; 92:1037 Anesthesiology 1989; 70:112–117 184 Yates SW, Viera AJ. Physostigmine in the treatment of 206 Sinex JE. Pulse oximetry: principles and limitations. Am J ␥-hydroxybutyric acid overdose. Mayo Clin Proc 2000; Emerg Med 1999; 17:59–67 75:401–402 207 Donnelly GB, Randlett D. Images in clinical medicine: 185 Mullins ME, Dribben W. Physostigmine treatment of ␥- methemoglobinemia [letter]. N Engl J Med 2000; 343:337 hydroxybutyric acid overdose: appropriate or inappropriate 208 Corbridge TC, Murray P. Toxicology in adults. In: Hall J, use of a reversal agent? Mayo Clin Proc 2000; 75:872–873 Schmidt GS, Wood LDH, eds. Principles of critical care. 186 ElSohly MA, Salamone SJ. Prevalence of drugs used in cases New York, NY: McGraw Hill, 1998; 1473–1525 of alleged sexual assault. J Anal Toxicol 1999; 23:141–146 209 Sternbach G., Osler W. Narcotic-induced pulmonary 187 LeBeau MA, Montgomery MA, Miller ML, et al. Analysis of edema. J Emerg Med 1983; 1:165–167 biofluids for ␥-hydroxybutyrate (GHB) and ␥-butyrolactone 210 Katz S, Aberman A, Frand UI, et al. Heroin pulmonary (GBL) by headspace GC-FID and GC-MS. J Anal Toxicol edema: evidence for increased pulmonary capillary perme- 2000; 24:421–428 ability. Am Rev Respir Dis 1972; 106:472–474 188 Kalasinsky KS, Dixon MM, Schmunk GA, et al. Blood, brain, 211 Sporer KA, Dorn E. Heroin-related noncardiogenic pulmo- and hair GHB concentrations following fatal ingestion. J nary edema: a case series. Chest 2001; 120:1628–1632 Forensic Sci 2001; 46:728–730 212 Corbridge T, Cygan J, Greenberger P. and 189 Okusa MD, Crystal LJT. Clinical manifestations and man- acute . Intensive Care Med 2000; 26:347–349 agement of acute lithium intoxication. Am J Med 1994; 213 Cygan J, Trunsky M, Corbridge T. Inhaled heroin-induced 97:383–389 status asthmaticus: five cases and a review of the literature. 190 Amdisen A. Clinical features and management of lithium Chest 2000; 117:272–275 poisoning. Med Toxicol 1988; 3:18–32 214 Ng B, Alvear M. addiction: a drug of 191 Bailey B, McGuigan M. Lithium poisoning from a poison primary abuse. Am J Drug 1983; 19:153–158 control center perspective. Ther Drug Monit 2000; 22:650– 215 Marinella MA. Meperidine-induced generalized seizures 655 with normal renal function. South Med J 1997; 90:556–558 192 Tomaszewski C, Musso C, Pearson RJ, et al. Lithium 216 Hershey LA. Meperidine and central neurotoxicity. Ann absorption prevented by sodium polystyrene sulfonate in Intern Med 1983; 98:548–549 volunteers. Ann Emerg Med 1992; 21:1308–1311 217 Sporer KA. Acute heroin overdose. Ann Intern Med 1999; 193 Linakis JG, Hull KM, Lacouture PG, et al. Sodium polysty- 130:584–590 rene sulfonate treatment of lithium toxicity: effects on serum 218 Darke S, Zador D. Fatal heroin ’overdose’: a review. Addic- potassium concentrations. Acad Emerg Med 1996; 3:333– tion 1996; 91:1765–1772 337 219 Zador D, Sunjic S, Darke S. Heroin-related deaths in New 194 Linakis JG, Savitt DL, Wu TY, et al. Use of sodium South Wales, 1992: toxicological findings and circumstances. polystyrene sulfonate for reduction of plasma lithium con- Med J Aust 1996; 164:204–207 centrations after chronic lithium dosing in mice. J Toxicol 220 Ruttenber AJ, Kalter HD, Santinga P. The role of ethanol Clin Toxicol 1998; 36:309–313 abuse in the etiology of heroin-related death. J Forensic Sci 195 Smith SW, Ling LJ, Halstenson CE. Whole-bowel irrigation 1990; 35:891–900 as a treatment for acute lithium overdose. Ann Emerg Med 221 Hoffman JR, Schriger DL, Luo JS. The empiric use of 1991; 20:536–539 naloxone in patients with altered mental status: a reappraisal. 196 Hansen HE, Amdisen A. Lithium intoxication: report of 23 Ann Emerg Med 1991; 20:246–252

920 Critical Care Review

