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Transcript of 2EMHFWLYHV - cdn.ymaws.com%dufhorx[ hw do - 7r[lfro &olq 7r[lfro 7uhdwphqw ri (wk\ohqh *o\fro...
3/4/2019
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Kristen C. Sherlin, PharmD
Emergency Medicine Clinical Pharmacist
University of Louisville Hospital
Objectives
1. Identify medications known to cause toxicity in overdose situations
2. Review management principles of toxic overdoses
3. Demonstrate understanding through participation in active learning activity
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Resources Toxidromes
Acetaminophen Toxic Alcohols
Calcium Channel Blockers
Beta Blockers
Acetaminophen
Mechanism: prostaglandin inhibitor
Most common cause of acute hepatic failure 30% incidence in patients presenting 8
hours after ingestion
FDA maximum recommended dose: 4 grams daily
Ciejka. Clin Lab Med. 2016.
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Acetaminophen Metabolism
Ciejka. Clin Lab Med. 2016.
Acetaminophen Overdose Clinical Presentation
Ciejka. Clin Lab Med. 2016.
Acetaminophen Overdose Monitoring
Ciejka. Clin Lab Med. 2016.
Treatment of Acetaminophen Overdose N-acetylcysteine (NAC)
Nearly 100% effective if administered within 8 hours of ingestion
Available in oral and IV formulations ○ IV form should be used in severe cases
Common side effects:○ Nausea/vomiting○ Anaphylactoid reactions
Activated charcoal May administer if patient has stable mental
status and presents within 1 hour of ingestion
Ciejka. Clin Lab Med. 2016.
Treatment of Acetaminophen Overdose Administer NAC to acute APAP
overdose with either possible or probable risk for hepatotoxicity (level B) Ideally within 8-10 hours postingestion
Administer NAC to patients with hepatic failure thought to be due to APAP (level B)
Ciejka. Clin Lab Med. 2016.
Treatment of Acetaminophen Overdose
NAC
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Treatment of Acetaminophen Overdose
Oral IV
Loading dose: 140 mg/kg x 1 dose For treatment within 8 hours of ingestion: • Initial bolus: 150 mg/kg IV over 1 hour • Infusion: 50 mg/kg over 4 hours • Then: 100 mg/kg over 16 hours
Then: 70 mg/kg every 4 hours x 17 doses
For treatment > 8 hours after ingestion, chronic ingestion, or for those with hepatic failure:• Infusion: 12.5 mg/kg/hr over 48 hours
May be discontinued once the protocol is complete if: • Serum APAP level < 10 μg/mL
• No signs of ongoing hepatic injury
Acetadote [package insert]
Toxic Alcohols
Ethylene glycol
Methanol
Propylene glycol
Isopropanol
Mégarbane. Open Access Emerg Med. 2010;2:67-75.
Ethylene Glycol Mechanism of Toxicity
Mégarbane. Open Access Emerg Med. 2010;2:67-75.
Ethylene Glycol Clinical Presentation Early
Inebriation or altered mental status
Late Metabolic acidosis Hyperventilation Anion gap Oxalate crystalluria Renal failure Clinical hypocalcemia Life-threatening arrhythmias Coma Seizures Death
Mégarbane. Open Access Emerg Med. 2010;2:67-75.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.
Ethylene Glycol Toxicity Diagnosis
Serum chemistry Blood gases
Plasma EG concentration
Osmolal gap Difference between the measured osmolality
and the calculated osmolality ○ Normal = < 10 mOsm/kg H20
Calculated Osmolality mOsm/L = 2(Na+) + BUN/2.8 + glucose/18
Mégarbane. Open Access Emerg Med. 2010;2:67-75.Gennari, et al. N Engl J Med. 1984;310(2):102-5.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.
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Treatment of Ethylene Glycol Toxicity
Mégarbane. Open Access Emerg Med. 2010;2:67-75.
Treatment of Ethylene Glycol Toxicity
Criteria for Fomepizole
Documented recent history of ingestion of
a toxic amount of toxic alcohol and osmolal gap > 10
mOsmol/L
Documented plasma concentration ≥ 20
mg/dL
Suspected ingestion with at least 3 of the following criteria: • Arterial pH < 7.3• Serum bicarbonate
concentration < 20 mmol/L
• Osmolal gap > 10 mOsm/L
• Oxalate crystalluria
Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.
Treatment of Ethylene Glycol Toxicity Fomepizole Dosing
Loading dose: 15 mg/kg IV infused over 30 minutes
Followed by 10 mg/kg IV q12h x 4 doses Then 15 mg/kg q12h until ethylene
glycol concentration < 20 mg/dL and pH is normalized
Dose adjustment If patient requires concomitant hemodialysis
(HD)
Antizol [package insert]. April 2009.
