New Antidotes in Clinical New Antidotes in Clinical ToxicologyToxicology

William Darko, B.Pharm(Hons), Pharm.D.

Director, Post Graduate Year – 1 Pharmacy Residency Program

Clinical Pharmacist, Cardiovascular/Critical Care Services

Associate Professor of Pharmacy Practice Assistant Professor of Medicine, Section of Clinical

PharmacologyUniversity Hospital, SUNY Upstate Medical

UniversitySyracuse, New York

ObjectivesObjectivesList the indication(s) for each antidoteExplain the clinical pharmacology of each

antidoteDemonstrate understanding of clinical

evidence supporting the choice of each antidote

Identify the side effects and monitoring parameters associated with each antidote

Understand the process of compounding or preparing each antidote for administration

Apply acquired knowledge to sampled questions

BackgroundBackground2007: 25th annual report of the

AAPCC◦Information reported by 61 centers

Reported 4,224,157 total cases◦2,482,041 human exposure cases

NYS updated list of antidotes – June 2009 ◦About 42 antidotes listed

Road Map

A 22 year old male was admitted to our institution after intentional overdose of an unknown quantity of acetaminophen tablets. He then called EMS and states that “I overdosed because I wanted attention from my girlfriend who is seeing another guy, please save me. I don’t want to die”. He was conscious on arrival to our emergency department but did complain of abdominal pain and nausea. A stat APAP level, BMP, and liver panel 6.5 hours post ingestion was reported as;APAP160 mcg/mL, AST 1554 U/L, Scr 0.9 mg/dL, BUN 15.9 mg/dL INR 1.20, PT 59 sec. The PCC was consulted and the recommendation was to start N – acetyl cysteine

1.What is the dose of NAC required for this patient? IV or oral? duration??2. What is the evidence for each route in this patient?3.How should NAC be prepared for administration?4.What adverse drug effects should you monitor?

Rumack – Matthew Nomogram

Fatalities from APAP overdose are common but preventable by timely administration of NAC

Risk Factors for the Development of Hepatotoxicity

Frequency of acetaminophen dosing

Prolong duration of excessive acetaminophen dosing

Increase capacity for CYP2E1 activation to NAPQI

Decreased glutathione (GSH) availability ( < 30% of baseline)

Decreased capacity of glucuronidation and sulfation

Balance in the activity of GSH and CYP2E1***

Mechanism of Action of NAC

Each of these preventive mechanisms must be in place early. None is of benefit after NAPQI has initiated cell injury. There is an 8 hours window of opportunity

N - AcetlycysteineIntravenous (Acetadote®) Oral (Mucomyst®)

Vd 0.47L/Kg 0.417L/Kg

Protein Binding

83% 83%

Half LifeAdults

New Born

5.611.0

5.611.0

Dose 150 mg/Kg LD, then 50 mg /Kg over 4 hours, followed by 100 mg/kg for 16 hoursUse caution in asthmatics

140 mg/Kg LD, then 70 mg /Kg every 4 hours x 17 dosesAny NAC dose vomited within 1 hr should be repeated

Adverse Reaction

17% anaphylactoid reaction :Rash, flushing, vomiting, hypotension, and death. Occur during loading dose

Nausea and vomiting

Indication Acetaminophen toxicity within 8 to 10 hours post ingestion. preferably within 8 hours

Preparation Loading dose in 200 mL D5W. Second dose in 500 mL DW and remaining in 1000 mL D5W

Mix with enough juice in a drinking cup. Cover to mask smell of NAC

Difference Between Intravenous and Oral N - acetylcysteine

Item Intravenous NAC Oral NAC

Safety - 17% rate of anaphylatoid reaction of which 1% serve: this include rash, flushing, vomiting, and bronchospasm , hypotension and death – these reactions are dose and concentration depended- Higher risk of dosing errors- Risk of infusion large volume of free water to pediatric patients if standard dose is used and in some instances leading to hyponatremic seizures

Nausea and vomiting present prior to oral NAC ( ~~50% of patients) may be worsen with oral NACDiarrhea Rare skin rash and other complications

Administration 1. Higher serum concentration , hence preferred in cerebral edema or in pregnancy

