Beta blocker and Ca+ Channel blocker overdose; BB and CCB OD

Beta Blocker and Calcium Channel Blocker Overdose

Synonyms

BB and CCB OD

Related Conditions

BB Overdose

1. Description of the problem

What every clinician needs to know

Beta blocker (BB) and calcium channel blocker (CCB) overdoses are associated with significant morbidity and mortality.

Treatment is similar for both types of overdoses and should be aggressive.

As with sepsis, vital signs can be misleading during the evaluation of a patient with BB or CCB toxicity. The use of alternative markers for perfusion is preferred (i.e. blood pH, serum lactate level or mixed venous oxygen saturation).

Clinical features

BB Overdose

Decreased myocardial contractility.
Decreased automaticity.
Decreased AV conduction velocity.
Bronchoconstriction.
Mental status may be depressed.
Seizures (most commonly observed with propranolol).
QRS prolongation (AKA membrane stabilizing activity [MSA]).
QT prolongation (observed with sotalol and acebutolol).
Hypoglycemia (most often observed in children).

CCB Overdose

Decreased myocardial contractility.
Decreased automaticity.
Decreased AV conduction velocity.
Decreased SVR.
Pulmonary edema, peripheral edema and elevated JVD may result from decreased contractility and vasodilatation (i.e., CHF-like presentation).
Hyperglycemia.
Mental status generally remains clear until brain becomes significantly hypoperfused.
Class of CCB may alter the clinical presentation: phenylalkylamine and benzothiazepine classes (verapamil and diltiazem, respectively) will bind both myocardial and smooth muscle calcium channels, while dihydropyridine class drugs (i.e. those ending with “-pine”) at therapeutic doses more avidly block smooth muscle calcium channels and may cause hypotension with reflex tachycardia. At overdoses, calcium channel selectivity may be lost, which will result in hypotension and bradycardia.

Key management points

BB toxicity key points

Co-ingestions are the single most important factor associated with morbidity in BB ingestions.
Patients with BB ingestion who have significantly overdosed will become symptomatic within 6 hours of the ingestion. If they are asymptomatic after this time they can be medically cleared.
Exceptions to the 6-hour rule include patients with sustained-release ingestions and sotalol ingestions, who must be admitted for a 24-hour observation period as toxicity may be delayed.

CCB toxicity key points

Dihydropyridines may cause hypotension with reflex tachycardia. With large ingestions, hypotension and bradycardia may be observed.
Diltiazem and verapamil will cause both hypotension and bradycardia.
Patients with immediate-release CCB ingestions who are asymptomatic for 6-8 hours after ingestion can be medically cleared.
Patients who ingested sustained- or extended-release preparations must be admitted for 24 hours of observation as toxicity can be delayed.
The severity of hyperglycemia has been found to directly correlate with the severity of the CCB overdose.
Unlike BB overdoses, mental status generally remains clear until the brain is hypoperfused.

2. Emergency Management

Stabilizing the patient

A: Airway – maintain open airway.

B: Breathing – ventilate if necessary, treat bronchospasm with bonchodilators.

C: Circulation – treat bradycardia with atropine initialy 0.01-0.03 mg/kg. Obtain IV access and place patient on continuous monitoring with ECG for at least 6 hours after the ingestion.

D: Decontamination – consider charcoal administration if the patient presents within 1-2 hours from the ingestion time, has a normal mental status, can protect his or her airway and can drink the solution.

Seizures should be treated with benzodiazepines.

QRS prolongation (when QRS is above 120 ms) should be treated with sodium bicarbonate at 1-2 mEq/kg.

The Poison Center can be contacted at any time for additional advice (1-800-222-1222).

3. Diagnosis

Diagnostic criteria and tests

There is no gold standard to the diagnosis, which is based on history. Look for history/signs of ingestion, access to medications and clinical signs of hypotension and/or bradycardia.

Check for co-ingestions with serum levels of ethanol, acetaminophen and salicylate.

Check an EKG for signs of bradycardia or widening of the QRS and QT intervals.

Specific drug levels can be obtained, but they are not generally clinically useful as they usually take hours to obtain or must be sent out. Comprehensive urine drug screens using gas chromatography/mass spectrometry may or may not detect high levels of BBs and CCBs.

Lactate levels and blood pH may have utility as a marker of tissue perfusion and toxicity.

Careful measurement of urine output may help monitor kidney perfusion.

BUN and creatinine may be useful in monitoring renal function.

Calcium levels should be monitored to assess signs of hyper/hypocalcemia.

