New Antidotes in Clinical Toxicology

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New Antidotes in Clinical Toxicology

• 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 Pharmacology
• University Hospital, SUNY Upstate Medical
  University
• Syracuse, New York

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Objectives

• List the indication(s) for each antidote
• Explain the clinical pharmacology of each
  antidote
• Demonstrate 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

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Background

• 2007 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

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Road Map
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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 dont
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?
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Fatalities from APAP overdose are common but
preventable by timely administration of NAC
Rumack Matthew Nomogram
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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 ( lt 30 of baseline)
Decreased capacity of glucuronidation and sulfation
Balance in the activity of GSH and CYP2E1
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Mechanism of Action of NAC
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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
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N - Acetlycysteine N - Acetlycysteine N - Acetlycysteine
Intravenous (Acetadote) Oral (Mucomyst)
Vd 0.47L/Kg 0.417L/Kg
Protein Binding 83 83
Half Life Adults New Born 5.6 11.0 5.6 11.0
Dose 150 mg/Kg LD, then 50 mg /Kg over 4 hours, followed by 100 mg/kg for 16 hours Use caution in asthmatics 140 mg/Kg LD, then 70 mg /Kg every 4 hours x 17 doses Any 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 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
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Difference Between Intravenous and Oral N - acetylcysteine Difference Between Intravenous and Oral N - acetylcysteine 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 NAC Diarrhea Rare skin rash and other complications
Administration 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 hepatotoxicity 2.Absorption may be delayed by up to 1 hour 3.Difficult to administer in patients with altered mental status due to the risk of aspiration 4.Circulation concentration 20 30 fold lower than IV
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Difference Between Intravenous and Oral N - acetylcysteine Difference Between Intravenous and Oral N - acetylcysteine 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 failure 2. Inability to tolerate oral NAC after antiemetic 3. Acetaminophen poisoning in pregnancy 4. Patients with high APAPor approaching the 8 hour mark from the time of ingestion 1.Oral NAC may prove effective but has not yet been demonstrated 3.Placental transfer of oral NAC may be limited (not studied) Less incidence for ADE preferred agent for asthmatic patients unless circumstances preclude use
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Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine 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 lt 8 hrs complete protection 10 12 hrs 7 12 15 hrs 56 gt 15 hrs Tx was ineffective IV NAC is indicated for the treatment of APAP above treatment line if started lt15 hrs of ingestion. Treatment between15 24 is ineffective but should not be withheld if time of ingestion is in doubt
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Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine
References Study Population Study Design Results Conclusions
Smilkstein et al 1988 NEJM3191557 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 doses AST/ALT activity was reviewed for hepatotoxicity (gt 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 ingestion Tx delay 8 16 resulted in increase ALT/AST gt1000 72 hr oral NAC regimen is at least as effective as 20 hour IV when started within 8 hours from time of APAP ingestion
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Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine Summary of Published Studies on Intravenous and Oral N acytylcysteine
References Study Population Study Design Results Conclusions
Buckley et al 1999Clin Toxicology37(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 NAC Rate of hepatotoxicity lt 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.
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Intravenous Vs Oral NAC

• The choice of oral vs IV NAC is complex
• Each has advantages and disadvantages
• IV 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

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Conclusion

• NAC is indicated for the treatment of APAP
  toxicity
• IV NAC oral NAC in efficacy
• Best results when NAC is initiated within 8 hours
  post APAP ingestion
• Preparation and delivery should be timely
• Anaphylactoid reactions are rare with oral but
  occur with IV NAC

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Intravenous Fat Emulsion (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

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• 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 lt10
  mcg/mL, HCO3 17 mmol/L. LFTs wnl.
• PCC was consulted. 20 Fat emulsion was
  recommended.
• What is the dose of IFE
• How do you prepare a 20 IFE for the treatment of
  drug toxicity
• What is the duration of therapy?
• What side effects should you monitor?
• Where is the evidence?

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Intravenous Fat Emulsion and drug Toxicity 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
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Intravenous Fat Emulsion in Local Anesthetic Toxicity 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/min o 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 restored o 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 restored o 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
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Intravenous Fat Emulsion in Local Anesthetic Toxicity 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
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Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models 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 1998881071- 75 Rat Bupivacaine Pretreatment 15 mL/kg of 10, 20, or 30 Increase mean lethal dose
Weinberg G et al. Reg Anesth Pain Med 2003105217 - 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 200624 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 200517180 181 Rat Thiopental Rescue 8 mL/kg of 20 Trend toward decrease respiratory depression
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Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models Summary of the Use of Intravenous Lipid Emulsion in the Management of Lipid Soluble Toxins in animal Models 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 200714105 111 Dog Verapamil Rescue 7 mL/kg of 20 Improved MAP increase survival
Tebbutt S et al. Acad Emerg Med 200613134 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 20024430 Rat Clomipramine Simultaneous 2.5 mL of 10 Improved survival time
Harvey M et al Ann Emerg Med 200749178 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 200512S12 Ref abstract Mouse Organophosphate Pretreatment 15 mL/kg of 20 No change in the LD50
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Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins 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 2006105217 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 200661800 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
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Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid soluble toxins 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 20081061578 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. 200851412 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
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Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins 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 20081061575 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 200980 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 20100 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
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Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins after Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins after Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins after Summary of Human Case Reports of the Benefit of Intravenous Fat Emulsion in the Treatment of Lipid Soluble Toxins after 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. 200964191 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
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Conclusion

• IFE 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 toxicity
• IFE is effective in the management of lipid
  soluble drug toxicity
• Potential antidote of choice for lipid soluble
  toxins/drugs
• Control studies warranted

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Hydroxocobalamin
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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 patient 2. What precaution will you take
prior to administration of hydoxocobalamin to
this patient? 3. What adverse effects will you
expect? How will you monitor?
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• 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 199437655 659 Baud
FJ et al N Eng J Med 19913251761
1766 Silverman SH et al J Trauma 198828171
176
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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
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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 hypotension Has 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
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Adopted from Shepherd G and Velez IL. Ann
Pharmacother 200842661 669
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Chromaturia and skin redness
Cescon WD and Juurlink ND. CMAJ. 2009180(2)180
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715.00
185.00
Adopted from The Ann Pharmacotherapy 200842664
with modification
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Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning 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 25551 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. lt100 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.
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Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning
References Study Population Study Design Results Conclusion
Fortin JL et al Clin. 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 lt13 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.
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Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning Clinical Evidence Hydroxocobalamin for the Treatment of Cyanide Poisoning
References Study Population Study Design Results Conclusion
Barron SW et al Ann Emerg. Med 200749(6)794 801 e1 e2 Prehospital use of hydoxocobalamin for smoke induced cyanide poisoning Prospective uncontrolled open label study. Patients gt 15 yrs (mean 49.6 yrs), had soot in mouth/nose/expect- oration and had altered neurologic status CN 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 (gt39µmol/L ) in 42 patients, 67 survived. Median CN conc. of 52 µmol/L. Overall Survival rate was 72 (n50) CN conc. gt 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
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Administration Protocol

• Hydroxocobalamin 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

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Formulary Consideration

• Hydroxocobalamin 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 action
• Though has higher drug cost, would likely have
  little impact on hospitals drug budget
• At minimum, stock enough cyanide antidote to
  treat one patient for up to 24 hours

Dart RC et al Ann Emerg. Med 200036126 - 132
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Conclusions

• Hydroxocobalamin 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

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QUESTIONS??