1.May cause delay in therapy due to higher rate of vomiting. This delay is correlated with increase risk of hepatotoxicity2.Absorption may be delayed by up to 1 hour3.Difficult to administer in patients with altered mental status due to the risk of aspiration4.Circulation concentration 20 – 30 fold lower than IV

Difference Between Intravenous and Oral N - acetylcysteine

Item Intravenous NAC Oral NAC

Duration of Therapy/ Treatment protocol

20 – 21 hours of therapy (loading dose over 1 hour)

72 hours of therapy

Total Cost IV – 20% (30 mL) = $137.79

Oral- 20% (30 mL) = $3.53

Decreased overall cost of care due to shorter duration of therapy , decreased length of hospital stay leading to reduction in inpatient cost and decrease overall hospital cost

Increase cost of care due to longer duration of therapy

Specific Indication 1. Fulminant hepatic failure2. Inability to tolerate oral NAC after antiemetic 3. Acetaminophen poisoning in pregnancy4. Patients with high [APAP]or approaching the 8 hour mark from the time of ingestion

1.Oral NAC may prove effective but has not yet been demonstrated3.Placental transfer of oral NAC may be limited (not studied) Less incidence for ADE – preferred agent for asthmatic patients unless circumstances preclude use

Summary of Published Studies on Intravenous and Oral N – acytylcysteine

References Study Population

Study Design Results Conclusions

Prescott et al BMJ 1979(2): 1097 - 1100

100 cases with sever APAP poisoning

Pts were treated with IV NAC within 24 hrs 300 mg/kg over 20 hrs ( 150mg /kg in 200 mL D5W over 15 min, 50 mg/kg in 500 ml D5W over 4 hrs, and 100 mg/Kg in one liter D5W over the next 16 hrs. The efficacy of NAC was assessed by comparing with 57 pt receiving supportive treatment

NAC within 10 hrs: Only 1/62 pts (1.6%) developed liver damage vs 33/57 pt (56%) given supportive care. Pt who received NAC within 8 hrs had almost complete resolution NAC within10 – 24 hrs; 53% liver toxicity = supportive tx< 8 hrs complete protection10 – 12 hrs: 7%12 – 15 hrs 56% > 15 hrs: Tx was ineffective

IV NAC is indicated for the treatment of [APAP] above treatment line if started <15 hrs of ingestion.Treatment between15 – 24 is ineffective but should not be withheld if time of ingestion is in doubt

Summary of Published Studies on Intravenous and Oral N – acytylcysteine

References Study Population

Study Design Results Conclusions

Smilkstein et al 1988 NEJM;319:1557 – 1562

Reported cases of suspected APAP overdose(1976 – 1985)

Prospective, national, multicenter, open - label study of oral NAC (LD : 140 mg/kg, then after 4hrs 70 mg/kg q4 hrs x 17 dosesAST/ALT activity was reviewed for hepatotoxicity (> 1000 IU/L). Risk of hepatotoxic was compared to study by Prescott et al

11,195 cases reported to Rocky Mountain Poison and Drug Center. 2540 included. Serious hepatotoxicity was uncommon if NAC was started within 8 hrs of APAP ingestionTx delay; 8 – 16 resulted in increase ALT/AST >1000

72 hr oral NAC regimen is at least as effective as 20 hour IV when started within 8 hours from time of APAP ingestion

Summary of Published Studies on Intravenous and Oral N – acytylcysteine

References Study Population

Study Design Results Conclusions

Buckley et al 1999;Clin Toxicology;37(6):759 - 767

APAP poisoning patients

Retrospective analysis of a series of APAP poisoning patients treated with a IV NAC protocol + AC. The outcome was incorporated into a meta-analysis of previous studies to compare IV and oral NAC

341 IV and 1462 oral NACRate of hepatotoxicity: < 10 hrs (3% IV and 6% oral)Late 10 – 24 hrs(30 and 26%)Overall 0 – 24 hrs (16 and 19% ) were all similar.

The difference between IV and oral NAC is artifactual. The authors recommended treating patients with IV NAC due to shorter hospital stay, convenience, nausea with oral NAC, and concern over reduced bioavailability with AC.

