Antidotes for Toxicological Emergencies - Practical Rev_AJHP 2012

8/10/2019 Antidotes for Toxicological Emergencies - Practical Rev_AJHP 2012

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PRIMER Toxicological emergencies

199Am J Health-Syst PharmVol 69 Feb 1, 2012

P R I M E R

Antidotes for toxicological emergencies:A practical review

JEANNAM. MARRAFFA, VICTORCOHEN, ANDMARYANNHOWLAND

Purpose. Appropriate therapies for com-

monly encountered poisonings, medica-

tion overdoses, and other toxicological

emergencies are reviewed, with discussionof pharmacists role in ensuring their ready

availability and proper use.

Summary. Poisoning is the second leading

cause of injury-related morbidity and mor-

tality in the United States, with more than

2.4 million toxic exposures reported each

year. Recently published national consen-

sus guidelines recommend that hospitals

providing emergency care routinely stock

24 antidotes for a wide range of toxicities,

including toxic-alcohol poisoning, expo-

sure to cyanide and other industrial agents,

and intentional or unintentional overdoses

of prescription medications (e.g., calcium-channel blockers, -blockers, digoxin,

isoniazid). Pharmacists can help reduce

morbidity and mortality due to poisonings

and overdoses by (1) recognizing the signs

JEANNA M. MARRAFFA, PHARM.D., DABAT, is Clinical Toxicologist,Upstate New York Poison Center, Syracuse, and Assistant Professor,Department of Emergency Medicine, State University of New YorkUpstate Medical University, Syracuse. VICTORCOHEN, PHARM.D., isAssistant Professor of Pharmacy Practice, Arnold & Marie SchwartzCollege of Pharmacy and Health Sciences, Long Island University,Brooklyn, NY, and Clinical Pharmacy Manager, Maimonides MedicalCenter, New York, NY. MARY ANN HOWLAND, PHARM.D., DABAT,FAACT,is Clinical Professor of Pharmacy, College of Pharmacy andAllied Health Professions, St. Johns University, Queens, NY; AdjunctProfessor of Emergency Medicine, New York University (NYU)School of Medicine, New York, and Senior Consultant in Residence,New York City Poison Center.

Address correspondence to Dr. Marraffa at Upstate NewYork Poison Center, 750 East Adams Street, Syr acuse, NY 13210([email protected]).

Robert Hoffman, M.D., is acknowledged for his thoughtful reviewof this article and astute comments.

The authors have declared no potential conflicts of interest.Copyright 2012, American Society of Health-System Pharma-

cists, Inc. All rights reserved. 1079-2082/12/0201-0199$06.00.DOI 10.2146/ajhp110014

Supplementary material is available with

the full text of this article at www.ajhp.org and symptoms of various types of toxic

exposure, (2) guiding emergency room

staff on the appropriate use of antidotes

and supportive therapies, (3) helping toensure appropriate monitoring of patients

for antidote response and adverse effects,

and (4) managing the procurement and

stocking of antidotes to ensure their timely

availability.

Conclusion. Pharmacists can play a key

role in reducing poisoning and overdose

injuries and deaths by assisting in the early

recognition of toxic exposures and guid-

ing emergency personnel on the proper

storage, selection, and use of antidotal

therapies.

Index terms: Antidotes; Dosage; Drugs;Hospitals; Pharmaceutical services; Phar-

macists, hospital; Pharmacy, institutional,

hospital; Poisoning; Protocols

Am J Health-Syst Pharm. 2012; 69:199-212

Poisoning is a leading cause ofmorbidity and mortality inthe United States1; in fact, it is

the second leading cause of injury-related mortality, and its incidenceis rising. The American Associationof Poison Control Centers NationalPoison Data System receives reportsof more than 2.4 million humanpoison exposures and approximately1300 poisoning-related deaths an-nually.2 However, it is likely that the

associated mortality is much higherthan those statistics would indicate,as it is estimated that only about 5%of U.S. poisoning deaths are reportedto poison control centers.3,4

Antidotes play a critical role inthe care of poisoned or overdosedpatients. Recently issued nationalconsensus guidelines include a rec-ommended list and the quantitiesof antidotes that should be readilyavailable in hospitals that provideemergency care.5 Some of the anti-

dotes should be available for imme-diate administration on a patientsarrival, which requires stocking inthe emergency department (ED)at most hospitals; other antidotesshould be available within 60 min-

utes and can be stocked in the hospi-tal pharmacy provided that promptdelivery to the ED can be assured.A recommended antidote stockinglist and sample inventory log canbe found in eFigure 1 and eTable 1,


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200 Am J Health-Syst PharmVol 69 Feb 1, 2012

available at www.ajhp.org. This listshould be adapted by each individualfacility based on a needs assessment.Most importantly, this list should bedecided on by vested parties (e.g.,

pharmacists, physicians, and otherhealth care practitioners involved inproviding emergency care and criti-cal care).

One of the many roles of the EDpharmacist is participating in themanagement of toxicological emer-gencies. The goal of this review isto provide essential information toguide the appropriate use of anti-dotes. The antidotes discussed (in al-phabetical order) are those whose use

likely entails the greatest involvementof ED pharmacists. As recommenda-tions may change, clinicians shouldalways consult a regional poisoncontrol center (1-800-222-1222) toascertain the most current recom-mendations on antidote use and toreport exposures and poisonings.

Antidotes for toxic-alcohol

poisoning

The use of ethanol or, preferably,fomepizole for alcohol dehydroge-nase (ADH) inhibition is a mainstayin the management of toxicity dueto ingestion of methanol, ethyleneglycol, or diethylene glycol.6-8

The toxicity of methanol and ofethylene glycol is well described,and each year in the United Statesthere are about 5000 exposures thatrequire treatment and 2030 as-sociated deaths reported to poisoncenters.2,9,10 Methanol and ethyleneglycol, as parent compounds, are rel-

atively nontoxic. However, they aremetabolized by ADH to toxic me-tabolites that can cause end-organdamage and death. Methanol is me-tabolized via ADH to formic acid,which results in anion-gap metabolicacidosis and ocular toxicity. Reti-nal toxicity secondary to methanolpoisoning is usually irreversible.6,11Ethylene glycol is metabolized viaADH to glycolic acid, which resultsin anion-gap metabolic acidosis, and

oxalic acid, which results primarilyin renal toxicity due to the forma-tion of calcium oxalate crystals.7,12

Both can produce irreversible CNStoxicity.

Poisoning by diethylene glycol(historically and tragically used as aglycerin substitute and also in house-hold products such as wallpaperstripper and Sterno brand heatingfuel13,14) is less common but associ-ated with very high morbidity andmortality.15,16 Diethylene glycol ismetabolized via ADH to hydroxy-ethoxyacetic acid and diglycolic acidand causes anion-gap metabolic aci-dosis, bilateral cortical necrosis, and

sensorimotor polyneuropathy.

16-20

Ethanol.For many years, ethanolhas been used to inhibit ADH andlimit the metabolism of methanoland ethylene glycol to their respectivemetabolites.21 The dose of ethanolneeded to competitively inhibit ADHdepends on the comparative affinityof the specific toxic alcohol for ADH.Most authorities recommend using adose of ethanol sufficient to achieveand maintain a serum ethanol con-centration of 100150 mg/dL. In thepresence of ethanol, the half-lives ofethylene glycol (in patients with nor-mal renal function) and methanolare approximately 17.5 and 45 hours,respectively.6,7

Ethanol can be administeredintravenously or orally. However,a commercial i.v. preparation ofethanol is no longer available, andextemporaneous preparation is tootime-consuming to be consideredsatisfactory. A loading dose is neces-

sary to quickly achieve the desiredserum concentration of 100150mg/dL; then a maintenance dose isadministered, using serum ethanolconcentrations to maintain the de-sired target. Repeat evaluations ofthe serum ethanol concentration arerequired to ensure that the targetlevel is achieved and maintained.Individual differences in ethanolmetabolism occur due to pharmaco-genetics and whether the patient is

induced or becomes induced second-ary to chronic ethanol exposure.6,7

The risks associated with etha-nol administration include centralnervous system (CNS) depression,

hypoglycemia (due to decreasedgluconeogenesis), nausea, and vom-iting. Intravenous administration ofethanol poses an additional risk ofphlebitis and hypertonicity with hy-ponatremia. Frequent assessment ofthe serum ethanol concentration andmonitoring of venous blood glucoseare required.

Fomepizole. Fomepizole com-petitively inhibits ADH and is aneffective and safe antidote for both

ethylene glycol and methanol toxic-ity.6,7 In the presence of fomepizole,the half-lives of ethylene glycol (inpatients with normal renal function)and methanol are 14.5 and 40 hours,respectively.22

The Food and Drug Administra-tion (FDA)-approved regimen offomepizole is an i.v. loading doseof 15 mg/kg over 30 minutes fol-lowed by a dose of 10 mg/kg every 12hours, with the frequency of dosingincreased to every 4 hours duringhemodialysis.23 Fomepizole inducesits own metabolism, presumablythrough the cytochrome P-450 2E1isoenzyme; therefore, after 48 hoursof drug administration, the fomepi-zole dose should be increased to 15mg/kg every 12 hours.

