CONTENTS

• Clinical presentation
• Differential diagnosis & evaluation
• Tier-1 therapies
  • Decontamination
  • Airway control & vascular access
  • Basic hemodynamic interventions
  • Glucagon or milrinone
  • IV calcium
  • Atropine
  • Hyperinsulinemic euglycemia
• Tier-2 therapies
  • Methylene blue
  • ECMO
  • Hemodialysis
  • Transvenous pacemaker
  • Intralipid
• Other issues that may require treatment
  • Hypoglycemia
  • Sodium channel blockade
  • Potassium channel blockade
• Podcast
• Questions & discussion
• Pitfalls

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clinical presentation

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general

• Onset of symptoms depends on the medication and formulation:
  • Ingestion of immediate-release formulations should cause clinical deterioration within ~6-8 hours.
  • Extended-release formulations or sotalol may present later, with deterioration occurring within 24 hours.
• Cardiovascular: Bradycardia, hypotension, and shock are common.
• Endocrine
  • CCB poisoning usually causes hyperglycemia, whereas BBl poisoning may cause hypoglycemia.
  • 💡 In an undefined intoxication with bradycardia and hypotension, the glucose may provide a clue pointing to either CCB or BBl intoxication.
• Gastrointestinal: nausea, vomiting.
• Neurologic: Delirium, seizure, coma (may result from brain hypoperfusion, or may be due to lipophilic beta-blockers; see below).

specific features of CCBs

• Nondihydropyridine CCBs (verapamil and diltiazem): Cause myocardial suppression more than vasodilation. Presentation is marked by early development of hypotension and bradycardia.
• Dihydropyridine CCBs (e.g., nifedipine, isradipine, amlodipine, felodipine, nimodipine) initially cause vasodilation. However, at high doses they lose selectivity for the vasculature and suppress the myocardium.
  • Lower doses: can cause a primarily vasodilatory shock state (hypotension with reflex tachycardia).
  • Higher doses: will affect heart as well (vasodilation combined with bradycardia).

specific features of various BBl

• (1) Lipophilic agents (e.g., propranolol) are more likely to enter the brain and cause delirium or seizure.
• (2) Cardiac sodium channel blockade (acebutolol, betaxolol, carvedilol, oxprenolol, pindolol, propranolol) – may cause QRS widening and monomorphic VT. EKGs may also reveal a Brugada pattern. Hypotension can be more severe than one would expect, based solely on the degree of bradycardia.
• (3) Cardiac potassium channel blockade (acebutolol, sotalol) may prolong the QTc and cause torsade de pointes.
• (4) Peripheral vasodilators (betaxolol, bucindolol, carteolol, carvedilol, celiprolol, labetalol, nebivolol) may cause hypotension due partially to peripheral vasodilation.

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differential diagnosis and evaluation

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The differential diagnosis of bradycardia is listed here.

Evaluation will depend on the clinical context. Some investigations to consider may include:

• History & physical examination (focusing on medication list and access to various substances).
• EKG:
  • Any BBl or CCB may cause bradycardia and various heart blocks.
  • BBl with sodium channel blockade activity may also cause QRS widening, tall R-waves in aVR, and a Brugada pattern.
• Labs:
  • Fingerstick glucose if altered mental status.
  • Chemistries (including Ca, Phos, & Mg).
  • Digoxin level, for patients taking digoxin.
  • Consider checking TSH, Lyme serology (if no definite history of medication ingestion).
  • Consider checking acetaminophen and salicylate levels if coingestion is possible.

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decontamination

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activated charcoal

• May be considered if:
  • Patient presents within 1-2 hours of ingestion (which rarely happens).
  • Patient is intubated for another reason (in which case, the benefits may outweigh the risks).

whole bowel irrigation

• Whole bowel irrigation should be considered for large ingestion of sustained-release medications or amlodipine (which may function as a long-acting medication). This is a particularly important consideration if ECMO isn't immediately available, as these intoxications can outstrip all other therapeutic modalities.
• In order to be effective, bowel irrigation should be performed early (prior to the onset of shock and ileus). Glucagon may not be compatible with whole bowel irrigation, since a glucagon infusion induces relaxation of gastrointestinal smooth muscle.
• Some nuts and bolts of whole bowel irrigation:
  • This may be conceptualized as an accelerated preparation for a colonoscopy.
  • An isotonic solution of polyethylene glycol (i.e., “GoLytely”) may be infused via an orogastric tube, beginning at a rate of 1.5-2 liters/hour. If emesis occurs, reduce the rate by 50%.
  • Continue until effluent is clear (just as one would for a colonoscopy prep). If the patient received a dose of charcoal, passage of charcoal per rectum may also be a sign of adequate evacuation.