Intravenous Vs Oral NACIntravenous Vs Oral NACThe choice of oral vs IV NAC is complexEach has advantages and disadvantagesIV and oral NAC are equally efficacious in

treating APAP toxicity◦Except established liver failure and pregnancy

Efficacy of oral NAC and IV NAC protocols are equivalent when started within 8 hours post ingestion

Decision on route should be based on ADE, safety, and ease of use but NOT efficacy

ConclusionConclusionNAC is indicated for the treatment

of APAP toxicityIV NAC = oral NAC in efficacy Best results when NAC is initiated

within 8 hours post APAP ingestionPreparation and delivery should be

timelyAnaphylactoid reactions are rare

with oral but occur with IV NAC

Intravenous Fat Emulsion Intravenous Fat Emulsion (IFE)(IFE)

Traditionally, IFE is used to provide nutrition in the form of free fatty acids to patients requiring Total Perenteral Infusion (TPN)

IFE is currently used in the treatment of toxicity due to local anesthetics and other lipid – soluble drugs ◦This therapy is currently investigational

and not FDA approved in the United States

A 25 year old female with history of drug overdose, was admitted after ingesting an unknown quantity of her fathers amlodipine and acetaminophen tablets. At the time of presentation by the EMS her blood pressure was 80/49 mmHg, HR was 90 bpm. She was receiving normal saline at 150 mL/hour after a bolus of 1000 mL. She was lethargic at presentation with cold extremities. Norepinephrine infusion was started. Her laboratory values were as follows:Scr 2.7 mg/dL, BUN 37 mg/dL, APAP level <10 mcg/mL, HCO3 17 mmol/L. LFT’s wnl. PCC was consulted. 20% Fat emulsion was recommended.

1.What is the dose of IFE 2.How do you prepare a 20% IFE for the treatment of drug toxicity3.What is the duration of therapy?4.What side effects should you monitor?5.Where is the evidence?

Intravenous Fat Emulsion and drug Toxicity Mechanism of Action

IFE appears to create an intravascular “lipid Sink” and have the capacity to bind and sequestrate lipophilic drugs present in toxic concentrations from target sites

The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic Toxicity.

http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009

Intravenous Fat Emulsion in Local Anesthetic Toxicity

Guidelines for the Treatment of Cardiac Arrest with IFE

•Give an intravenous bolus injection of 20% IFE at 1.5 ml/kg over 1 min (based on a 70kg weight)o Give a bolus of 100 ml• Continue CPR• Start an intravenous infusion of 20% IFE at 0.25 ml/kg/mino Give at a rate of 400 ml over 20 min• Repeat the bolus injection twice at 5 min intervals if an adequate circulation has not been restoredo Give two further boluses of 100 ml at 5 min intervals• After another 5 min, increase the rate to 0.5 ml/kg/min if an adequate circulation has not been restoredo Give at a rate of 400 ml over 10 min• Continue infusion until a stable and adequate circulation has been restored

The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Severe Local Anesthetic Toxicity.

http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on July 27th 2009

Intravenous Fat Emulsion in Local Anesthetic Toxicity

Adverse Events Associated with the Use of IFE

Incidence of less than 1%: a) Dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, and irritation at the site of infusion, and, rarely, thrombocytopenia in neonates; b) Delayed adverse reactions such as hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, transient increases in liver function tests, and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly. splenomegaly and shock).

The deposition of a brown pigmentation in the reticuloendothelial system, the so-called “intravenous fat pigment

The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic Toxicity.