Fomepizole is generally well toler-ated. Adverse events reported with theuse of fomepizole include mild irrita-tion at the i.v. infusion site, headache,nausea, dizziness, drowsiness, and a

bad or metallic taste in the mouth.Although there are no head-to-

head comparisons of fomepizole ver-sus ethanol for the management oftoxic-alcohol poisoning, the formersease of administration and relativelack of serious adverse effects have el-evated it to preferred status. The clin-ical advantages of fomepizole overethanol are a much higher potencyof ADH inhibition (K

i= 0.1 mol/L,

a 1000-fold higher affinity than that


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of ethanol), better maintenance oftherapeutic blood concentrations,and fewer adverse effects; moreover,the administration of fomepizole isless labor-intensive.12

Additional and supportive ther-apy. In addition to antidote ad-ministration, hemodialysis shouldbe considered in all toxic-alcoholexposures in which toxic metaboliteshave already formed, as evidenced byanion-gap metabolic acidosis or end-organ damage, and for patients withtoxic serum methanol or ethyleneglycol concentrations whose elimina-tion of parent or toxic metabolitesis expected to be inordinately pro-

longed (e.g., cases involving signifi-cant methanol exposure or ethyleneglycol ingestion by a patient withrenal impairment). Empiric hemo-dialysis is recommended if the serummethanol concentration is >25 mg/dL and if the serum ethylene glycolconcentration is >50 mg/dL withrenal insufficiency.6,7 Hemodialysisalso should be considered in casesof severe isopropyl alcohol poison-ing in patients with hemodynamicinstability.

Intravenous administration of50 mg of folic acid every six hoursenhances methanol elimination andhas been shown to prevent retinaltoxicity in animal models.8,24,25 Also,urinary alkalinization (i.e., a urinepH of >8) with i.v. sodium bicarbon-ate enhances formate eliminationand may reduce the distribution offormic acid to the eye.

Theoretically, the use of i.v. thia-mine hydrochloride 100 mg and

i.v. pyridoxine hydrochloride 50mg every six hours should shuntthe metabolism of ethylene glycolaway from production of oxalicacid to production of less toxic me-tabolites26,27; though there are no datafrom studies of humans to supportthis practice, these agents are welltolerated and the potential benefitsoutweigh any risks.

Implications for the pharmacist.Methanol or ethylene glycol toxic-

ity should be suspected in a patientwith anion-gap metabolic acidosisin whom laboratory testing revealsa low (or no) ethanol concentra-tion, no ketones, and a normal lactic

acid concentration (clinicians needto be aware that some test resultscan be skewed by glycolic acid, thetoxic metabolite of ethylene glycol).Fomepizole and adjuvants that actas cofactors should be used as soonas toxic alcohols are included in thedifferential diagnosis. Fomepizoleshould be continued until the pa-tient is no longer acidemic and thetoxic-alcohol serum concentrationis presumed or confirmed to be


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adequate response to calcium thera-py; those with severe toxicity usuallyrequire additional therapies.

Calcium is available as either cal-cium chloride or calcium gluconate.

Because of differences in the molecu-lar weights of the chloride and glu-conate components, 30 mL of 10%calcium gluconate is equivalent to 10mL of 10% calcium chloride. Extrav-asation of calcium must be avoided.In particular, calcium chloride isextremely damaging to tissue shouldextravasation occur. For this reason,it is recommended that calcium chlo-ride be administered through a cen-tral line or only with good peripheral

venous access. Care should also betaken not to extravasate calcium glu-conate, but the consequences are lesssevere, so the administration of cal-cium gluconate through a peripheralvein is more appropriate.

A reasonable starting dose inadults is 30 mL of calcium gluconateor 10 mL of calcium chloride, withadditional doses administered in 1520 minutes. After three doses, carefulmonitoring of ionized calcium isnecessary to avoid dangerous hyper-calcemia. Calcium is administered toimprove hemodynamics.

Hypercalcemia may lead to anileus, myocardial depression, hypo-reflexia, and an altered mental status.The administration of calcium toa patient with cardioactive-steroid(e.g., digoxin) toxicity may lead toasystole and should be avoided.

Implications for the pharmacist.To avoid hypercalcemia and its as-sociated risks, close monitoring of

the serum ionized calcium level isrequired, especially in patients re-ceiving multiple doses of exogenouscalcium. The use of calcium shouldbe avoided in a patient with knownor suspected digoxin toxicity.

Glucagon. It is glucagons abil-ity to increase cardiac cyclic ad-enosine monophosphate (cAMP)directly and independently of the-adrenergic receptor that has estab-lished its role in the management of

-blocker overdoses.29 The increasein cardiac cAMP enhances inotropyand chronotropy and may improveconduction. Glucagon can also beused to manage CCB toxicity because

not only is it difficult to distinguishan overdose of a -blocker from anoverdose of a CCB, as the two typesof medications are frequently con-sumed together, but also because theglucagon-induced increase in cAMPoccurs regardless of whether the cal-cium channel is blocked. In severelypoisoned patients, glucagon willlikely be ineffective and additionalinterventions are necessary.29

Glucagon causes dose-dependent

and rate-related nausea and vomit-ing with a risk of aspiration; thus,antiemetics such as metoclopramideand serotonin antagonists are oftenused in patients receiving the drug.29Other adverse effects of glucagon caninclude hyperglycemia, followed byhypoglycemia in rare cases; gastro-intestinal (GI) smooth-muscle re-laxation and diarrhea; hypokalemia;and, rarely, allergic reactions. Tachy-phylaxis with continued adminis-tration of glucagon is a theoreticalconcern.

Glucagon has a rapid onset of ac-tion and a short duration of effect,rarely longer than 15 minutes. Aswith other therapies used in toxicol-ogy, definitive glucagon dosing rec-ommendations are lacking; a dosageof 50 g/kg, or 35 mg up to a cumu-lative dose of 10 mg, is reasonable.28

This dose can be repeated as neces-sary. If there is a favorable responseto glucagon boluses, a continuous

infusion may be used.Implications for the pharmacist.

The doses of glucagon necessaryfor the management of -blockeror CCB toxicity are much higherthan those typically used to inducehyperglycemic or antispasmodic ef-fects. The endpoints for discontinu-ing glucagon infusions are not clear;however, it is reasonable that oncea patient is hemodynamically stablefor a minimum of 6 hours, a slow ta-

per of a single agent at a time can beemployed. Anecdotal evidence andclinical experience suggest that oncetherapy is discontinued, close obser-vation is necessary for a minimum of

12 hours.HIET. The management and

outcomes of patients severely poi-soned by CCBs or -blockers haveimproved substantially since theadvent of HIET.31,32 High-dose in-sulin has long been reported to bean inotrope.33It was only in the late1990s that HIET was demonstratedto be effective in treating patientsseverely poisoned with CCBs or-blockers.32 The mechanism of

HIETs effectiveness has not beenclearly delineated; the available datasuggest it enhances carbohydrateuse and energy production by myo-cardial cells, resulting in improvedcontractility. 34-37 Because of thealterations in myocardial cell me-tabolism, it is not surprising that thebeneficial effects of HIET in patientswith CCB or -blocker toxicity aredelayed, generally occurring after1560 minutes.37-39Therefore, HIETshould be started early in the courseof management. If a patient remainshypotensive and bradycardic afterreceiving fluids, atropine, calcium,and glucagon, HIET should be ad-ministered. As HIET is particularlyeffective in improving myocardialcontractility, the early administra-tion of HIET may avoid the need forvasopressors or allow the use of low-er doses, thereby reducing the po-tential for ischemic consequences.39

The major adverse effects associ-

ated with HIET are hypoglycemiaand hypokalemia. The sicker thepatient is from a CCB overdose, themore likely it is that hyperglycemiawill develop before HIET is institut-ed; as the patient recovers, the needfor supplemental glucose increases.30Insulin causes an intracellular shiftof serum potassium, and potassiumsupplementation should be con-sidered when the serum potassiumconcentration is


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HIET should begin with an i.v.loading dose of 1 unit/kg of regularinsulin followed by an infusion of0.51 unit/kg/hr.39The infusion dos-age can be increased every 2030

minutes. Doses of 2.53 units/kg/hr have been used depending onthe response. Experimental studieshave used even higher doses.40Serumglucose should be maintained at aconcentration of >100 mg/dL dur-ing HIET. A maximum insulin dosehas not been established. If the initialblood glucose concentration is 8 mmol/L, or72 mg/dL)47and a venous blood gas

with a high partial pressure of oxy-gen and a high oxygen saturation are,in the appropriate clinical context,highly suggestive of cyanide toxic-ity and warrant empiric antidotaltherapy.

Amyl nitrite and sodium nitrite.The mechanism of action of amylnitrite and sodium nitrite as anti-dotes for cyanide poisoning is toproduce methemoglobinemia andvasodilation.48 Vasodilation may

contribute to their therapeutic andadverse effects.

Intravenous sodium nitrite pro-duces significant methemoglobin-emia.49 The cyanide bound to cyto-

chrome oxidase is then preferentiallybound to methemoglobin, formingcyanomethemoglobin. Rhodanese,an endogenous enzyme, then facili-tates the formation of thiocyanate, amuch less toxic metabolite, which isrenally excreted.

The creation of methemoglobin-emia through the use of nitrites forcyanide poisoning entails some riskand, in particular, may be detrimen-tal or even lethal to a patient with

smoke inhalation and concurrentcarboxyhemoglobinemia or lunginjury.50Neither carboxyhemoglobinnor methemoglobin is capable ofcarrying oxygen, so such patients candevelop functional hypoxia. There-fore, the administration of the nitritecomponent of therapy for cyanidepoisoning should be avoided in pa-tients with smoke inhalation unlessit can be demonstrated that the car-boxyhemoglobin level is negligible.The dosage of nitrites should not beadjusted to achieve a predeterminedmethemoglobin concentration, sincethe formation of cyanomethemo-globin can potentially be misreadas methemoglobin formation by anoximeter during patient monitoring.(A methemoglobin concentrationabove 20% should halt further nitriteadministration.)