Fomepizole
Adverse reactions Headache Nausea Dizziness Drowsiness Metallic taste
Food interactions Ethanol decreases the rate of fomepizole
elimination by ~ 50% Fomepizole decreases rate of elimination of
ethanol by ~ 40%
Antizol [package insert]. April 2009.
Hemodialysis Indications
Arterial pH < 7.0
Drop in arterial pH > 0.05 resulting in an
abnormal pH despite bicarbonate
infusion
Inability to maintain arterial pH > 7.3
despite bicarbonate therapy
Decrease in bicarbonate
concentration> 5 mmol/L despite
bicarbonate therapy
Renal failure
Deteriorating vital signs despite
intensive supportive care
Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.
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Other Treatment Principles for Ethylene Glycol Toxicity
Gastric lavage, activated charcoal, or ipecac syrup are not recommended
Asymptomatic inhalation exposures can be managed out-of-hospital
Unintentional, asymptomatic ingestions > 24h since exposure without alcohol co-ingestion do not need medical treatment
Sodium bicarbonate should be administered if pH < 7.3
Calcium is only recommended if hypocalcemia significantly contributes to symptoms
Pyridoxine and thiamine
Mégarbane. Open Access Emerg Med. 2010;2:67-75.Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.
Alternative Treatments??
Treatment of Ethylene Glycol Toxicity
Treatment of Ethylene Glycol Toxicity
Barceloux, et al. J Toxicol Clin Toxicol. 1999;37(5):537-60.Rietjens, et al. Neth J Med, 2014;72(2):73-9.
Fomepizole
Advantages
Higher affinity for ADH
Minimal adverse effects
Monitoring not necessary
Certain patients may not need
dialysis
Disadvantages
Expensive
Limited shelf life
Less experience
Ethanol
Advantages
Inexpensive
Available in most medical centers
Traditional antidote
Disadvantages
Significant adverse effects
Requires ICU hospitalization
Intensive monitoring
Rietjens, et al. Neth J Med, 2014;72(2):73-9.
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Calcium Channel Blockers (CCBs): Pharmacology
Dihydropyridines: antagonism of L-type calcium channels in the peripheral vasculature Produce potent vasodilation, have minimal effect on
cardiac contractility Ex: Amlodipine, nicardipine, nimodipine
Non-dihydropyridines: antagonism of L-type calcium channels in the myocardium Produce a reduction in cardiac contractility, heart
rate Ex: diltiazem, verapamil
Dewitt CR. Toxicol Rev. 2004;23(4):223-38.
Mowry JB. Clin Toxicol (Phila). 2015;53(10):962-1147.
Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Calcium Channel Blocker: Clinical Presentation Cardiovascular effects
Hypotension
Bradycardia○ Most commonly with non-
dihydropyridine overdoses
Tachycardia○ Most commonly with
dihydropyridine overdoses
Signs of heart failure○ Pulmonary edema
○ Jugular venous distention
Endocrine effects Hyperglycemia
Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Image: De león DD. Nat Clin Pract Endocrinol Metab. 2007;3(1):57-68.
Beta Blockers: Pharmacology
Antagonism of beta-1 and beta-2 receptors
Receptor activity Beta-1: primarily located in cardiac tissue, increased
inotrophy/chronotrophy
Beta-2: most prominent in vascular smooth muscle and bronchioles, leads to vasodilation and bronchodilation
Mowry JB. Clin Toxicol (Phila). 2015;53(10):962-1147.
Image: Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Beta Blocker Overdose: Clinical Presentation Cardiovascular
Hypotension
Bradycardia
Signs of cardiogenic shock
○ Pulmonary edema
○ Jugular venous distention
1st degree heart block
Pulmonary Bronchospasm
Neurologic Delirium
Coma
Seizures
Endocrine Hypoglycemia
Image: Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Beta Blockers: Pharmacology
Lipophilicity of a beta blocker is a major determinant of central nervous system penetration and effects of beta blocker overdose May potentiate seizures, delirium, coma
Lipophilic beta blockers Propranolol
Nebivolol
Carvedilol
Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Reith DM. J Toxicol Clin Toxicol. 1996;34(3):273-8.
Overdose TreatmentCalcium Glucagon Catecholamines
Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.
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Calcium Preparations
Calcium gluconate Calcium chloride
10 mL of 10% solution
4.5 mEq of Ca2+
10 mL of 10%
13.6 mEq of Ca2+
• Must be administered via central venous access• Adjust infusion based on ionized calcium
• Calcium is contraindicated in concurrent digoxin toxicity
Calcium gluconate. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.Calcium chloride. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.