http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009

Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models

Reference Model

Toxin IFE Protocol Outcome

Weinberg GL et al. Anesthesiology 1998;88:1071- 75

Rat Bupivacaine

Pretreatment: 15 mL/kg of 10%, 20%, or 30%

Increase mean lethal dose

Weinberg G et al. Reg Anesth Pain Med 2003;105:217 - 218

Dog Bupivacaine

Rescue: 4mL/kg bolus of 20% followed by 0.5 mL/kg over 10 min

Increase survival time; improved hemodynamics, PO2 and pH

Cave G et al. J Med Toxicol 2006;2:4 – 7

Rat Propranolol

Pretreatment: 16 mL/kg of 20%

Trend towards improved survival time; improved HR; decrease QRS prolongation

Cave G et al. Emerg Med Australas 2005;17:180 – 181

Rat Thiopental

Rescue: 8 mL/kg of 20%

Trend toward decrease respiratory depression

Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models

Reference Model Toxin IFE Protocol Outcome

Bania TC et al. Acad Emerg Med 2007;14:105 – 111

Dog Verapamil Rescue: 7 mL/kg of 20%

Improved MAP; increase survival

Tebbutt S et al. Acad Emerg Med 2006;13:134 – 139

Rat Verapamil Rescue: 12.4 mL/kg of 20%

Increase survival time and LD50; slower development of bradycardia

Goor Y et al Vet an Human Tox 2002;44:30

Rat Clomipramine Simultaneous; 2.5 mL of 10%

Improved survival time

Harvey M et al Ann Emerg Med 2007;49:178 – 185

Robbit

Clomipramine Rescue: 12 and 8 mL/kg of 20% compared to sodium bicarbonate

Improved MAP and cardiovascular collapse

Bunia TC et al Acad Emerg Med 2005;12:S12 – Ref abstract

Mouse

Organophosphate

Pretreatment: 15 mL/kg of 20%

No change in the LD50

Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins

Reference Case Toxin IFE Protocol

Outcome

Rosenblatt AM et al. Anesthesiology 2006;105:217 – 8

58 Yr – old 82 kg male with prolong cardiac arrest after interscalene block . Developed cardiac arrest characterized by seizure, asystole, no pulse, and no blood pressure

Bupivacaine

100 ml of 20% Intralipid®, then 0.5 mL/kg/min over 2 hours

Patient recovered with no neurologic sequelae. There was no complication from Intralipid® administration

Litz JR et al Anaesthesia 2006;61:800 – 801

84 – yr – old 50 kg female , s/p axillary brachial plexus block with 40 mL of 1% (instead of 0.5%) ropivacaine. Developed cardiac arrest, failed normal cardiopulmonary resuscitation

Ropivacaine

100 mL of 20% Intralipid®, then 10 mL/min. Total of 200 mL at 4 mL/kg

Patients recovered completely and was discharged home in 4 days

Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins

Reference Case Toxin IFE Protocol

Outcome

Warren AJ et al. Anesth Analg 2008;106:1578 – 80

60 yr – old 83 kg male , s/p supraclavicular brachial plexus block. Developed respiratory and cardiac arrest but failed normal cardiopulmonary resuscitation protocol

Bupivacaine

250 mL IV infusion of Liposyn® III 20% over 30 minutes without bolus

He recovered and was discharged 3 days later

Sirianni JA et al. Ann Emerg Med. 2008;51:412 – 415

17 year – old, 55kg girl, found unresponsive at home with possible intentional ingestion of her medications as per pill count. Developed seizures and cardiac arrest 10 hours post ingestion. She decompensated after a brief cardiac resuscitation

Bupriopion(7.95 gms) and Lamotrigine (4 gms)

Intralipid® started 52 min into a second ACLS , a single IV bolus of 100 mL bolus of Intralipid® 20%

Patients was discharged from the PICU after 24 days stay with slight tremor

Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble

Toxins

References Case Toxin IFE Protocol Outcome

Litz JR et al Anesth Analg 2008;106:1575 – 7

91 yr – old 57 kg male developed incomplete block. He developed central nervous system and cardiac toxicity (supraventricular extrasystoles with intermittent bigeminy)

Mepivacaine and plain Prilocaine

Intralipid® 20% IV bolus of 1 mL/kg and repeated after 3 minutes (total 100 mL), then 0.25 mL/kg/min (14 mL/min) to a total of 200 mL

Patient recovered and later surgery was performed uneventfully.

Young CA et al. Resuscitation 2009;80: S91 - 93

32 yr – old male overdosed on sustained – released verapamil 13.44 gms, levothyroxine, bupropion, zolpidem CR, quetiapine, clonazepam, and benazepril. He failed glucagon and calcium gluconate therapy BP. Was found to be in junctional bradycardia and hypotensive despite pressors

Verapamil Intralipid® 20%;100 mL over 20 min, then 0.5 mL/kg/h for 23 hours

Patient recovered and was discharged home on day 5 without any neurological deficit

Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble

Toxins after

References Case Toxin IFE Protocol Outcome

Finn HDS et al Anaesthesia. 2009;64:191 – 194

61 yr – old 67 kg unresponsive after overdosed on 4.3 g of quetiapine, 3.1gm of sertraline and possibly benzodiazepines.