In the context of cyanide poison-ing, the differences between nitriteslie in the route of administration and

the degree of methemoglobinemiathey produce.49,51 Amyl nitrite is in-haled, produces a minimal amountof methemoglobin, and is designedto be administered pending the es-tablishment of i.v. access, as is oftenthe case in the prehospital setting.Sodium nitrite is administered intra-venously and results in a methemo-globin concentration of about 15%in healthy adults.49In other scenariosof cyanide toxicity, particularly the


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intentional ingestion of cyanide salts,amyl nitrite can be given to adults asone ampul (0.3 mL) inhaled until i.v.access is obtained, followed by 300mg (10 mL of 3%) i.v. sodium nitrite

over two to four minutes.41

Childrenshould receive 6 mg/kg (0.2 mL/kg of3%) sodium nitrite up to the adultdose, at the same rate. This dosingstrategy has been established as safein children with a hemoglobin con-centration of 7 g/dL). Half of therecommended dosage can be admin-istered if cyanide toxicity reappearsor, for prophylaxis, two hours afterthe initial dosage.

Sodium thiosulfate. As noted

above, cyanide is metabolized by theenzyme rhodanese to a less toxic me-tabolite, thiocyanate, which is renallyeliminated. However, this metabolicpathway is capacity limited. Thio-sulfate enhances the activity of rho-danese by donating a sulfur group,thereby increasing the amount ofthiocyanate that rhodanese canproduce.52 Sodium thiosulfate isrelatively well tolerated, but there is apotential for nausea and vomiting, aswell as rate-related hypotension.

Because of its relatively favor-able adverse-effect profile, sodiumthiosulfate should be given to allpatients with suspected cyanidetoxicity, including those with smokeinhalation. The recommended dos-age of sodium thiosulfate for adultsis 12.5 g i.v. (50 mL of 25% solu-tion); for pediatric patients, it is 0.5g/kg i.v. (2 mL/kg of 25% solution)up to the adult dose. One half ofthe initial dose can be administered

two hours later if toxicity reappearsor as a preventive measure. Intrave-nous sodium thiosulfate should beadministered either as a bolus injec-tion or infused over 1030 minutesimmediately after sodium nitrite viathe same i.v. line.41

Hydroxocobalamin. Vitamin B12a

,or hydroxocobalamin, detoxifiescyanide and forms cyanocobalamin,which is renally excreted. Hydroxo-cobalamin is an appealing cyanide

antidote because it is relatively safe,does not compromise the bloodsoxygen-carrying capacity, and, unlikethe nitrites or sodium thiosulfate,does not produce hypotension. These

features make hydroxocobalamin anideal agent for empiric use in patientswith smoke inhalation who are sus-pected to have cyanide toxicity.53,54

Hydroxocobalamin has been foundeffective for the treatment of acutecyanide poisoning in animal models;in one study of laboratory dogs ren-dered cyanide toxic, mortality wasgreatly reduced among dogs givenhydroxocobalamin in comparisonwith those given placebo (21% versus

82%, respectively).

55

In healthy volunteers, the use ofhydroxocobalamin has been linkedto chromaturia, dose-dependenterythema, headache, GI distress, pru-ritus, dysphagia, and infusion-sitereactions. Allergic reactions are lessfrequent but occasionally are severeenough to require intervention. Inone study, 25% of volunteers whoreceived hydroxocobalamin experi-enced a substantial rise in diastolicblood pressure, and three also had arise in systolic blood pressure; theseblood pressure changes were attrib-uted to the effects of hydroxocobala-min on nitric oxide scavenging.56 Adelayed pustular rash appeared onthe face and neck of a few partici-pants in that study and took severalweeks to resolve.

Hydroxocobalamin is known tocause a reddish discoloration of theurine that typically resolves within48 hours.57 Once hydroxocobalamin

is administered, the use of laboratorytests that depend on colorimetrictechniques is no longer valid, as bothhydroxocobalamin and cyanoco-balamin are bright red and will causeinterference; assays for bilirubin,creatinine, aspartate transaminase(AST), iron, glucose, magnesium,and hemoglobin and most urineassays are among the tests affected.There was a recent case report of ahydroxocobalamin-related colori-

metric change resulting in problemswith hemodialysis; the machine in-terpreted the discoloration as a bloodleak and shut down automatically.58

Discoloration of urine by hydroxo-

cobalamin also has been reported tointerfere with a spectroscopic assayfor urinary thiocyanate that is oftenused to confirm cyanide exposure.

The use of hydroxocobalamincan also skew the results of serumcarboxyhemoglobin determinations,falsely increasing or falsely decreas-ing the measured concentration.Therefore, if possible, blood samplesshould be drawn before the adminis-tration of hydroxocobalamin.59-62

The empiric adult dose of hy-droxocobalamin is 5 g, which can beinfused over a period of 15 minutes,with the infusion repeated if neces-sary; the pediatric dose is 70 mg/kg,up to a maximum of the adult dose,administered at the same infusionrate.43

There are no published data onthe compatibility of hydroxocobala-min with other substances, and thedrug should therefore not be ad-ministered through the same line asother agents.43 If another line is notavailable, sodium thiosulfate can beadministered through the same lineafter hydroxocobalamin administra-tion is completed, with care takento avoid mixing and inactivatingthe hydroxocobalamin with sodiumthiosulfate.

Implications for the pharmacist.Cyanide toxicity should be consid-ered in patients with sudden cardio-vascular collapse, especially in the

appropriate context of occupationalexposure (e.g., laboratory or indus-trial work) or in a fire victim withhemodynamic instability, elevatedlactic acid, or coma. Cyanide anti-dotes should be immediately avail-able in the ED.

Digoxin-specific antibody

fragments

Digoxin-specific antibody frag-ments (Fab) are lifesaving agents


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in the management of toxicity as-sociated with the use of digoxin andother cardioactive steroids, includingdigitoxin and those derived fromoleander, fox glove, lily of the valley,

and toad venom.63

They are safe andeffective in both adults and childrenwith acute or chronic toxicity.64-69

Digitalis, the most widely usedcardioactive steroid, has a narrowtherapeutic index.64,68 Cardioactivesteroids act on the heart to enhancecontractility, act on the conductionsystem of the heart to produce a vari-ety of effects, and also act on the au-tonomic nervous system. The agentstoxicity is related to an exaggeration

of those effects and often involvesan increase in intracellular calcium.Electrocardiographic changes sec-ondary to digoxin toxicity can bemarked and highly variable.

In patients with acute digoxinpoisoning, empiric treatment withdigoxin-specific Fab should be con-sidered in any patient exhibitingconsequential rhythm or conductiondisturbances, including symptom-atic bradycardia or progressive heartblock unresponsive to atropine;ventricular arrhythmias such as ven-tricular tachycardia or fibrillation; ora serum potassium concentration of>5.0 meq/L in the absence of anotheridentifiable cause.70,71 Significantnausea and vomiting after an acutedigoxin overdose might also warrantthe use of digoxin-specific Fab, sinceconduction disturbances are likelyto follow. This form of therapy alsoshould be considered if there is firmevidence of ingestion of >4 mg of

digoxin by a child or >10 mg by anadult, as those total body loads ofdigoxin will almost certainly causesignificant cardiac toxicity as thedigoxin moves from the blood com-partment to the heart.

The indications for digoxin-specific Fab therapy in cases of chron-ic digoxin poisoning are less clearbut similar to those for cases of acutepoisoning. Treatment with digoxin-specific Fab should be considered in

any patient with a life-threatening orpotentially life-threatening dysrhyth-mia, including severe sinus brady-cardia or heart block unresponsiveto atropine, as well as ventricular ec-

topy, tachycardia, or fibrillation.71-73

GI complaints are less common inthe context of chronic digoxin poi-soning, but confusion and an alteredmental status are more frequent inthe elderly and might suggest theneed for digoxin-specific Fab in apatient with a chronically elevatedserum digoxin concentration (>2.5ng/mL). Patients at risk for chronicdigoxin toxicity include elderly pa-tients with declining renal function,

patients who have received inappro-priate dosages of digoxin, patientswith electrolyte abnormalities, andpatients administered drugs knownto inhibit the elimination of digoxin.

Digoxin-specific Fab is gener-ally well tolerated. The adverse-effectprofile includes the potential forhypokalemia, worsening of heart fail-ure, a rapidly conducted ventricularrate, and, rarely, allergic reactions.64

The dosage calculation for digoxin-specific Fab can be made according tothe known ingested digoxin dose, ac-cording to the serum digoxin concen-tration, or empirically. The empiricdosing for acute toxicity is 1020 vials(each 38- or 40-mg vial binds 0.5 mgof digoxin); the empiric dosing forchronic toxicity is 35 vials for adultsand 12 vials for children.73To calcu-late a dosage using a known serumdigoxin concentration, the concentra-tion (in nanograms per milliliter) ismultiplied by the patients weight (in

kilograms) and divided by 100; theresult is rounded up to the nearest in-teger to arrive at the required numberof vials.