Optimum Calcium Dosing
Failure of human cases are probably under resuscitated
Animal models suggest need for high doses
• 8-20 mg/kg (0.4-1 mEq/kg) Bolus
• 36-300 mg/kg/hr (1.8-15 mEq/kg/hr)Infusion
• 1.5-2 x [Ca2+] associated with improved cardiodynamicsEndpoint
Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.
Calcium Guidelines
20 mg/kg Ca2+
bolus (0.2 ml/kg CaCl2)
Favorable hemodynamic
response
20-50 mg/kg/hrCa2+ continuous infusion (0.2-0.5 ml/kg/hr CaCl2)
No hemodynamic changes
Alternate therapy
Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.
Calcium Adverse Effects
Hypokalemia
Hypotension
Bradycardia
Dysrhythmia
Tissue extravasation
CCB Treatment Guideline
47St-onge M. Crit Care Med. 2016;10.
Glucagon Evidence Highest level in beta-blocker overdose
Successes and failures in calcium channel blockers
Indications Hypotension
Bradycardia
Dose Bolus: 2-5 mg IV
Infusion: 1-10 mg/hr
Calcium gluconate. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH.Hessler RA. Cardiologic Principles II: Hemodynamics. Goldfrank's Toxicologic Emergencies, 10eNew York, NY: McGraw-Hill; 2015.
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Glucagon Limitations
Cost Glucagon 1 mg = $205.92
Availability Survey of 47 hospitals in Washington DC
○ 30 mg in 26%
○ 50 mg in 15%
Nausea and vomiting
Transient response
Glucagon. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OHLove, Jeffrey N et al. AEM. 1993;22(2):267-268.
High Dose Insulin and Glucose Infusion Rationale
Promotes carbohydrate metabolism in stressed myocardium○ Positive inotrophy and chronotrophy
Administration Initial insulin bolus: 0.5-1 unit/kg IV
0.5-1 unit/kg IV infusion, titrated to mean arterial pressure (MAP)
Dextrose infusion: 0.5 gm/kg/hr to maintain serum glucose levels
Aggressive potassium replacement
50Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
St-onge M. Clin Toxicol (Phila). 2014;52(9):926-44.
St-onge M. Crit Care Med. 2016;10.
Vasopressor Therapy
Norepinephrine is typically first choice High doses and multiple agents may be necessary
Dobutamine may be added for confirmed cardiogenic shock
Avoid Dopamine
Vasopressin as monotherapy
51Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
St-onge M. Clin Toxicol (Phila). 2014;52(9):926-44.
St-onge M. Crit Care Med. 2016;10.
Methylene Blue
Mechanism Inhibitor of guanylate cyclase
Decreased levels of cGMP
Scavenger of NO
Reduces vasodilation, counteracts calcium channel blocker mechanism of action
52Aggarwal N. BMJ Case Rep. 2013;2013
Intravenous Lipid Emulsion (ILE) Therapy Infusion of parenteral nutrition lipid formulation as a therapy
for overdoses Initially studied in local anesthetic overdoses
Now studied in wide range of overdoses
Mechanism theories “Lipid sink”
Free fatty acid source of energy for myocardium
Administration 1 to 1.5 ml/kg IV boluses of 20% solution over 1 minute
○ Repeat up to 3 times
0.25 to 0.5 ml/kg/min infusion until hemodynamic stability occurs
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Intravenous Lipid Emulsion Therapy Adverse Effects
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Hypertriglyceridemia
Fat embolism
Infection
Hypersensitivity reactions
Venous thromboembolism
Acute kidney injury
Pancreatitis
Lipid dose of a 70 kg patient Bolus dose: 14-21 gm
Continuous infusion: 3.5-7 gm/min
Palatnick W. Emerg Med Pract. 2014;16(2):1-19.
Hayes BD. Clin Toxicol (Phila). 2016;54(5):365-404.
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BB Lipophilicity and ILE Efficacy
Lipid sink mechanism of action for ILE may limit usefulness in non-lipophilic drugs Less partitioning of the drug molecules into the infused
lipid reservoir from tissues
55Samuels TL. Anaesthesia. 2011;66(3):221-2.
Beta Blocker
Lipid Solubility Coefficient (log
P)
Relative Lipid Solubility
Carvedilol 3.29 High
Propranolol 2.8 High
Metoprolol 1.35 Low to moderate
Atenolol 0.56 Low
Browne A. J Med Toxicol. 2010;6(4):373-8.
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