Arterial blood gases may be useful in monitoring acid-base status as well as ventilation status.

Serum glucose may be useful for monitoring for hyper or hypoglycemia.

Establishing the diagnosis

There is no gold standard to the diagnosis, which is based on history and clinical presentation.

Bradycardia and hypotension with significant history of exposure/access to CCBs and BBs should suggest this diagnosis.

Other possible diagnoses

Digoxin: can cause PVCs, atrial tachycardias, ventricular arrhythmias (biventricular ventricular tachycardia is pathognomonic but rarely seen with digoxin toxicity). Rarely does digoxin toxicity cause hypotension despite the ability to cause profound bradydysrhythmias.

Clonidine: can present with bradycardia and hypotension and may be confused with opioid toxicity due to its ability to cause somnolence and miosis as well.

Cholinergic agents: can present with bradycardia, but may have other presentations such as salivation, lacrimation, defecation, muscle fasciculations and urination.

Shock from other sources must be excluded: structural heart disease, myocardial infarction, sepsis, etc.

Confirmatory tests

There are no specific confirmatory tests that should be performed.

4. Specific Treatment

First-line and other therapies

In general, treatment for BB and CCB overdoses is similar. Fluid boluses with saline initially should be used to augment mild hypotension. The authors prefer generous vasopressor doses when fluid boluses are ineffective, particularly because all hospitals carry vasopressors in large supply and all health care providers are comfortable with their uses and doses.

First-line therapy

Glucagon is considered the first-line therapy for BB toxicity. Glucagon still may be helpful for CCB toxicity based on mixed evidence. Many inpatient pharmacies do not stock a sufficient amount of glucagon to treat BB or CCB toxicity effectively. Glucagon is a great treatment for BB toxicity when sufficient doses are given.

Calcium salts such as calcium chloride and calcium gluconate are taught as the first-line agents for CCB overdoses. Calcium administration may help with hypotension from BB toxicity as well. Generally, give IV calcium salts until serum calcium level is high normal. Continuous IV calcium infusions don’t likely have any benefit once serum calcium levels are maximized with bolus doses.

Second-line therapy

Treatment with vasopressors (significantly higher than normal doses may be required). Remember, particularly with BB toxicity, the vasopressor has to compete with a beta-receptor that is blocked by the overdosed drug. The authors have used epinephrine doses as high as 75 mcg/min to treat sick BB overdoses, with good results.

Third-line therapy

Atropine may reverse bradycardia, but its effect is often short-lived so its long-term use is often not practical.

Phosphodiesterase inhibitors may be considered. These drugs decrease the breakdown of cAMP. Pharmacologically, these drugs will not offer further benefit when glucagon is already in use. They are difficult to titrate and may cause hypotension due to peripheral vasodilatation.

Last-line therapy

Pacemakers, intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), cardiac bypass.

All mechanical adjuncts have been used in anecdotal case reports, but there is no evidence of efficacy or improved outcomes.

Hyperinsulinemia/Euglycemia therapy (HIE) has been considered by some as the treatment of choice for CCB toxicity and as a good adjunct for BB toxicity. Evidence for its use is based on animal studies and case reports. However, the authors have not fully embraced HIE therapy because it often distracts the physician from maximizing the above therapies, which have a better track record. In addition, the effect from HIE may be delayed 15-60 minutes after the start of the infusion. In addition, HIE may induce hypokalemia or hypoglycemia

Drugs and dosages

Atropine: 0.01-0.03-mg/kg IV boluses to a max of 3 g for bradycardia. (Large atropine doses may cause anticholinergic delirium.)

Glucagon: 0.05-mg/kg IV bolus or 2-5 mg bolus, may repeat every 1-2 minutes to a max of 10 mg. Start glucagon drip at 1-5 mg/hr (0.15 mg/kg in pediatric cases). May increase infusion to a max of 10 mg/hr. (These doses often induce vomiting in awake patients.)

Calcium Salts: Calcium chloride 1-3 g or calcium gluconate 3-9 g IV bolus until serum calcium levels are high normal.

Vasopressor infusions

Epinephrine: 0.1 mcg/kg/min IV or 7 mcg/min for 70-kg adult as starting dose. (There is no max dose. Extremely large doses may be required.)

Norepinephrine: 0.1 mcg/kg/min IV or 7 mcg/min for 70-kg adult as starting dose. (There is no max dose. May supplement with dobutamine for additional beta-agonism.)

Isoproterenol: 2 mcg/min IV as starting dose. (There is no max dose. Theoretically, this is the best drug for treatment of a BB overdose.)

