Beta-blocker toxicity: Difference between revisions

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NS, glucagon
==Background==
*Coingestion with [[Calcium Channel Blockers]], [[Tricyclic Antidepressants]], and [[Antipsychotics]] increases mortality
*Agents with membrane-stabilizing activity (e.g. sodium channel blockade) are especially lethal as they [[QT prolongation|prolong QT]], leading to dysrhythmias
**[[Propranolol]]
**[[Sotalol]]
*[[Propranolol]] is particularly CNS toxic, as it is highly lipophilic and passes blood brain barrier freely, causing seizures and comatose state<ref>NIH. PROPRANOLOL HYDROCHLORIDE. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3176</ref>
*At toxic levels, beta-blockers will inhibit both beta-1 and beta-2 activity regardless for their affinity for specific receptors at therapeutic levels


==Clinical Features==
*Effects will typically be seen within 6 hours of ingestion with the exception of sotalol which can have a delayed and prolonged toxicity
*Cardiac
**[[Bradycardia]]
***Most common presenting sign
**[[Hypotension]]
**[[Ventricular dysrhythmias]]
*CNS
**[[Mental status changes]]
***Delirium, coma
**[[Seizure]] (esp with [[propranolol]])
*Other
**[[Hypoglycemia]] (interfere with gluconeogenesis and glycogenolysis; uncommon in adults)
***Helps to differentiate from [[Calcium Channel Blocker Toxicity]]
**Bronchospasm (uncommon)
**[[Hypothermia]]
**Brugada pattern of EKG with propanolol overdose
**Sotalol has type III anti-arrhythmic that can lead to prolonged QT causing [[torsade de pointes]] and possibly [[ventricular fibrillation]]
**Propranolol has sodium channel blockade activity leading to [[wide QRS]]<ref>Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-278. doi:10.3109/15563659609013789</ref>


==Differential Diagnosis==
{{Symptomatic bradycardia}}


==Evaluation==
*[[ECG]]
**PR prolongation
**[[Bradycardia]]
**[[QT Prolongation]] with sotalol<ref>Link MS, Foote CB, Sloan SB, Homoud MK, Wang PJ, Estes NA 3rd. Torsade de pointes and prolonged QT interval from surreptitious use of sotalol: use of drug levels in diagnosis. Chest. 1997;112(2):556-557. doi:10.1378/chest.112.2.556</ref>
**[[Wide QRS]] with propanolol
**Any bradydysrhythmia
**Obtain multiple ECGs over time to monitor any changes
*Glucose
*Chemistry
**Creatinine (esp with atenolol)
*Continuous cardiac monitoring
*Respiratory rate
**Propranolol can induce central apnea


[[Category:Tox]]
==Management==
#Adress airway, breathing, and circulation
#Consider [[activated charcoal]] if present within 2 hr of ingestion
#[[Symptomatic bradycardia]]
#*[[Atropine]] 0.5-1mg q3-5min up to 3mg
#*Avoid atropine in wide-complex bradycardia and consider chronotropes such as [[epinephrine]], [[dobutamine]], [[dopamine]], [[isoproterenol]]
#*Consider [[transcutaneous pacing|transcutaneous]] vs [[transvenous pacing]]
#Hypotension
#*IV fluids
#[[Hypoglycemia]]
#*Adult - [[D50W]]
#*Ped - 2.5mL/kg of [[D10W]]
 
;If IV fluid and [[atropine]] are not sufficient then consider:
 
===[[Glucagon]]===
*Acts independently of Beta-adrenergic receptors in cardiac tissue
*Half-life is 20 min, thus, if effective, need to start drip quickly after bolus
*Adult: 5 mg IV bolus over one minute <ref>Kerns W. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007;25(2):309-331. (Review)</ref> <ref>Bailey B (2003). Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. Journal of toxicology. Clinical toxicology, 41 (5), 595-602 PMID: 14514004</ref>
*Ped: 50mcg/kg
*Rebolus if no response after 10 min
*Effects persist for 10-15 min
*If effective start infusion at:
**Adult: 2-5 mg/hr
**Ped: 70 mcg/kg/hr
**Tachyphylaxis occurs quickly with glucagon so frequent monitoring of heart rate and blood pressure is necessary as the drip might need to be uptitrated
*Routine treatment with glucagon is not suggested as a sole antidote<ref>Graudins A et al. Calcium channel antagonist and beta‐blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar; 81(3): 453–461.</ref>
**Continuous drip is usually limited by insufficient quantities from pharmacy
**Consider concurrent administration of [[ondansetron]] (causes nausea and vomiting)
 