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians 222 Goldfrank LR, Hoffman RS. The poisoned patient with with and without acute renal failure in patients with phen- altered consciousness. JAMA 1995; 274:562–569 cyclidine intoxication. Am J Nephrol 1981; 1:91–96 223 Schwartz JG, Garriott JC, Somerset JS, et al. Measurements 245 Eastman JW, Cohen SN. Hypertensive crisis and death of fentanyl and sufentanil in blood and urine after surgical associated with phencyclidine poisoning. JAMA 1975; 231: application: implication in detection of abuse. Am J Forensic 1270–1271 Med Pathol 1994; 15:236–241 246 Bessen HA. Intracranial hemorrhage associated with phen- 224 Levine B, Smialek JE. Considerations in the interpretation cyclidine abuse. JAMA 1982; 248:585–586 of urine analyses in suspected opiate intoxications. J Foren- 247 Boyko OB, Burger PC, Heinz ER. Pathological and radio- sic Sci 1988; 43:388–389 logical correlation of subarachnoid hemorrhage in phencyc- 225 Merriman T, Stokes K. Small bowel obstruction secondary lidine abuse: case report. J Neurosurg 1987; 67:446–448 to administration of activated charcoal. AustNZJSurg 248 Price WA, Giannini AJ. Management of PCP intoxication. 1995; 65:288–289 Am Fam Physician 1985; 32:115–118 226 Tandberg D, Abercrombie D. Treatment of heroin overdose 249 Giannini AJ, Loiselle RH, DiMarzio LR, et al. Augmentation with endotracheal naloxone. Ann Emerg Med 1982; 11:443– of haloperidol by ascorbic acid in phencyclidine intoxication. 445 Am J 1987; 144:1207–1209 227 Goldfrank LR. The several uses of naloxone. Emerg Med 250 Chan TY. Potential dangers from topical preparations con- 1984; 16:105–116 taining methyl salicylate. Hum Exp Toxicol 1996; 15:747– 228 Schwartz JA, Koenigsberg MD. Naloxone-induced pulmo- 750 nary edema. Ann Emerg Med 1987; 16:1294–1296 251 Chan TY. The risk of severe salicylate poisoning following 229 Mariani PJ. Seizures associated with low-dose naloxone. the ingestion of topical medicaments or aspirin. Postgrad Am J Emerg Med 1989; 7:127–129 Med J 1996; 72:109–112 230 Osterwalder JJ. Naloxone-for intoxications with intravenous 252 Chan TY. Improvements in the packaging of drugs and heroin and heroin mixtures-harmless or hazardous? A prospec- chemicals may reduce the likelihood of severe intentional tive clinical study. J Toxicol Clin Toxicol 1996; 34:409–416 poisonings in adults. Hum Exp Toxicol 2000; 19:387–391 231 Vale JA. Toxicokinetic and toxicodynamic aspects of organ- 253 Hawton K, Townsend E, Deeks J, et al. Effects of legislation ophosphorus (OP) insecticide poisoning. Toxicol Lett 1998; restricting pack sizes of paracetamol and salicylate on self 102:649–652 poisoning in the United Kingdom: before and after study. 232 Sungur M, Guven M. Intensive care management of organo- BMJ 2001; 322:1203–1207 phosphate insecticide poisoning. Crit Care (London) 2001; 254 Done AK. Salicylate intoxication. Pediatrics 1960; 26:800– 5:211–215 807 233 Wu ML, Deng JF, Tsai WJ, et al. Food poisoning due to 255 Temple AR. Acute and chronic effects of aspirin toxicity and methamidophos-contaminated vegetables. J Toxicol Clin their treatment. Arch Intern Med 1981; 141:364–369 Toxicol 2001; 39:333–336 256 Eichenholz A, Mulhausen RO, Redleaf PS. Nature of 234 Geller RJ, Singleton KL, Tarantino ML, et al. Nosocomial acid-base disturbance in salicylate intoxication. Metabolism poisoning associated with emergency department treatment 1963; 12:164–175 of organophosphate toxicity–Georgia, 2000. J Toxicol Clin 257 Gabow PA, Anderson RJ, Potts DE, et al. Acid-base distur- Toxicol 2001; 39:109–111 bances in the salicylate-intoxicated adult. Arch Intern Med 235 Namba T, Nolte CT, Jackrel J, et al. Poisoning due to 1978; 138:1481–1484 organophosphate insecticides: acute and chronic manifesta- 258 Hill JB. Salicylate intoxication. N Engl J Med 1973; 288: tions. Am J Med 1971; 50:475–492 1110–1113 236 Hayes MM, van der Westhuizen NG, Gelfand M. Organo- 259 Thisted B, Kantz T, Strom J, et al. Acute salicylate self- phosphate poisoning in Rhodesia: a study of the clinical poisoning in 177 patients treated in ICU. Acta Anaesth features and management of 105 patients. S Afr Med J 1978; Scand 1987; 31:312–316 54:230–234 260 McGuigan MA. A two-year review of salicylate deaths in 237 Saadeh