Implications for the pharmacist.The goal of treatment with digoxin-specific Fab is to reverse digoxin-induced cardiotoxicity. Monitoringshould include electrocardiographyand serum potassium determina-tions. Once digoxin-specific Fab hasbeen administered, serum digoxin

concentrations are no longer usefulin dosage calculation, as there is aresultant increase in the total digoxinconcentration; therefore, repeat di-goxin concentrations should not be

obtained for 24 hours.74,75

Flumazenil

The intentional ingestion ofbenzodiazepines is a commoncause of overdoses.2 Flumazenilis a competitive antagonist at thebenzodiazepine-receptor binding siteon -aminobutyric acid-A. Typically,when benzodiazepines are ingestedin overdose, the patient exhibits atoxidrome, or toxic syndrome, of

CNS depression with relatively nor-mal vital signs. Deaths attributedsolely to the oral ingestion of benzo-diazepines are rare.

While the idea of using flumazenilto reverse benzodiazepine toxic-ity may be tempting, the risks usu-ally outweigh the benefits.76,77 In abenzodiazepine-dependent patient,flumazenil can precipitate symp-toms of benzodiazepine withdrawal,including seizures.77-80 Additionally,in cases of multiple-drug ingestion,flumazenil may remove the protec-tive effect of the benzodiazepineand unmask cardiac arrhythmiasand seizures.76,77,80Therefore, the useof flumazenil in overdose patientsis discouraged unless it can be de-termined with certainty that onlya benzodiazepine was ingested andthat the patient is not benzodiaz-epine dependent and has no historyof seizure.

Flumazenil also may serve a role

in the treatment of children whopresent with altered mental statusin whom possible ingestion of abenzodiazepine is suspected as thesole toxic exposure. In this scenario,invasive diagnostic techniques suchas computed tomography of thehead and lumbar puncture may beavoided. In such cases, flumazeniltherapy will not reduce the requiredED observation time; but if the childimproves clinically, flumazenil can


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help confirm the diagnosis of benzo-diazepine toxicity.

Flumazenil can also be used toreverse CNS depression associatedwith benzodiazepine administra-

tion during procedural sedation ifthe patient is known not to be ben-zodiazepine dependent. The initialdosage of flumazenil is 0.2 mg/minadministered via a slow i.v. infusion.In the context of conscious sedation,many patients respond to total dosesof 0.4 mg while some patients mayrequire a total dose of up to 1 mg.81The reversal of benzodiazepine tox-icity occurs rapidly after flumazeniladministration; if resedation occurs,

doses can be repeated at intervalsof no less than 20 minutes. Rese-dation after flumazenil therapy ismost likely to develop if >10 mg ofmidazolam or a longer-acting ben-zodiazepine is used for conscioussedation. No more than 3 mg offlumazenil should be given in onehour. In general, if resedation is notobserved within two hours of theadministration of a 1-mg dose offlumazenil, subsequent serious rese-dation is unlikely.81,82

Implications for the pharmacist.Due to the associated riskbenefitratio, flumazenil is rarely indicated inthe management of acutely poisonedpatients.76These patients often havean unclear history, which makes theadministration of flumazenil poten-tially dangerous. Flumazenil does notconsistently reverse hypoventilationsecondary to benzodiazepine use.80In the rare instances when flumazenilmay be considered, it is important

to ascertain that the patient is nottaking benzodiazepines chronically,has a normal electrocardiogram, andis not experiencing toxicity due to apolydrug ingestion. In the context ofreversal of conscious sedation, it isimportant to ensure that the patienthas no contraindications to flumaze-nil, as described above.

Intravenous fat emulsion

Intravenous fat emulsion (IFE)

has long been used to supply caloriesin the form of free fatty acids to pa-tients requiring parenteral nutrition.More recently, fatty acid emulsionhas been used as an antidote for

drug-induced cardiovascular col-lapse83-88; the first supportive stud-ies were laboratory investigationsdemonstrating the successful use offatty acid emulsion in increasing thelethal threshold in animal models ofbupivacaine-induced cardiac toxic-ity.85,88,89 Since those early animalstudies, there have been multiplecase reports of patients successfullyresuscitated after cardiovascular col-lapse due to toxicity from local anes-

thetics.

80-84

Those promising resultsled investigators to hypothesize thatIFE would produce similar resultsin other scenarios of drug toxicitycaused by lipid-soluble drugs suchas CCBs, -blockers, and tricyclicantidepressants.95-98A case report bySirianni et al.99demonstrated the roleof IFE in reversing the effects of anintentional overdose of bupropionand lamotrigine. The mechanism ofaction has not been precisely eluci-dated, but the lipid sink theory (i.e.,lipophilic molecules of a local anes-thetic partition into a lipemic plasmacompartment, making them unavail-able to the tissue) is foremost atthis time95; other actions that mightcontribute to the beneficial effects ofIFE include the direct activation ofmyocardial calcium channels100 andthe modulation of myocardial energyby providing the heart with energy inthe form of fatty acids.84,95

Despite the promising case re-

ports, research on the risks andbenefits of IFE as an antidote fortoxin-induced cardiovascular col-lapse remains in the discoveryphase. Recently reported data fromanimal studies suggest that IFE hasvery limited adverse effects at thedoses currently recommended.101Potential IFE-related adverse eventsinclude the development of fatembolism, or sludging, as well asinterference with certain laboratory

analyses due to the resultant lipemicblood86; other unknowns includethe potential for drug interactionswith other therapeutic interventionssuch as HIET.

IFE should be considered afirst-line antidote for bupivacaine-induced toxicity.86,87,90-93It should alsobe considered in a patient with pre-sumed toxin-induced cardiovascularcollapse after the failure of advancedsupportive care measures, includingother accepted antidotal therapy.In addition to local anesthetics, po-tentially toxic agents that should beconsidered possibly amenable to IFEtherapy include those that are lipo-

philic and toxic to the myocardium(e.g., tricyclic antidepressants; CCBs,especially verapamil and diltiazem;bupropion; propranolol).

The use of IFE for the reversalof cardiotoxicity is not approved byFDA, and the dosing of IFE for thisindication is unclear. Based on thepublished case reports of the success-ful use of IFE, a reasonable dosingstrategy in adults is 20% IFE 100 mL(or 1.5 mL/kg) administered over12 minutes by i.v. push. The bolusdose can be repeated if necessary.99Some reports described the use of acontinuous infusion of IFE at a rateof 0.250.5 mL/kg/min for 3060minutes after the bolus dose. Themaximum dose of IFE has not beenestablished.83,84

Implications for the pharmacist.IFE has changed the managementof bupivacaine-induced cardiotoxic-ity.87 Before the use of IFE, patientswith cardiac arrest secondary to bu-

pivacaine use were rarely resuscitat-ed.92,93 Today, IFE should be used inany patient with bupivacane-inducedcardiac toxicity. The likely scenariofor IFE use in the ED is treatment ofa patient experiencing toxin-relatedcardiovascular collapse who is notimproving with aggressive standardresuscitation measures and otheraccepted antidotal therapies. Toxinsthat are lipophilic and cause cardiactoxicity are most likely to respond


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to IFE therapy, but data supportingsuch use of IFE are limited.

N-acetylcysteine

N-acetylcysteine (NAC) is a life-

saving therapy in the managementof acetaminophen poisoning.102-109While acetaminophen is still pres-ent in the plasma, NAC acts as anantidote, primarily by replenishingglutathione stores. Secondarily, itacts as a glutathione substitute andreplenishes sulfate. These mecha-nisms of action all serve to eitherlimit the formation of the toxic me-tabolite or to detoxify it; in this way,if NAC is administered in a timelyfashion, acetaminophen toxicity canbe prevented.108,109

The Rumack-Matthew10 6 no-mogram is used to predict whetherpatients will develop hepatotoxicity,defined as a serum AST concentra-tion of >1000 units/L, based on aninitial plasma acetaminophen con-centration obtained four or morehours after a single acute ingestionof acetaminophen. Indications forthe initiation of NAC include aserum acetaminophen level on or

above the Rumack-Matthew nomo-gram; situations in which a serumacetaminophen level is not availablewithin eight hours of a potentiallytoxic ingestion; and hepatotoxicity, asdefined by clinical symptoms or liverenzyme elevations above baseline.

Once fulminant hepatic failurehas occurred, whether it is acetamin-ophen related or not, and even whenall of the acetaminophen has alreadybeen metabolized, i.v. NAC therapy is

still beneficial and may be life saving.In patients with acetaminophen-induced fulminant hepatic failure,i.v. NAC decreased mortality by 50%relative to use of a placebo.110NAC isbelieved to work through antioxidantand antiinflammatory effects, somerelated to glutathione formation, toimprove oxygen delivery and utili-zation. Intravenous NAC improvescerebral, cardiac, and renal bloodflow, resulting in the improved func-

tion of extrahepatic organs. NACmay also be beneficial in preventingor treating the hepatotoxicity associ-ated with carbon tetrachloride,111,112

Amanita phalloides ,113 and other

toxins.114,115

Although no head-to-head stud-ies comparing i.v. and oral NAChave been published, both routesare believed to be equally efficaciouswhen NAC is administered withineight hours of an acetaminophenoverdose116; NAC is effective andbeneficial when given later, althoughthe rate of hepatotoxicity increases.However, only i.v. NAC is demon-strated to be beneficial in patients

with fulminant hepatic failure.

110,117

Theoretically, oral administrationshould provide a higher concentra-tion of NAC to the liver due to thehigh extraction ratio, and i.v. dosingshould provide a higher serum NACconcentration that may be more ben-eficial at extrahepatic sites.