Dopamine: 5 mcg/kg/min IV as starting dose. (If dose exceeds 30 mcg/kg/min, a more direct-acting vasopressor such as norepinephrine or epinephrine may be more beneficial.)

Phenylephrine: 0.5 mcg/kg/min IV or 3.5 mcg/min for 70-kg adult as starting dose. (This drug may be useful for a dihydropyridine overdose without bradycardia.)

Phosphodiesterase inhibitors

Milrinone 50-mcg/kg IV bolus, then 0.25-1 mcg/kg/min as an infusion. Amrinone 75-mcg/kg IV bolus with a 2- to 20-mcg/kg/min infusion.

HIE doses

Regular insulin bolus 1 U/kg IV, infusion 0.5-1 U/kg/hr. Add glucose bolus 25-50 g IV, infusion 0.25-0.5 g/kg/hr to prevent hypoglycemia (glucose is not recommended if blood sugar is above 400 mg/dL prior to initiating HIE therapy).

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Hemodynamics should improve with treatment. The use of a Swan-Ganz catheter may help identify the source of hypotension as either a contractility problem, an SVR problem or both.

Check an EKG for signs of bradycardia, or widening of the QRS and QT intervals. Specific drug levels can be obtained but are not generally clinically useful as they usually take hours to obtain or must be sent out. Comprehensive urine drug screens using gas chromatography/mass spectrometry may or may not detect high levels of BBs and CCBs.

Lactate levels and blood pH may have utility as a marker of tissue perfusion and toxicity.

Careful measurement of urine output may help monitor kidney perfusion.

BUN and creatinine may be useful in monitoring renal function.

Calcium levels should be monitored to assess signs of hyper- or hypocalcemia.

Arterial blood gases may be useful in monitoring acid-base status as well as ventilation status.

Serum glucose may be useful for monitoring for hyper/hypoglycemia.

Incorrect diagnosis

Suspect the wrong diagnosis if the patient does not improve or worsens with therapy. Also suspect an incorrect diagnosis if the patient develops a fever or clinical signs more consistent with infection/sepsis.

Follow-up

Symptomatic patients require admission and medical management. All regular-release BB and CCB overdose patients should be monitored for 6 hours prior to discharge. On the other hand, all patients with sustained-release BB and CCB overdoses and sotalol should be monitored for 24 hours for signs of delayed toxicity. Asymptomatic and medically stable/cleared patients should be evaluated on the reason for the ingestion/overdose. Psychiatry consult should be obtained when appropriate (i.e. suicidal ideation).

Pathophysiology

BB physiology

Beta-adrenergic receptors are coupled with G-proteins.

Activation of beta receptors leads to the conversion of ATP to cyclic AMP (cAMP).
AMP activates phosphokinase A (PKA), which opens calcium channels.
Calcium interacts with the sarcoplasmic reticulum (SR) and releases sequestered calcium.
Calcium binds to troponin C, causing a conformational change.
Troponin and tropomyosin are displaced, allowing actin and myosin to interact leading to systole.
Calcium is pumped back to SR, muscle relaxes leading to diastole.

BBs antagonize beta receptors, decreasing cellular levels of cAMP.

In overdose, BB selectivity is lost.

CCB Physiology

Voltage-gated L-type calcium channels open.

Calcium enters cell along an electrochemical gradient at T-tubules near SR.
Calcium activates ryanodine receptor.
Opens calcium channels on SR, releasing sequestered calcium.
Troponin and tropomyosin are displaced, allowing actin and myosin to interact leading to systole.
Calcium binds to troponin C, causing a conformational change.
Calcium is pumped back to SR, muscle relaxes leading to diastole.

CCBs antagonize voltage-gated L-type calcium channels.

Additionally, there are L-type calcium channels on the beta islet cells of the pancreas, which may partially explain the usefulness of HIE therapy.

Generally cardiac myocytes rely on fatty acid metabolism for energy.
In CCB overdose, there appears to be a shift to carbohydrate-dependent metabolism.
However, CCB overdoses prevent secretion of insulin and thus reduce uptake of glucose.
Leads to an impaired insulin release, impaired glucose uptake, impaired myocyte energy production and hyperglycemia.