AM, Farsakh NA, al-Ali MK. Cardiac manifestations Ontario. Arch Intern Med 1987; 147:510–512 of acute carbamate and organophosphate poisoning. Heart 261 Dugandzic RM, Tierny MG, Dickinson GE, et al. Evalua- 1997; 77:461–464 tion of the validity of the Done nomogram in the manage- 238 Coye MJ, Barnett PG, Midtling JE, et al. Clinical confirma- ment of acute salicylate intoxication. Ann Emerg Med 1989; tion of organophosphate poisoning by serial cholinesterase 18:1186–1190 analyses. Arch Intern Med 1987; 147:438–442 262 Pierce RP, Gazewood J, Blake RL. Salicylate poisoning from 239 Nouira S, Abroug F, Elatrous S, et al. Prognostic value of enteric-coated aspirin: delayed absorption may complicate serum cholinesterase in organophosphate poisoning. Chest management. Postgrad Med 1991; 89:61–64 1994; 106:1811–1814 263 Anderson RJ, Potts DE, Gabow PA, et al. Unrecognized 240 Bardin PG, Van Eeden SF. Organophosphate poisoning: adult salicylate intoxication. Ann Intern Med 1976; 85:745– grading the severity and comparing treatment between 748 atropine and glycopyrrolate. Crit Care Med 1990; 18:956– 264 Greer HD, Ward HP, Corbin KB. Chronic salicylate intox- 960 ication in adults. JAMA 1965; 193:85–88 241 Lee P, Tai DY. Clinical features of patients with acute 265 Heffner JE, Sahn SA. Salicylate-induced pulmonary edema. organophosphate poisoning requiring intensive care. Inten- Ann Intern Med 1981; 95:405–409 sive Care Med 2001; 27:694–699 266 Kirshenbaum LA, Mathews SC, Sitar DS, et al. Does 242 Goswamy R, Chaudhuri A, Mahashur AA. Study of respira- multiple-dose charcoal therapy enhance salicylate excretion? tory failure in organophosphate and carbamate poisoning. Arch Intern Med 1990; 150:1281–1283 Heart Lung 1994; 23:466–472 267 Prescott LF, Balali-Mood M, Critchley JA, et al. Diuresis or 243 McCarron MM, Schulze BW, Thompson GA, et al. Acute urinary alkalinisation for salicylate poisoning? BMJ 1982; phencyclidine intoxication: incidence of clinical findings in 285:1383–1386 1,000 cases. Ann Emerg Med 1981; 10:237–242 268 Garella S. Extracorporeal techniques in the treatment of 244 Akmal M, Valdin JR, McCarron MM, et al. Rhabdomyolysis exogenous intoxications. Kidney Int 1988; 33:735–754 www.chestjournal.org CHEST / 123/3/MARCH, 2003 921

Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians 269 Gillman PK. Serotonin syndrome: history and risk. Fundam 289 Sessler CN. Theophylline toxicity and overdose: predispos- Clin Pharmacol 1998; 12:482–491 ing factors, clinical features, and outcome of 116 consecutive 270 Settle EC. Antidepressant drugs: disturbing and potentially cases. Am J Med 1990; 88:567–576 dangerous adverse effects. J Clin Psychiatry 1998; 59:S25– 290 Paloucek FP, Rodvold KA. Evaluation of theophylline over- S30 doses and . Ann Emerg Med 1988; 17:135–144 271 Power BM, Hackett LP, Dusci LJ, et al. Antidepressant 291 Sessler CN, Cohen MD. Cardiac arrhythmias during the- toxicity and the need for identification and concentration ophylline toxicity: a prospective continuous electrocardio- monitoring in overdose. Clin Pharmacokinet 1995; 29:154– graphic study. Chest 1990; 98:672–678 171 292 Hall KW, Dobson KE, Dalton JG, et al. Metabolic abnor- 272 Sternbach H. The serotonin syndrome. Am J Psychiatry malities associated with intentional theophylline overdose. 1991; 148:705–713 Ann Intern Med 1984; 101:457–462 273 Graber MA, Hoehns TB, Perry PJ. Sertraline-phenelzine 293 Hoffman A, Pinto ED, Gilhar D. Effects of pretreatment drug interaction: a serotonin syndrome reaction. Ann Phar- macother 1994; 28:732–735 with on theophylline-induced seizures in the 274 Bodner RA, Lynch T, Lewis L, et al. Serotonin syndrome. rat. J Crit Care 1993; 8:198–202 Neurology 1995; 45:219–223 294 Delanty N, Vaughan CJ, French JA. Medical causes of 275 Nemeroff CB, DeVane CL, Pollock BG. Newer antidepres- seizures. Lancet 1998; 352:383–390 sants and the system. Am J Psychiatry 295 Kearney TE, Manoguerra AS, Curtis GP, et al. Theophylline 1996; 153:311–320 toxicity and