The FDA-approved dosing of i.v.NAC is 150 mg/kg as a loading doseinfused over 1 hour followed by 50mg/kg over 4 hours and 100 mg/kgover 16 hours. Anaphylactoid reac-tions can occur, particularly with theloading dose, which is a concern inthe ED; the manufacturer recom-mends that the loading dose be givenover 60 minutes to minimize thisrisk.118In the event of an anaphylac-toid reaction, discontinuing the infu-sion is the first step, to be followed bysupportive therapy. Once the reac-tion abates, i.v. NAC therapy can berestarted at a much slower infusionrate or oral NAC can be adminis-

tered. In patients with severe reactiveairway disease, oral NAC (whichrarely produces an anaphylactoidreaction) might be preferred to i.v.NAC. Improper dilution or dosinghas resulted in overdoses of NAC,leading to hyponatremia, cerebraledema, and death.105,110,117,119

The FDA-approved dosing of oralNAC is 140 mg/kg as a loading dosefollowed by 70 mg/kg every fourhours for a total of 17 doses. The

oral dose must be repeated if emesisoccurs within one hour. Althoughoral NAC is rarely associated withanaphylactoid reactions, nausea andvomiting occur frequently, may de-

lay the time to administration of aneffective dose, and often require theadministration of an antiemetic.120,121

The benefits of NAC outweighthe risks in pregnant patients withacetaminophen toxicity who meetthe criteria for NAC administration.Although there are conflicting data,i.v. NAC is often recommended withthe belief that i.v. NAC more readilycrosses the placenta.122,123

NAC should not be discontinued

until the acetaminophen concentra-tion is undetectable or lower than thelevel of sensitivity; the AST concen-tration is normal or significantly im-proved; the synthetic function of theliver has improved, as evidenced byan International Normalized Ratioof


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Naloxone

The most commonly used anti-dote in the ED setting,2naloxone is acompetitive antagonist at all opioidreceptors, including the -opioid

receptor.126,127

It is a well-establishedantidote for respiratory depressionsecondary to opioid toxicity. Theefficacy and safety of naloxone aredose dependent. In a previouslyopioid-naive patient experiencingan opioid overdose, even high dosesof naloxone can be given safely.128However, in an opioid-dependentpatient, an inappropriate dose of nal-oxone has the potential to precipitateopioid withdrawal and to produce or

worsen acute lung injury. Therefore,it is advisable to start with a dose of0.04 or 0.05 mg in all patients andadjust the dose upward in incrementsof 0.040.05 mg; that approach cansafely reverse the respiratory depres-sant effects of the opioids withoutproducing unwanted and potentiallydangerous withdrawal. Opioid with-drawal with abrupt catecholaminerelease, especially in an apneic pa-tient, is likely to induce vomiting andaspiration or acute lung injury.

Although case reports have sug-gested that naloxone may be usefulin reversing toxicity due to cloni-dine,129,130 ibuprofen,131 valproicacid,132,133 and captopril,134 the re-ported effects were quite variable,often minor, and usually inadequate.

Buprenorphine is a partial-agonist whose toxic effects cannotbe easily reversed with naloxone.Buprenorphine has a very high affin-ity for the -receptor and most likely

affects -receptor subtypes in a dose-dependent and variable manner; thismakes reversal with naloxone tricky,and a bell-shaped doseresponsecurve has been described, indicatingthat a dose too low or too high willbe ineffective. In one experimentalmodel, adults required an i.v. nalox-one loading dose of 23 mg followedby a continuous infusion of 4 mg/hrfor one hour before the respiratorydepressant effects of buprenorphine

were reversed135-139; dosages greaterthan 4 mg/hr were actually ineffec-tive, consistent with a bell-shapeddoseresponse relationship.

The i.v. route of naloxone admin-

istration is preferred due to a predict-able, quick, and titratable onset ofaction. Oral or sublingual adminis-tration result in poor absorption andlimited effects.140Although naloxoneis well absorbed with other paren-teral routes of administration (in-tralingual, endotracheal, intranasal,subcutaneous, and intramuscular), adelayed onset of action or difficultyin titrating the dose makes thoseroutes less desirable.

An initial naloxone dose of0.040.05 mg i.v. in both opioid-dependent and opioid-naive adultpatients is recommended.140Increas-ing the dose until reversal of respira-tory depression maximizes the ben-efits while minimizing the potentialfor significant opioid withdrawal.Titration can be accomplished bydoubling the dose every one to twominutes or escalating the dose from0.05 mg to 0.1 mg to 0.4 mg to 2mg to 10 mg. During dose titration,bag-valve mask ventilation should beused as necessary. Although there isnot a consensus on the initial dose,starting with a lower dose of nalox-one (0.040.05 mg) rather than thestandard 2-mg dose is consideredbest practice. A lack of sufficientpatient response to treatment with10 mg of naloxone should call intoquestion a diagnosis of isolated opi-oid toxicity. Patients experiencing anoverdose of synthetic opioids (e.g.,

buprenorphine, fentanyl, metha-done) often require higher doses ofnaloxone but generally respond todoses of 10 mg.

Due to the relatively short half-lifeof naloxone, the duration of its clini-cal effect is generally 3090 minutes.This relatively brief duration of effectis critical to clinicians because theduration of effect of the opioid isfrequently much longer than that ofnaloxone and, therefore, respiratory

depression may recur. Repeat dosesor a continuous infusion at an hourlydose equal to two thirds of the initialdose of naloxone may be necessary,so close monitoring of the patient

is required in the ED. It is recom-mended that the naloxone infusionbe started at two thirds of the hourlydose that was effective in reversingthe respiratory depression. This isbased on a pharmacokinetic studydone in the 1980s.140

Octreotide

A long-acting synthetic analogof somatostatin, octreotide is usedin toxicology to counteract the

insulin-releasing properties of thesulfonylurea and miglitinide oral hy-poglycemics.141-148 Sulfonylureas andmiglitinides stimulate insulin releaseby binding to adenosine triphosphate(ATP)-sensitive potassium channelson the beta-islet cell of the pancreas,increasing intracellular ATP concen-trations, which increases intracellularcalcium concentrations. Octreotideinhibits pancreatic beta-islet cell in-sulin release via G-protein-coupledreceptors141,142 that inhibit cAMPproduction; this decreases intracel-lular calcium influx, thereby causinga decrease in insulin release.143

Octreotide is used as an adjunctto dextrose to manage hypoglyce-mia induced by sulfonylureas andother exogenous causes of insulinrelease.142,144-146 Octreotide limits theproduction of hypoglycemia anddecreases the need for supplementaldextrose in such cases.

There are no published data from

randomized clinical trials confirmingthe unique effects of octreotide inpatients with sulfonylurea-inducedhypoglycemia. One study of humanvolunteers confirmed the ability ofoctreotide to reduce dextrose re-quirements in fasting patients givensulfonylureas.141 Case reports de-scribed the reversal of sulfonylurea-induced hypoglycemia with octreo-tide in both adults and children.147Vallurupalli148described two patients


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with sulfonylurea-induced hypogly-cemia and congestive heart failurewho had blood glucose concentra-tions of 31 and 36 mg/dL, respective-ly, due to inadequate oral intake of

glucose and underlying renal failure.Despite repeat doses of dextrose, bothpatients remained hypoglycemic. Oneof those patients received two dosesof octreotide 50 g 12 hours apart;after the initial dose, the first bloodglucose value was 62 mg/dL, and theconcentration rose to 121 mg/dL afterthe second dose. In the second casereported by Vallurupalli, the patientinitially received 25 g of octreotidesubcutaneously, but the hypoglyce-

mia persisted until two additionaldoses of 50 g given 12 hours apartwere administered.

Adverse effects associated withseveral doses of octreotide are mini-mal and may include diarrhea andabdominal discomfort. Octreotidehas a relatively benign adverse-effectprofile with short-term use, and itis therefore recommended that oc-treotide be considered in any patientwith recurrent hypoglycemia after asingle dose of i.v. hypertonic dextrose(0.51 g/kg) when the differential di-agnosis includes sulfonylurea toxic-ity. The use of i.v. dextrose should befollowed by feeding the patient.

Subcutaneous administrationis the most frequently describedmethod of octreotide delivery in thescientific literature.142,146 The usualadult dose of octreotide is 50 gsubcutaneously, with doses repeatedevery six hours as needed.

Implications for the pharmacist.

Octreotide decreases insulin releasefrom the pancreas when secondary toan insulin secretatogue. In otherwisehealthy patients (i.e., patients withoutdiabetes) with an intact pancreas, theadministration of exogenous dextroseto reverse the hypoglycemia causedby ingestion of an oral hypoglycemicinduces the pancreas to release moreinsulin, which can exacerbate the hy-poglycemia. Some clinicians advocatethe use of octreotide after the first

hypoglycemic episode, although mostsuggest that it should be initiated af-ter the second hypoglycemic event.142The duration of effect of the ingestedxenobiotic causing the hypoglycemia

should help determine the initialnumber of doses of octreotide andthe duration of monitoring after thelast dose of octreotide.

Conclusion

Pharmacists can play a key rolein reducing poisoning and overdoseinjuries and deaths by assisting in theearly recognition of toxic exposuresand guiding emergency personnel onthe proper storage, selection, and use

of antidotal therapies.References

1. Centers for Disease Control and Preven-tion. Unintentional poisoning deathsUnited States, 19992004.MMWR MorbMortal Wkly Rep.2007; 56:93-6.