Particular BBs have specific properties:

Membrane-stabilizing activity (MSA): inhibits myocardial fast sodium channels leading to a widening QRS, induce dysrhythmias, cause bradycardia, and decreased contractility.
Lipophilicity: BBs are in general more lipophilic than CCBs and can cross the blood-brain barrier, causing neurologic sequelae=>seizures and altered mental status
Intrinsic sympathomimetic activity (ISA): some BBs are partial agonists, showing less hypotension and bradycardia initially in overdose.
Sotalol: Also is a class III antidysrhythmic (potassium channel blocker and QT prolongation).

There are basically 2 classes of CCBs: Dihydropyridines preferentially block L-type channels in the smooth muscle vasculature. Non-dihydropyridines directly affect L-type channels in the myocardium and the smooth muscle.

Epidemiology

CCBs and BBs are cardiovascular drugs associated with significant morbidity and mortality. In 2004, the American Association of Poison Control Centers noted that 3% of all poisonings were due to cardiovascular medication, which was the 5th leading cause of death, the majority of which were due to CCBs and BBs.

Prognosis

Prognosis depends on the amount of drug ingested, presence of co-ingestants, the length of time from ingestion to treatment, and comorbidities. Time to treatment, the presence of co-ingestants and the particular drug properties of each agent appear to be the most significant prognostic factors.

If the patient recovers from the overdose, he or she generally does well without long-term sequelae from the overdosed substances.

Disposition for these patients from the emergency department depends on the severity of the overdose, but clinicians should err on the side of admitting to a higher level of care (i.e., ICU) as these overdoses can quickly escalate without warning.

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Bailey, B. “Glucagon in betablocker and calcium channel blocker overdoses: A systematic review”. Clin Toxicol. vol. 41. 2003. pp. 595-602. (Review of the pathophysiology of BB and CCB overdoses and the spectrum of treatments.)

Greene, SL, Gawarammana, I, Wood, DM. “Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: A prospective observational study”. Int Care Med. vol. 33. 2007. pp. 2019-24. (Hypoglycemia during hyperinsulinemia/euglycemia therapy occurs rarely in CCB overdoses and is considered safe in the critical care setting.)

Holger, JS, Engebretsen, KM, Fritzlar, SJ. “Insulin versus vasopressin and epinephrine to treat B-Blocker toxicity”. Clin Toxicol. vol. 45. 2007. pp. 396-401. (Insulin and glucose was found superior to epinephrine for survival in this animal model, with increased SVR appearing to be detrimental for survival in this setting.)

Holger, JS, Engebretsen, KM, Obetz, CL. “A comparison of vasopressin and glucagon in beta-blocker induced toxicity”. Clin Toxicol. vol. 44. 2006. pp. 45(There was no significant survival difference between the use of vasopressin versus glucagon in this animal model study.)

Levine, M, Boyer, EW, Pozner, CN, Gelb, AJ, Tomsen, T. “Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil”. Crit Care Med. vol. 35. 2007. pp. 2071-5. (Serum glucose concentrations directly correlate with the severity to the CCB overdose.)

Love, JN, Love, JH, Howell, JM. “Acute beta blocker overdose: Factors associated with the development of cardiovascular morbidity”. Clin Toxicol. vol. 38. 2000. pp. 275-81. (Co-ingestion of other medications with BBs is associated with increased mortality. Patients who have had significant overdoses of immediate-release BB will become symptomatic within 6 hours of ingestion.)

Nickson, CP, Little, M. “Early use of high-dose insulin euglycaemic therapy for verapamil toxicity”. Med J Australia. vol. 191. 2009. pp. 350-2. (High-dose insulin therapy was used to stabilize this patient; the patient clinically worsened when therapy was stopped and improved when it was restarted with vasopressor adjunct.)

Patel, NP, Meredith, EP, Goldberg, S, Eiger, G. “Hyperinsulinemic euglycemia therapy for verapamil poisoning: A review”. Am J Critical Care. vol. 16. 2007. pp. 498-503. (This review of CCB physiology suggests use of hyperinsulinemia/euglycemia therapy for patients not responding to supportive therapy.)

Sim, MT, Stevenson, FT. “A fatal case of iatrogenic hypercalcemia after calcium channel blocker overdose”. J Med Toxicol. vol. 4. 2008. pp. 25(Infusions of calcium salts have been used for CCB OD but have resulted in fatalities due to hypercalcemia.)

Wax, PM, Erdman, AR, Chyka, PA. “B-Blocker ingestion: an evidence-based consensus guideline for out-of-hospital management”. Clin Toxicol. vol. 43. 2005. pp. 131-46. (Review of epidemiologic data as well as likely chronological order of clinical interventions. Intervention data are reviewed and graded depending on strength of literature (expert opinion evidence to animal and case series reviews).

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.