the ␤-adrenergic system. Ann Intern Med 1985; 276 Dalfen AK, Stewart DE. Who develops severe or fatal 102:766–769 adverse drug reactions to selective serotonin reuptake inhib- 296 Kempf J, Rusterholtz T, Ber C, et al. Haemodynamic study itors? Can J Psychiatry 2001; 46:258–263 as guideline for the use of ␤ blockers in acute theophylline 277 Radomski JW, Dursun SM, Reveley MA, et al. An explor- poisoning. Intensive Care Medicine 1996; 22:585–587 atory approach to the serotonin syndrome: an update of 297 Seneff M, Scott J, Friedman B, et al. Acute theophylline clinical phenomenology and revised diagnostic criteria. Med toxicity and the use of esmolol to reverse cardiovascular Hypothesis 2000; 55:218–224 instability. Ann Emerg Med 1990; 19:671–673 278 Taylor IC, McConnell JG. Severe hyponatraemia associated 298 Greenberg A, Piraino BH, Kroboth PD. Severe theophylline with selective serotonin reuptake inhibitors. Scott Med J toxicity: role of conservative measures, antiarrhythmic 1995; 40:147–148 agents, and charcoal hemoperfusion. Am J Med 1984; 279 Goldstein L, Barker M, Segall F, et al. Seizure and transient 76:854–860 SIADH associated with sertraline [letter]. Am J Psychiatry 299 Marchlinski FE, Miller JM. Atrial arrhythmias exacerbated 1996; 153:732 by theophylline: response to verapamil and evidence for 280 Moritz F, Goulle JP, Girault C, et al. Toxicological analysis triggered activity in man. Chest 1985; 88:931–934 in agitated patients. Intensive Care Med 1999; 25:852–854 300 Whitehurst VE, Joseph X, Vick JA, et al. Reversal of acute 281 Gillman PK. The serotonin syndrome and its treatment. theophylline toxicity by calcium channel blockers in dogs J Psychopharmacol 1999; 13:100–109 and rats. Toxicology 1996; 110:113–121 282 Lappin RI, Auchincloss EL. Treatment of the serotonin 301 Sage TA, Jones WN, Clark RF. Ondansetron in the treat- syndrome with cyproheptadine. N Engl J Med 1994; 331: ment of intractable nausea associated with theophylline 1021–1022 toxicity. Ann Pharmacother 1993; 27:584–585 283 Chan BS, Graudins A, Whyte IM, et al. Serotonin syndrome 302 Roberts JR, Carney S, Boyle SM, et al. Ondansetron quells resulting from drug interactions. Med J Aust 1998; 16:523– drug-resistant emesis in theophylline poisoning. Am J 525 Emerg Med 1993; 11:609–610 284 Gillman PK. Serotonin syndrome treated with chlorproma- 303 Benowitz NL, Toffelmire EB. The use of hemodialysis and zine. J Clin Psychopharmacol 1997; 17:128–129 hemoperfusion in the treatment of theophylline intoxication. 285 Shannon M. Life-threatening events after theophylline over- Semin Dial 1993; 6:243–252 dose: a 10-year prospective analysis. Arch Intern Med 1999; 304 Hootkins R, Lerman MJ, Thompson JR. Sequential and 159:989–994 simultaneous “in series” hemodialysis and hemoperfusion in 286 Schiff GD, Hegde HK, LaCloche L, et al. Inpatient theo- the management of theophylline intoxication. J Am Soc phylline toxicity: preventable factors. Ann Intern Med 1991; Nephrol 1990; 1:923–926 114:748–753 305 Okada S, Teramoto S, Matsuoka R. Recovery from theo- 287 Shannon M. Predictors of major toxicity after theophylline phylline toxicity by continuous hemodialysis with filtration overdose. Ann Intern Med 1993; 119:1161–1167 [letter]. Ann Intern Med 2000; 133:922 288 Olson KR, Benowitz NL, Woo OF, et al. Theophylline 306 Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen overdose: acute single ingestion vs chronic repeated over- for acute carbon monoxide poisoning. New Engl J Med . Am J Emerg Med 1985; 3:386–394 2002; 347:1057–1067

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Downloaded from chestjournal.org on February 28, 2008 Copyright © 2003 by American College of Chest Physicians Adult Toxicology in Critical Care: Part II: Specific Poisonings Babak Mokhlesi, Jerrold B. Leikin, Patrick Murray and Thomas C. Corbridge Chest 2003;123;897-922 DOI 10.1378/chest.123.3.897 This information is current as of February 28, 2008

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