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airway control & vascular access

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airway control

• For patients who are clinically deteriorating, consider securing the airway early.
  • Intubation may be safer while the patient is fairly stable.
• For patients with hypotension who require intubation, try to quickly achieve hemodynamic stability prior to intubation if possible, to avoid post-intubation hypotension (e.g., volume loading and epinephrine infusion).

vascular access

• Central access will be needed in severe intoxications (e.g., for D50W administration, calcium, and vasopressors).
• For crashing patients, consider STAT placement of arterial and venous access (e.g., the dirty double).

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basic hemodynamic interventions

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echocardiography

• Try to determine whether the primary problem is vasodilation versus pump failure.
• Assess volume status.

volume resuscitation

• Administer fluid if there is evidence of hypovolemia. However, most patients aren't hypovolemic.
• In severe intoxications, volume overload often becomes a major problem – so avoid over-resuscitation.

vasopressors

• Epinephrine is generally a good choice, as it may help improve bradycardia and hypotension.
• Norepinephrine is useful for patients with substantial vasodilation, such as those intoxicated with:
  • Dihydropyridine CCB.
  • Beta-blockers with vasodilatory effects (e.g., betaxolol, bucindolol, carteolol, carvedilol, celiprolol, labetalol, nebivolol).
• Patients may require unusually high doses of vasopressors. Remember that there is no “maximal dose” of catecholamine vasopressors. However, hyperinsulinemic euglycemia therapy is probably preferable to high doses of vasopressors. Therefore, for patients on moderate-dose vasopressors, consider early initiation of hyperinsulinemic euglycemia therapy, with a goal of weaning off the vasopressors.

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glucagon or milrinone

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physiology

• Both glucagon and milrinone increase myocardial intracellular cAMP levels, thereby exerting positive inotropic and chronotropic effects.
• These agents bypass the beta-receptor, making them particularly attractive for patients with BBl poisoning.

candidates for glucagon/milrinone therapy?

• (1) Patients with bradycardia and cardiac pump failure.
  • These are most useful for patients with beta-blocker intoxication, bradycardia, and cardiogenic shock.
  • They could be attempted in a patient with CCB intoxication, bradycardia, and shock.
  • They are unlikely to help in patients with CCB intoxication and predominantly vasodilatory shock.
• (2) Risk of aspiration
  • ⚠️ Glucagon often induces emesis, so be careful in patients at risk of aspiration (e.g., patients with borderline mental status who are not intubated).
  • Milrinone might be considered among patients at high risk of aspiration.

glucagon

• (#1) Glucagon test dose
  • Start with a loading dose of 5 mg IV over 5 minutes (may repeat if ineffective).
• (#2) Glucagon infusion
  • If the test dose causes hemodynamic improvement, this may be followed with a continuous infusion at a rate between 1-10 mg/hour, set equal to the dose of glucagon that caused clinical improvement (e.g., if 5 mg worked, set the infusion equal to 5 mg/hour).
  • Glucagon has a half-life of about 15 minutes, so a continuous infusion is needed.
  • Glucagon infusions may exhaust the hospital's glucagon supply, so this may not be a sustainable long-term strategy. However, a glucagon infusion could be useful as a bridge for a few hours, until the high-dose insulin infusion starts to work.

milrinone

• Milrinone use is supported by less evidence than glucagon. There is some concern that milrinone could cause vasodilation and worsen hypotension. Additionally, titration of milrinone may be challenging because it is renally cleared with a moderately long half-life.
• Milrinone is a niche drug, which might be useful under the following conditions:
  • (1) Refractory bradycardia in a patient who has a good response to glucagon.
  • (2) There isn't enough glucagon available to administer a glucagon infusion, so milrinone is the only agent available to increase intracellular cAMP levels.
  • (3) Absence of refractory hypotension.