===Calcium===
*Beta-antagonism decreases intracellular calcium leading to smooth muscle relaxation; supplementation may reverse hypotension by increasing intracellular calcium levels
*[[Calcium gluconate]] 3g (30-60mL of 10% soln)
*[[Calcium chloride]] 1-3g IV bolus (10-20mL of 10% soln (requires large IV/central line)
**Preferred over calcium gluconate because it provides triple the amount of calcium on a weight-to-weight basis [2]
**Give Calcium 1g Q5min to titrate to BP effect
**If effect in BP is seen can give as a drip at 10-50mg/kg/hr
*Aim for calcium level of 14mg/dL and measure at least 30 minutes after administration
 
===[[High dose insulin therapy| High-dose insulin and glucose]]===
*Takes 30-60 min for effect
*Augments myocardial contraction leading to increased cardiac output<ref>High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning.  Engebretsen KM et al.  Clin Toxicol 2011;49:277-283</ref>
*Regular Insulin 1 Unit/kg IV Bolus accompanied by 0.5 gram/kg dextrose
*Regular insulin 1 Unit/kg/hr Drip, titrate infusion until hypotension is corrected or max 10u/kg/hr
*D50W drip at 0.1-0.2 gram/kg/hr
*Initial glucose checks q15 minutes until blood sugar stability established
*Replace potassium and magnesium if necessary
 
===[[Vasopressors]]===
*Consider to be added as adjunctive therapy to all other therapies
*Toxicity can also be managed with vasopressors alone<ref>Levine M et al. Critical Care Management of Verapamil and Diltiazem Overdose with a Focus on Vasopressors: A 25-Year Experience at a Single Center.  Ann Emerg Med 2013 May 1</ref>
*[[Epinephrine]]
**Adult: Start 1 mcg/min and titrate to MAP=60
**Ped: Start 0.1mcg/kg/min
 
===Bicarbonate===
*Bolus if QRS is wide
**Sodium channel blockade from propranolol
 
===[[QT Prolongation]]===
*Magnesium if QT is prolonged
**Sotalol known to prolong QT
 
===[[Intralipid|Intralipid Therapy]]===
'''''Draw all labs prior to infusion'''''
*Support as an antidote comes from animal studies and case reports<ref>Rothschild L, Bern S, Oswald, et al. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010; 18:51.</ref>
*IV 20% [[Intralipid]] at 1.5 mL/kg Bolus<ref>Cave, G. Intravenous Lipid Emulsion as Antidote Beyond Local Anesthetic Toxicity: A Systematic Review. 2009.  16(9)815–824</ref>
**Bolus could be repeated 1-2 times if persistent asystole
**Followed by infusion of 0.25 mL/kg/min for 30-60 minutes or until hemodynamic stability achieved
*if responsive to bolus initiate infusion at 0.25 mL/kg/min for 1hr (e.g. about 600 mL over 30 minutes in a 70kg adult)
**Infusion rate could be increased if the BP declines
 
===[[Hemodialysis]]===
*Only effective for [[nadolol]], [[sotalol]], and [[atenolol]]
 
===[[ECMO]]===
*Consider VA ECMO for refractory cases
*Note that if ECMO is chosen, intralipids are avoided due to potential of clotting of the ECMO circuits
 
===Sedation===
*Consider [[ketamine]] as post-intubation sedation for hemodynamics
 
==Disposition==
*Admit all symptomatic patients
*Admit all sotalol ingestions (long half-life)
*Observe all others for ~ 6hr
 
==See Also==
*[[Beta blockers]]
 
==External Links==
*[https://www.nuemblog.com/blog/beta-blocker-overdose NUEM - Beta-Blocker Toxicity]
*[https://emcrit.org/ibcc/ccb/ EMCrit - Calcium Channel Blocker (CCB) & Beta Blocker (BBl) Overdose]
 
==References==
<references/>
 
[[Category:Cardiology]]
[[Category:Toxicology]]

Latest revision as of 01:50, 1 July 2021

Background

  • Coingestion with Calcium Channel Blockers, Tricyclic Antidepressants, and Antipsychotics increases mortality
  • Agents with membrane-stabilizing activity (e.g. sodium channel blockade) are especially lethal as they prolong QT, leading to dysrhythmias
  • Propranolol is particularly CNS toxic, as it is highly lipophilic and passes blood brain barrier freely, causing seizures and comatose state[1]
  • At toxic levels, beta-blockers will inhibit both beta-1 and beta-2 activity regardless for their affinity for specific receptors at therapeutic levels

Clinical Features

Differential Diagnosis

Symptomatic bradycardia

Evaluation

  • ECG
  • Glucose
  • Chemistry
    • Creatinine (esp with atenolol)
  • Continuous cardiac monitoring
  • Respiratory rate
    • Propranolol can induce central apnea

Management

  1. Adress airway, breathing, and circulation
  2. Consider activated charcoal if present within 2 hr of ingestion
  3. Symptomatic bradycardia
  4. Hypotension
    • IV fluids
  5. Hypoglycemia
If IV fluid and atropine are not sufficient then consider