2. Bronstein AC, Spyker DA, CantilenaLR Jr et al. 2009 annual report of theAmerican Association of Poison ControlCenters National Poison Data System(NPDS): 27th annual report. Clin Toxicol(Phila).2010; 48:979-1178.

3. Linakis JG, Frederick KA. Poisoningdeaths not reported to the regionalpoison center. Ann Emerg Med. 1993;

22:1822-8.4. Shepherd G, Klein-Schwartz W. Acci-

dental and suicidal adolescent poisoningdeaths in the US, 19791994. Arch Pedi-atr Adolesc Med.1998; 152:1181-5.

5. Dart RC, Borron SW, Caravati EM etal. Antidote Summit Authorship G. Ex-pert consensus guidelines for stockingof antidotes in hospitals that provideemergency care. Ann Emerg Med. 2009;54:386-94.e1.

6. Brent J, McMartin K, Phillips S et al., forthe Methylpyrazole for Toxic AlcoholsStudy Group. Fomepizole for the treat-ment of methanol poisoning. N Engl JMed.2001; 344:424-9.

7. Brent J, McMartin K, Phillips S et al.,for the Methylpyrazole for Toxic Alco-hols Study Group. Fomepizole for thetreatment of ethylene glycol poisoning.N Engl J Med.1999; 340:832-8.

8. Barceloux DG, Bond GR, KrenzelokEP et al., for the American Academy ofClinical Toxicology Ad Hoc Committeeon the Treatment Guidelines for Metha-nol Poisoning. American Academy ofClinical Toxicology practice guidelineson the treatment of methanol poisoning.J Toxicol Clin Toxicol.2002; 40:415-46.

9. Bronstein AC, Spyker DA, CantilenaLR Jr et al. 2008 annual report of theAmerican Association of Poison Control

Centers National Poison Data System(NPDS): 26th annual report. Clin Toxicol(Phila).2009; 47:911-1084.

10. McMartin KE, Brent J, META StudyGroup. Pharmacokinetics of fomepizole(4MP) in patients.J Toxicol Clin Toxicol.1998; 36:450-1.

11. Sanaei-Zadeh H, Zamani N, Shadnia S.Outcomes of visual disturbances aftermethanol poisoning. Clin Toxicol.2011;49:102-7.

12. McMartin KE, Heath A. Treatment ofethylene glycol poisoning with intrave-nous 4-methylpyrazole. N Engl J Med.1989; 320:125.

13. Hanif M, Mobarak MR, Ronan A et al.Fatal renal failure caused by diethyleneglycol in paracetamol elixir: the Bangla-desh epidemic. BMJ.1995; 311:88-91.

14. Okuonghae HO, Ighogboja IS, LawsonJO et al. Diethylene glycol poisoning inNigerian children. Ann Trop Paediatr.1992; 12:235-8.

15. Rollins YD, Filley CM, McNutt JT etal. Fulminant ascending paralysis asa delayed sequela of diethylene glycol(Sterno) ingestion. Neuro log y. 2002;59:1460-3.

16. Marraffa JM, Holland MG, Stork CM etal. Diethylene glycol: widely used solventpresents serious poisoning potential.J Emerg Med.2007; 35:401-6.

17. Hasbani MJ, Sansing LH, Perrone Jet al. Encephalopathy and peripheralneuropathy following diethylene glycolingestion.Neurology.2005; 64:1273-5.

18. Alfred S, Coleman P, Harris D et al. De-layed neurologic sequelae resulting fromepidemic diethylene glycol poisoning.Clin Toxicol (Phila).2005; 43:155-9.

19. Hari P, Jain Y, Kabra SK. Fatal encepha-lopathy and renal failure caused by di-ethylene glycol poisoning.J Trop Pediatr.2006; 52:442-4.

20. Landry GM, Martin S, McMartin KE.Diglycolic acid is the nephrotoxic me-tabolite in diethylene glycol poisoninginducing necrosis in human proximaltubule cells in vitro. Toxicol Sci. 2011;123:374-83.

21. Jacobsen D, McMartin KE. Antidotes formethanol and ethylene glycol poisoning.J Toxicol Clin Toxicol.1997; 35:127-43.

22. Wallemacq PE, Vanbinst R, Haufroid Vet al. Plasma and tissue determination of4-methylpyrazole for pharmacokinetic

analysis in acute adult and pediatricmethanol/ethylene glycol poisoning.Ther Drug Monit.2004; 26:258-62.

23. Antizol (fomepizole) injection productinformation. Palo Alto, CA: Jazz Phar-maceuticals, Inc.; 2007 Jan.

24. Noker PE, Eells JT, Tephly TR. Methanoltoxicity: treatment with folic acid and5-formyl tetrahydrofolic acid. AlcoholClin Exp Res.1980; 4:378-83.

25. Noker PE, Tephly TR. The role of folatesin methanol toxicity. Adv Exp Med Biol.1980; 132:305-15.

26. Nath R, Thind SK, Murthy MS et al. Roleof pyridoxine in oxalate metabolism.Ann N Y Acad Sci.1990; 585:274-84.


12/14



27. Sharma S, Sidhu H, Narula R et al. Com-parative studies on the effect of vitaminA, B1 and B6 deficiency on oxalate me-tabolism in male rats. Ann Nutr Metab.1990; 34:104-11.

28. Kerns W II. Management of beta-adrenergic blocker and calcium chan-

nel antagonist toxicity. Emerg Med ClinNorth Am.2007; 25:309-31.

29. DeWitt CR, Waksman JC. Pharmacol-ogy, pathophysiology and manage-ment of calcium channel blocker andbeta-blocker toxicity. Toxicol Rev. 2004;23:223-38.

30. Levine M, Boyer EW, Pozner CN et al.Assessment of hyperglycemia after calci-um channel blocker overdoses involvingdiltiazem or verapamil. Crit Care Med.2007; 35:2071-5.

31. Boyer EW, Duic PA, Evans A.Hyperinsulinemia/euglycemia therapyfor calcium channel blocker poisoning.Pediatr Emerg Care.2002; 18:36-7.

32. Yuan TH, Kerns WP II, TomaszewskiCA et al. Insulin-glucose as adjunctivetherapy for severe calcium channel an-tagonist poisoning.J Toxicol Clin Toxicol.1999; 37:463-74.

33. Farah AE, Alousi AA. The actions ofinsulin on cardiac contractility. Life Sci.1981; 29:975-1000.

34. Mgarbane B, Karyo S, Baud FJ. The role ofinsulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calciumchannel antagonist and beta-blockerpoisoning. Toxicol Rev.2004; 23:215-22.

35. Lheureux PE, Zahir S, Gris M et al. Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the managementof overdose of calcium-channel block-ers. Crit Care. 2006; 10:212.

36. Kline JA, Leonova E, Raymond RM.Beneficial myocardial metabolic effectsof insulin during verapamil toxicity inthe anesthetized canine. Crit Care Med.1995; 23:1251-63.

37. Kline JA, Tomaszewski CA, SchroederJD et al. Insulin is a superior antidotefor cardiovascular toxicity induced byverapamil in the anesthetized canine.J Pharmacol Exp Ther.1993; 267:744-50.

38. Kerns W II, Ransom M, Tomaszewski Cet al. The effects of extracellular ions onbeta-blocker cardiotoxicity. Toxicol ApplPharmacol.1996; 137:1-7.

39. Kerns W. Antidotes in depth: insulin-

euglycemia therapy. In: Nelson LS,Lewin NA, Howland MA et al., eds.Goldfranks toxicologic emergen-cies. 9th ed. New York: McGraw-Hill;2011:893-5.

40. Engebretsen KM, Kac Z, Marek KK etal. High dose insulin therapy in beta-blocker and calcium channel blockerpoisoning. Clin Toxicol.2011; 49:277-83.

41. Cyanide antidote kit (sodium nitriteinjection, sodium theosulfate injection,amyl nitrite inhalants) package insert.Lake Forest, IL: Akorn, Incorporated;2008.

42. Nithiodote (sodium nitrite injection andsodium thiosulfate injection) package

insert. Scottsdale, AZ: Hope Pharmaceu-ticals; 2011.

43. Cyanokit (hydroxocobalamin for in-jection) product information. Semoy,France: Merck Sante; 2009.

44. Barillo DJ, Goode R, Esch V. Cyanidepoisoning in victims of fire: analysis of

364 cases and review of the literature.J Burn Care Rehabil.1994; 15:46-57.

45. Eckstein M, Maniscalco PM. Focus onsmoke inhalationthe most commoncause of acute cyanide poisoning. Pre-hospital Disaster Med.2006; 21:S49-55.

46. Fortin JL, Waroux S, Giocanti JP et al.Hydroxocobalamin for poisoning causedby ingestion of potassium cyanide: a casestudy.J Emerg Med.2010; 39:320-4.

47. Baud FJ, Borron SW, Mgarbane B et al.Value of lactic acidosis in the assessmentof the severity of acute cyanide poison-ing. Crit Care Med.2002; 30:2044-50.

48. Chen KK, Rose C, Clowes G. Amylnitrite and cyanide poisoning. JAMA.

1933; 100:1921-2.49. Chen KK, Rose C. Nitrite and thiosulfatetherapy in cyanide poisoning. JAMA.1952; 149:113-9.