Sertraline and quetiapine

Intralipid® 20% was started 4 hours post ingestion.1.5 mL/kg (100 mL) bolus, then infusion of 6 mL/kg (400 mL) over next 1 hour

Recovered and was discharged without any neurological deficit

ConclusionConclusionIFE is not FDA approved for the treatment of

drug toxicity. Current success with IFE use is limited to

animal studies and case reports. ◦ Dose not well defined. Especially infusion after

bolus dose◦ Administer undiluted as 20% fat emulsion

More experience with local anesthetic toxicityIFE is effective in the management of lipid

soluble drug toxicity◦ Potential antidote of choice for lipid soluble

toxins/drugsControl studies warranted

Hydroxocobalamin

A 54 – year old woman brought to the hospital from an apartment fire. She had altered mental status, hypotension and evidence of inhalation injury, but no burns. Her carboxyhemoglobin level was 29% and her lactate was 16 mmol/L. She was treated with supplemental and hyperbaric oxygen for CO intoxication. Hydroxocobalamin 5 gm was administered intravenously for presumed cyanide poisoning.

1. How will you prepare hydroxycobalamin for Intravenous administration in this patient2. What precaution will you take prior to administration of hydoxocobalamin to this patient? 3. What adverse effects will you expect? How will you monitor?

2005 AAPCC report: Cyanide poisoning account for 220 of 2.4 million cases of human poisoning reported to poison centers •The most common source of CN toxicity is smoke inhalation •Estimated to cause 5,000 – 10,000 deaths annually in the US

•Mortality from smoke inhalation is about 24 – 31%

Smith Dl et al J Trauma 1994;37:655 – 659 Baud FJ et al N Eng J Med 1991;325:1761 – 1766Silverman SH et al J Trauma 1988;28:171 – 176

Source of Cyanide Poisoning

Smoke inhalation, acrylic nail polish(acetonitrile), electroplating, jewelers, occupational (industries that produce, solvents, plastics, herbicides, pesticides,), industries that polish metal, certain nuts, fruit pits (apricot, cherry), seeds (apple seeds), almond husks, and certain plants,

Mechanism of Cyanide Poisoning

Causes toxicity at the cellular level resulting in multisystem failure.

Ideal Cyanide Antidote

1.Relatively harmless if given to patients who are not cyanide toxic, 2. Should be readily available, 3.Scientifically proven to be effective, 4.Have rapid onset of action, 5. Have bioavailability in body tissue and 6. Be relatively inexpensive

Cyanokit® (Hydroxocobalamin)

Cobalt containing compound, that is a precursor of cyanocobalamin. FDA approval in December 2006 ( has been used in Europe since the 1970s)

Indication Treatment of known or suspected cyanide poisoning

Dose and Administration

Initial dose: 5.0 gm(2 vials) IV, a second dose may be given to a max dose of 10 gm. Administer by IV infusion over 15 – 30 minutes via a dedicated IV line. Pediatrics: 70 mg/kg followed by a 35 mg/kg if needed

Clinical Pharmacology

Binds cyanide to form cyanocobalamin and excreted renally. It has a rapid onset of action and crosses the blood – brain barrier in 1 – 3 minutes

Preparation Available as 2 vials of 2.5 gm lyophilized powder. Each vial should be reconstituted with 100 mL of 0.9% normal saline prior to administration(forms a clear red liquid when reconstituted). Reconstitution solution not included in kit

Adverse drug effects Discoloration of skin and urine (can interfere with spectrophotometric tests), slight elevation in blood pressure, injection site reaction, decrease lymphocyte count, nausea, chest discomfort, pustular/papular rash, headache, dysphagia and relative bradycardia

Standard three – part cyanide antidote Kit

Amyl nitrite, Sodium nitrite, and Sodium thiosulfate : Induce methemoglobin and nitrite causes hypotensionHas been used since 1950s

Controversy over 3 part CN antidote Kit

Academic controversy: Evidence is based on animal data, safety studies in healthy volunteers, and uncontrolled efficacy studies in humans

Adopted from Shepherd G and Velez IL. Ann Pharmacother 2008;42:661 – 669

Chromaturia and skin redness:

Cescon WD and Juurlink ND. CMAJ. 2009;180(2):180

$185.00 $715.00

Adopted from The Ann Pharmacotherapy 2008;42:664 with modification

Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide Poisoning

References Study Population

Study Design Results Conclusion

Barron SW et al Am J Emerg. Med. 2007; 25:551 – 558

Retrospective chart review. Excluded patients with smoking inhalation

Hydroxocobalamin 5 gm - 20 gm was given to 14 pts (12 were suicide attempts + standard supportive care

10 (71%) survived to discharge. 11 pts had cyanide conc. <100 µmol/L; 7 of these survived; 8 (57%) developed ADR (mostly discoloration of skin). Mean antidote adm time from ingestion was 3.1 hrs

Study shows that hydoxocobalamin could be used safely with benefit in patients with acute cyanide poisoning . However, this did not address cyanide poisoning associated with smoke inhalation.

Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide Poisoning

References Study Population Study Design Results Conclusion

Fortin JL et alClin. Toxicol 2006; 44(1):37 – 44

Respective review of pre-hospital use of hydroxocobalamin for smoke inhalation

Charts of 101 patients reviewed. Blood cyanide concentration not measured

30 patients survived (41.7%), 42 died. 29 pts with no data on survival outcome.38 pts were in cardiac arrest when found. 12 patients were HD unstable – 9 (75%) recovered 30 min after Tx.Pts with Glasgow score <13 benefited most

This study support previous safety findings of hydroxocobalamin. Survival was lower than expected. This suggest that hydroxocobalamin could be beneficial in patients with smoke inhalation and with neurologic impairment. Since symptoms were not correlated with CN concentration, benefit cannot be considered conclusive.

Clinical Evidence: Hydroxocobalamin for the Treatment of Cyanide Poisoning

References Study Population

Study Design Results Conclusion

Barron SW et al Ann Emerg. Med 2007;49(6):794 – 801 e1 – e2

Prehospital use of hydoxocobalamin for smoke – induced cyanide poisoning

Prospective uncontrolled open – label study. Patients > 15 yrs (mean 49.6 yrs), had soot in mouth/nose/expect- oration and had altered neurologic statusCN concentration and CO were measured. Pt received 5gm of IV hydroxocobalamin over 15 – 30 min. max 15 gm

Enrolled 69 pts (63 had pre – antidote blood conc.) CN was present (>39µmol/L ) in 42 patients, 67% survived. Median CN conc. of 52 µmol/L. OverallSurvival rate was 72% (n=50)CN conc. > 100 µmol/L, survival was 58% (11/19). The median dose of hydroxocobalamin was 5 gm. 19 pts developed ADR. Most commonly chromaturia and skin discoloration (10). HTN (3)

This study demonstrated that empiric adm of hydroxocobalamin was associated with survival benefit irrespective of presence of CN poisoning. Hydroxocobalamin appears to be safe and well tolerated for the treatment of out – of – hospital of presumptive CN poisoning from smoke inhalation

Administration ProtocolAdministration ProtocolHydroxocobalamin has gain acceptance

for the treatment of presumed cyanide poisoning in fire victims in the pre – hospital setting

FDNY – EMS in July 2009 adopted a protocol Patients exposed to smoke:◦Hypotension, altered mental status, Coma,

seizures◦Respiratory arrest, or cardiac arrest

3 tubes of blood will be drawn before hydroxocobalamin administration

Formulary ConsiderationFormulary ConsiderationHydroxocobalamin is an FDA approved

cyanide antidote with alternative mechanism

Offers straightforward administration with safety profile in patients with smoke inhalation◦No methemoglobenemia and hypotension

Offers a more rapid onset of actionThough has higher drug cost, would likely

have little impact on hospital’s drug budgetAt minimum, stock enough cyanide antidote

to treat one patient for up to 24 hours

Dart RC et al Ann Emerg. Med 2000;36:126 - 132

ConclusionsConclusionsHydroxocobalamin has demonstrated

efficacy and safety profile in the treatment of patients with cyanide poisoning

Lack of comparative data to support superiority over the 3 – part cyanide antidote

Hydroxocobalamin may be beneficial choice in cases: ◦Where diagnosis of CN poisoning is uncertain◦Where induction of metHb may be

detrimental

QUESTIONS??QUESTIONS??