Glucagon

  • Acts independently of Beta-adrenergic receptors in cardiac tissue
  • Half-life is 20 min, thus, if effective, need to start drip quickly after bolus
  • Adult: 5 mg IV bolus over one minute [4] [5]
  • Ped: 50mcg/kg
  • Rebolus if no response after 10 min
  • Effects persist for 10-15 min
  • If effective start infusion at:
    • Adult: 2-5 mg/hr
    • Ped: 70 mcg/kg/hr
    • Tachyphylaxis occurs quickly with glucagon so frequent monitoring of heart rate and blood pressure is necessary as the drip might need to be uptitrated
  • Routine treatment with glucagon is not suggested as a sole antidote[6]
    • Continuous drip is usually limited by insufficient quantities from pharmacy
    • Consider concurrent administration of ondansetron (causes nausea and vomiting)

Calcium

  • Beta-antagonism decreases intracellular calcium leading to smooth muscle relaxation; supplementation may reverse hypotension by increasing intracellular calcium levels
  • Calcium gluconate 3g (30-60mL of 10% soln)
  • Calcium chloride 1-3g IV bolus (10-20mL of 10% soln (requires large IV/central line)
    • Preferred over calcium gluconate because it provides triple the amount of calcium on a weight-to-weight basis [2]
    • Give Calcium 1g Q5min to titrate to BP effect
    • If effect in BP is seen can give as a drip at 10-50mg/kg/hr
  • Aim for calcium level of 14mg/dL and measure at least 30 minutes after administration

High-dose insulin and glucose

  • Takes 30-60 min for effect
  • Augments myocardial contraction leading to increased cardiac output[7]
  • Regular Insulin 1 Unit/kg IV Bolus accompanied by 0.5 gram/kg dextrose
  • Regular insulin 1 Unit/kg/hr Drip, titrate infusion until hypotension is corrected or max 10u/kg/hr
  • D50W drip at 0.1-0.2 gram/kg/hr
  • Initial glucose checks q15 minutes until blood sugar stability established
  • Replace potassium and magnesium if necessary

Vasopressors

  • Consider to be added as adjunctive therapy to all other therapies
  • Toxicity can also be managed with vasopressors alone[8]
  • Epinephrine
    • Adult: Start 1 mcg/min and titrate to MAP=60
    • Ped: Start 0.1mcg/kg/min

Bicarbonate

  • Bolus if QRS is wide
    • Sodium channel blockade from propranolol

QT Prolongation

  • Magnesium if QT is prolonged
    • Sotalol known to prolong QT

Intralipid Therapy

Draw all labs prior to infusion

  • Support as an antidote comes from animal studies and case reports[9]
  • IV 20% Intralipid at 1.5 mL/kg Bolus[10]
    • Bolus could be repeated 1-2 times if persistent asystole
    • Followed by infusion of 0.25 mL/kg/min for 30-60 minutes or until hemodynamic stability achieved
  • if responsive to bolus initiate infusion at 0.25 mL/kg/min for 1hr (e.g. about 600 mL over 30 minutes in a 70kg adult)
    • Infusion rate could be increased if the BP declines

Hemodialysis

ECMO

  • Consider VA ECMO for refractory cases
  • Note that if ECMO is chosen, intralipids are avoided due to potential of clotting of the ECMO circuits

Sedation

  • Consider ketamine as post-intubation sedation for hemodynamics

Disposition

  • Admit all symptomatic patients
  • Admit all sotalol ingestions (long half-life)
  • Observe all others for ~ 6hr

See Also

External Links

References

  1. ↑ NIH. PROPRANOLOL HYDROCHLORIDE. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3176
  2. ↑ Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-278. doi:10.3109/15563659609013789
  3. ↑ Link MS, Foote CB, Sloan SB, Homoud MK, Wang PJ, Estes NA 3rd. Torsade de pointes and prolonged QT interval from surreptitious use of sotalol: use of drug levels in diagnosis. Chest. 1997;112(2):556-557. doi:10.1378/chest.112.2.556
  4. ↑ Kerns W. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007;25(2):309-331. (Review)
  5. ↑ Bailey B (2003). Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. Journal of toxicology. Clinical toxicology, 41 (5), 595-602 PMID: 14514004
  6. ↑ Graudins A et al. Calcium channel antagonist and beta‐blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar; 81(3): 453–461.
  7. ↑ High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Engebretsen KM et al. Clin Toxicol 2011;49:277-283
  8. ↑ Levine M et al. Critical Care Management of Verapamil and Diltiazem Overdose with a Focus on Vasopressors: A 25-Year Experience at a Single Center. Ann Emerg Med 2013 May 1
  9. ↑ Rothschild L, Bern S, Oswald, et al. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010; 18:51.
  10. ↑ Cave, G. Intravenous Lipid Emulsion as Antidote Beyond Local Anesthetic Toxicity: A Systematic Review. 2009. 16(9)815–824
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