50. Hall AH, Kulig KW, Rumack BH. Sus-pected cyanide poisoning in smokeinhalation and complications of sodiumnitrite therapy.J Toxicol Clin Exp.1989;9:3-9.

51. Klimmek R, Krettek C, Werner HW.Ferrihaemoglobin formation by amylnitrite and sodium nitrite indifferentspecies in vivo and in vitro.Arch Toxicol.1988; 62:152-60.

52. Curry SC, Carlton MW, Raschke RA.Prevention of fetal and maternal cyanidetoxicity from nitroprusside with coin-fusion of sodium thiosulfate in gravidewes.Anesth Analg.1997; 84:1121-6.

53. Borron SW, Baud FJ, Mgarbane B etal. Hydroxocobalamin for severe acutecyanide poisoning by ingestion or inha-lation.Am J Emerg Med.2007; 25:551-8.

54. Fortin JL, Giocanti JP, Ruttimann M etal. Prehospital administration of hy-droxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years ofexperience in the Paris fire brigade. ClinToxicol (Phila).2006; 44(suppl 1):37-44.

55. Borron SW, Stonerook M, Reid F. Effi-cacy of hydroxocobalamin for the treat-ment of acute cyanide poisoning in adultbeagle dogs. Clin Toxicol (Phila). 2006;

44(suppl 1):5-15.56. Uhl W, Nolting A, Golor G et al. Safety of

hydroxocobalamin in healthy volunteersin a randomized, placebo-controlledstudy. Clin Toxicol (Phila).2006; 44(sup-pl 1):17-28.

57. Sutter M, Tereshchenko N, Rafii R et al.Hemodialysis complications of hydroxo-cobalamin: a case report. J Med Toxicol.2010; 6:165-7.

58. Cescon DW, Juurlink DN. Discolorationof skin and urine after treatment withhydroxocobalamin for cyanide poison-ing. CMAJ.2009; 180:251.

59. Curry SC, Connor DA, Raschke RA.Effect of the cyanide antidote hydroxo-

cobalamin on commonly ordered serumchemistry studies.Ann Emerg Med.1994;24:65-7.

60. Beaudeux JL, Flourie F, Peynet J et al.Hydroxocobalamin and sodium thiosul-fate interfere negatively with measure-ment of creatine kinase activity. Clin

Chem.1994; 40:2120-1.61. Beckerman N, Leikin SM, Aitchinson R

et al. Laboratory interferences with thenewer cyanide antidote: hydroxocobala-min. Semin Diagn Pathol. 2009; 26:49-52.

62. Pamidi PV, DeAbreu M, Kim D et al.Hydroxocobalamin and cyanocobala-min interference on co-oximetry basedhemoglobin measurements. Clin ChimActa.2009; 401:63-7.

63. Centers for Disease Control and Preven-tion. Deaths associated with a purportedaphrodisiacNew York City, February1993May 1995. MMWR Morb MortalWkly Rep.1995; 44:853-5.

64. Hickey AR, Wenger TL, Carpenter VP etal. Digoxin immune fab therapy in themanagement of digitalis intoxication:safety and efficacy results of an obser-vational surveillance study. J Am CollCardiol.1991; 17:590-8.

65. Woolf AD, Wenger TL, Smith TW etal. Results of multicenter studies ofdigoxin-specific antibody fragments inmanaging digitalis intoxication in thepediatric population. Am J Emerg Med.1991; 9(2, suppl 1):16,20 [discussion 33-4].

66. Antman EM, Wenger TL, Butler VPJr et al. Treatment of 150 cases of life-threatening digitalis intoxication withdigoxin-specific fab antibody fragments.Final report of a multicenter study. Cir-culation.1990; 81:1744-52.

67. Lapostolle F, Borron SW, Verdier C etal. Assessment of digoxin antibody usein patients with elevated serum digoxinfollowing chronic or acute exposure.Intensive Care Med.2008; 34:1448-53.

68. Lapostolle F, Borron SW, Verdier C et al.Digoxin-specific fab fragments as singlefirst-line therapy in digitalis poisoning.Crit Care Med.2008; 36:3014-8.

69. Slifman NR, Obermeyer WR, Aloi BK etal. Contamination of botanical dietarysupplements by digitalis lanata.N Engl JMed.1998; 339:806-11.

70. Bismuth C, Borron SW, Baud FJ et al.

Immunotoxicotherapy: successes, disap-pointments and hopes. Hum Exp Toxicol.1997; 16:602-8.

71. Domart Y, Bismuth C, Schermann JM etal. Digitoxin poisoning: reversing ven-tricular fibrillation with fab fragments ofanti-digoxin antibody.Nouv Presse Med.1982; 11:3827-30.

72. Smolarz A, Roesch E, Lenz E et al. Digox-in specific antibody (fab) fragments in34 cases of severe digitalis intoxication.J Toxicol Clin Toxicol.1985; 23:327-40.

73. Borron SW, Bismuth C, Muszynski J.Advances in the management of digoxintoxicity in the older patient. Drugs Aging.1997; 10:18-33.


13/14



74. Doherty JE, Perkins WH, Flanigan WJ.The distribution and concentration oftritiated digoxin in human tissues. AnnIntern Med.1967; 66:116-24.

75. Gibb T, Adams PC, Parnham AJ et al.Plasma digoxin: assay anomalies in Fab-treated patients. Br J Clin Pharmacol.

1983; 16:445-7.76. Goldfrank LR. Flumazenil: a pharma-

cologic antidote with limited medicaltoxicology utility, or . . . an antidote insearch of an overdose.Acad Emerg Med.1997; 4:935-6.

77. Haverkos GP, DiSalvo RP, Imhoff TE.Fatal seizures after flumazenil adminis-tration in a patient with mixed overdose.Ann Pharmacother.1994; 28:1347-9.

78. Lheureux P, Vranckx M, Leduc D et al.Risks of flumazenil in mixed benzodiaz-epine-tricyclic antidepressant overdose:report of a preliminary study in the dog.J Toxicol Clin Exp.1992; 12:43-53.

79. Mordel A, Winkler E, Almog S et al. Sei-

zures after flumazenil administration ina case of combined benzodiazepine andtricyclic antidepressant overdose. CritCare Med.1992; 20:1733-4.

80. Seger DL. Flumazeniltreatmentor toxin. J Toxicol Clin Toxicol. 2004;42:209-16.

81. McEvoy GK, Snow EK, Miller J et al., eds.AHFS drug information 2009. Bethesda,MD: American Society of Health-SystemPharmacists; 2009:2.

82. Romazicon (flumazenil) injectionproduct information. Nutley, NJ: RochePharmaceuticals, Inc.; 2007.

83. Weinberg G. Lipid rescue resuscitationfrom local anaesthetic cardiac toxicity.Toxicol Rev.2006; 25:139-45.

84. Weinberg G. Lipid infusion resuscita-tion for local anesthetic toxicity: proofof clinical efficacy. Anesthesiology. 2006;105:7-8.

85. Weinberg G, Ripper R, Feinstein DL etal. Lipid emulsion infusion rescues dogsfrom bupivacaine-induced cardiac toxic-ity. Reg Anesth Pain Med. 2003; 28:198-202.

86. Weinberg GL. Limits to lipid in theliterature and lab: what we know, whatwe dont know. Anesth Analg . 2009;108:1062-4.

87. Weinberg GL. Lipid infusion therapy:translation to clinical practice. AnesthAnalg.2008; 106:1340-2.

88. Weinberg GL, di Gregorio G, Ripper Ret al. Resuscitation with lipid versus epi-nephrine in a rat model of bupivacaineoverdose. Anesthesiology.2008; 108:907-13.

89. Hiller DB, Gregorio GD, Ripper R et al.Epinephrine impairs lipid resuscitationfrom bupivacaine overdose: a thresholdeffect.Anesthesiology.2009; 111:498-505.

90. Charbonneau H, Marcou TA, Mazoit JXet al. Early use of lipid emulsion to treatincipient mepivacaine intoxication. RegAnesth Pain Med.2009; 34:277-8.

91. Litz RJ, Roessel T, Heller AR et al. Rever-sal of central nervous system and cardiactoxicity after local anesthetic intoxica-

tion by lipid emulsion injection. AnesthAnalg.2008; 106:1575-7.

92. Markowitz S, Neal JM. Immediate lipidemulsion therapy in the successful treat-ment of bupivacaine systemic toxicity.Reg Anesth Pain Med.2009; 34:276.

93. Rosenblatt MA, Abel M, Fischer GW

et al. Successful use of a 20% lipidemulsion to resuscitate a patient after apresumed bupivacaine-related cardiacarrest.Anesthesiology.2006; 105:217-8.

94. Weinberg G, Hertz P, Newman J. Lipid,not propofol, treats bupivacaine over-dose.Anesth Analg.2004; 99:1875-6.

95. Bania TC, Chu J, Perez E et al. He-modynamic effects of intravenous fatemulsion in an animal model of severeverapamil toxicity resuscitated with at-ropine, calcium, and saline. Acad EmergMed.2007; 14:105-11.

96. Harvey M, Cave G, Hoggett K. Correla-tion of plasma and peritoneal diasyl-ate clomipramine concentration with

hemodynamic recovery after intralipidinfusion in rabbits. Acad Emerg Med.2009; 16:151-6.

97. Perez E, Bania TC, Medlej K et al.Determining the optimal dose ofintravenous fat emulsion for the treat-ment of severe verapamil toxicity in arodent model. Acad Emerg Med. 2008;15:1284-9.

98. Tebbutt S, Harvey M, Nicholson T etal. Intralipid prolongs survival in a ratmodel of verapamil toxicity.Acad EmergMed.2006; 13:134-9.

99. Sirianni AJ, Osterhoudt KC, Calello DPet al. Use of lipid emulsion in the re-suscitation of a patient with prolongedcardiovascular collapse after overdose ofbupropion and lamotrigine. Ann EmergMed.2008; 51:412-5.

100. Gueret G, Pennec JP, Arvieux CC. He-modynamic effects of intralipid afterverapamil intoxication may be due toa direct effect of fatty acids on myocar-dial calcium channels.Acad Emerg Med.2007; 14:761.

101. Hiller DB, di Gregorio G, Kelly K et al.Safety of high volume lipid emulsion in-fusion: a first approximation of LD50 inrats. Reg Anesth Pain Med.2010; 35:140-4.

102. Harrison PM, Keays R, Bray GP et al.Improved outcome of paracetamol-induced fulminant hepatic failure by late

administration of acetylcysteine. Lancet.1990; 335:1572-3.

103. Harrison PM, Wendon JA, Gimson AEet al. Improvement by acetylcysteine ofhemodynamics and oxygen transport infulminant hepatic failure.N Engl J Med.1991; 324:1852-7.

104. Keays R, Harrison PM, Wendon JAet al. Intravenous acetylcysteine inparacetamol induced fulminant hepaticfailure: a prospective controlled trial.BMJ.1991; 303:1026-9.

105. Prescott LF, Illingworth RN, CritchleyJA et al. Intravenous N-acetylcystine:the treatment of choice for paracetamolpoisoning. Br Med J.1979; 2:1097-100.

106. Rumack BH, Matthew H. Acetamino-phen poisoning and toxicity. Pediatrics.1975; 55:871-6.

107. Rumack BH, Peterson RG. Acetamino-phen overdose: incidence, diagnosis, andmanagement in 416 patients. Pediatrics.1978; 62(5, pt 2, suppl):898-903.

108. Smilkstein MJ, Knapp GL, Kulig KW etal. Efficacy of oral N-acetylcysteine inthe treatment of acetaminophen over-dose: analysis of the national multicenterstudy (1976 to 1985). N Engl J Med.1988; 319:1557-62.

109. Smilkstein MJ, Douglas DR, Daya MR.Acetaminophen poisoning and liverfunction.N Engl J Med.1994; 331:1310-1.

110. Galicia-Moreno M, Rodrguez-Rivera A,Reyes-Gordillo K et al. N-acetylcysteineprevents carbon tetrachloride-inducedliver cirrhosis: role of liver transform-ing growth factor-beta and oxidativestress. Eur J Gastroenterol Hepatol.2009;21:908-14.

111. Valles EG, de Castro CR, Castro JA.N-acetyl cysteine is an early but alsoa late preventive agent against carbontetrachloride-induced liver necrosis.Toxicol Lett.1994; 71:87-95.

112. Montanini S, Sinardi D, Pratic C et al.Use of acetylcysteine as the life-savingantidote in Amanita phalloides (deathcap) poisoning. Case report on 11patients. Arzneimitte lforschung. 1999;49:1044-7.

113. DellAglio DM, Sutter ME, SchwartzMD et al. Acute chloroform ingestionsuccessfully treated with intravenouslyadministered N-acetylcysteine. J MedToxicol.2010; 6:143-6.

114. Anderson IB, Mullen WH, Meeker JE etal. Pennyroyal toxicity: measurement oftoxic metabolite levels in two cases andreview of the literature.Ann Intern Med.1996; 124:726-34.

115. Yarema MC, Johnson DW, Berlin RJ etal. Comparison of the 20-hour intra-venous and 72-hour oral acetylcysteineprotocols for the treatment of acuteacetaminophen poisoning. Ann EmergMed.2009; 54:606-14.

116. Acetadote (acetylcysteine) injectionpackage insert. Nashville, TN: Cumber-land Pharmaceuticals Inc.; 2011.

117. Prescott LF, Illingworth RN, Critchley JAet al. Intravenous N-acetylcysteine: stillthe treatment of choice for paracetamol

poisoning. Br Med J.1980; 280:46-7.118. Heard K. A multicenter comparison of

the safety of oral versus intravenous ace-tylcysteine for treatment of acetamino-phen overdose. Clin Toxicol (Phila).2010; 48:424-30.

119. Heard KJ. Acetylcysteine for acetamino-phen poisoning. N Engl J Med. 2008;359:285-92.

120. Horowitz RS, Dart RC, Jarvie DR et al.Placental transfer of N-acetylcysteinefollowing human maternal acetamino-phen toxicity.J Toxicol Clin Toxicol.1997;35:447-51.

121. Selden BS, Curry SC, Clark RF et al. Trans-placental transport of N-acetylcysteine


14/14


l h h l b

in an ovine model.Ann Emerg Med.1991;20:1069-72.

122. Dart RC, Rumack BH. Patient-tailoredacetylcysteine administration. AnnEmerg Med.2007; 50:280-1.

123. Evans LE, Swainson CP, Roscoe P etal. Treatment of drug overdosage with

naloxone, a specific narcotic antagonist.Lancet.1973; 1:452-5.

124. Evans LE. Use of naloxone in opiate poi-soning. Br Med J.1973; 2:717.

125. Dixon R, Gentile J, Hsu HB et al.Nalmefene: safety and kinetics aftersingle and multiple oral doses of a newopioid antagonist. J Clin Pharmacol.1987; 27:233-9.

126. Jorm CM, Stamford JA. Actions of mor-phine on noradrenaline efflux in the ratlocus coeruleus are mediated via bothopioid and alpha 2 adrenoceptor mecha-nisms. Br J Anaesth.1995; 74:73-8.

127. Seger DL. Clonidine toxicity revisited.J Toxicol Clin Toxicol.2002; 40:145-55.

128. Easley RB, Altemeier WA III. Centralnervous system manifestations of anibuprofen overdose reversed by nalox-one. Pediatr Emerg Care.2000; 16:39-41.

129. Roberge RJ, Francis EH III. Use of nalox-one in valproic acid overdose: case reportand review.J Emerg Med.2002; 22:67-70.

130. Thanacoody HK. Chronic valproic acidintoxication: reversal by naloxone. EmergMed J.2007; 24:677-8.

131. Varon J, Duncan SR. Naloxone reversal

of hypotension due to captopril over-dose.Ann Emerg Med.1991; 20:1125-7.

132. Dahan A. Opioid-induced respiratoryeffects: new data on buprenorphine. Pal-liat Med.2006; 20(suppl 1):S3-8.

133. Dahan A, Aarts L, Smith TW. Incidence,reversal, and prevention of opioid-

induced respiratory depression.Anesthe-siology.2010; 112:226-38.

134. Sarton E, Teppema L, Dahan A. Nalox-one reversal of opioid-induced respiratorydepression with special emphasis on thepartial agonist/antagonist buprenorphine.Adv Exp Med Biol.2008; 605:486-91.

135. Van Dorp E, Yassen A, Sarton E et al.Naloxone reversal of buprenorphine-induced respiratory depression.Anesthe-siology.2006; 105:51-7.

136. Yassen A, Olofsen E, van Dorp E et al.Mechanism-based pharmacokinetic-pharmacodynamic modelling of the re-versal of buprenorphine-induced respi-ratory depression by naloxone: a study in

healthy volunteers. Clin Pharmacokinet.2007; 46:965-80.137. Goldfrank L, Weisman RS, Errick JK et

al. A dosing nomogram for continuousinfusion intravenous naloxone. AnnEmerg Med.1986; 15:566-70.

138. Boyle PJ, Justice K, Krentz AJ et al.Octreotide reverses hyperinsulinemiaand prevents hypoglycemia induced bysulfonylurea overdoses.J Clin EndocrinolMetab.1993; 76:752-6.

139. Fasano CJ, OMalley G, Dominici P etal. Comparison of octreotide and stan-dard therapy versus standard therapyalone for the treatment of sulfonylurea-induced hypoglycemia.Ann Emerg Med.2008; 51:400-6.

140. Calello DP, Kelly A, Osterhoudt KC. Case

files of the medical toxicology fellow-ship training program at the childrenshospital of Philadelphia: a pediatric ex-ploratory sulfonylurea ingestion. J MedToxicol.2006; 2:19-24.

141. McLaughlin SA, Crandall CS, McKinneyPE. Octreotide: an antidote forsulfonylurea-induced hypoglycemia.Ann Emerg Med.2000; 36:133-8.

142. Green RS, Palatnick W. Effectivenessof octreotide in a case of refractorysulfonylurea-induced hypoglycemia.J Emerg Med.2003; 25:283-7.

143. Rath S, Bar-Zeev N, Anderson K et al.Octreotide in children with hypogly-caemia due to sulfonylurea ingestion.

J Paediatr Child Health.2008; 44:383-4.144. Pelavin PI, Abramson E, Pon S et al.Extended-release glipizide overdose pre-senting with delayed hypoglycemia andtreated with subcutaneous octreotide.J Pediatr Endocrinol.2009; 22:171-5.

145. Vallurupalli S. Safety of subcutaneousoctreotide in patients with sulfonylurea-induced hypoglycemia and congestiveheart failure. Ann Pharmacother. 2010;44:387-90.

Antidotes for Toxicological Emergencies - Practical Rev_AJHP 2012

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