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IV calcium

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general

• Calcium is generally recommended, for either CCB or BBl poisoning.
• Calcium may be more effective at improving the blood pressure and the contractility (but less effective at increasing the heart rate).

dosing

• May use calcium chloride (1 gram) or calcium gluconate (3 grams). This dose may be repeated every 10-20 minutes as needed, up to an initial cumulative dose of ~3 grams calcium chloride or ~9 grams calcium gluconate.
  • IV calcium should be administered as slow pushes over at least ~5 minutes, to minimize side effects.
  • In patients without central access, calcium gluconate is preferred.
• Follow the ionized calcium level if possible, targeting a level of ~2 mM. Repeat doses of IV calcium may be required every 1-2 hours.
• Side effects of IV calcium may include nausea/vomiting, confusion, and constipation.

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atropine

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• Atropine may be attempted for treatment of bradycardia, but it's unlikely to work (especially in severe CCB intoxication).
• The dose is 1 mg IV Q5 min x1-3 doses (to a maximum cumulative dose of 3 mg).

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HyperInsulinemic Euglycemia (HIE)

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indications

• HIE seems to work best in patients with myocardial dysfunction (e.g., bradycardia, and especially reduced ejection fraction). It is unlikely to help in patients with predominantly vasodilatory shock (e.g., echocardiography showing a normal or increased ejection fraction).
• The most convincing evidence is in CCB toxicity, but HIE appears to work in BBl toxicity as well.
• HIE therapy should be started early in patients with cardiogenic shock, because it takes at least ~15-60 minutes to work. Thus, the delay between ordering treatment and actual clinical benefit may be hours.

initiation and up-titration of HIE

• Insulin:
  • Start with 1 unit/kg IV bolus, followed by a 1 unit/kg/hour infusion.
  • If the response is unsatisfactory, insulin may be up-titrated every 10-15 minutes within a range of 1-10 units/kg/hour.
  • A reasonable hemodynamic target for efficacy might be a heart rate over ~50 b/m and systolic blood pressure over ~90 mm. Of course, these are very rough benchmarks (with hemodynamics being titrated to perfusion endpoints as well).
• Dextrose:
  • (1) Administer 1-2 ampules of D50W (50-100 mL) when starting HIE, unless the glucose is already >250 mg/dL (14 mM).
  • (2) Initiate an IV dextrose infusion. Volume overload can become a major problem, so D50W is strongly preferred. The ideal way to provide dextrose is a continuous infusion of D50W via central line, beginning at a rate of ~1 mL/kg/hour (e.g., ~75 mL/hour D50W). Pharmacies should be able to provide D50W, using high-dextrose solutions that are used to formulate TPN. If the pharmacy is unable to provide D50W, then intermittent ampules of D50W may be used instead (since these are widely available).
  • (3) Follow the glucose q15-30 minutes until stable, then space out to every hour. Target a moderately elevated glucose level (~125-250 mg/dL, or 7-14 mM).
• Potassium
  • Follow potassium and replete for a target potassium level >3 mM.(30141827)
  • Note that when insulin is withdrawn, potassium will shift out of the cells. Thus, overaggressive potassium supplementation could theoretically lead to a risk of hyperkalemia when weaning the insulin off.
• Magnesium & phosphate
  • Insulin may promote hypomagnesemia and hypophosphatemia, requiring active repletion.
  • All electrolytes should be monitored carefully, including magnesium and phosphate. Initially, cycling electrolytes every hour may be desirable. As patients stabilize on the protocol, this interval may be spaced out.(30141827)

weaning off HIE

• HIE is often continued for ~1-2 days, but it may be required even longer (depending on the toxicokinetics of the ingestion). Following clinical improvement, insulin may be weaned off based on hemodynamics.
• Insulin will accumulate and continue working for many hours (or even days) after stopping the infusion.
  • (1) Remain vigilant for hypoglycemia or hypokalemia, even after shutting off the insulin infusion.
  • (2) Some authors suggest that the insulin infusion can be weaned relatively rapidly, because it will persist for several hours and auto-taper on its own.(32656624)

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Tier two therapies

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methylene blue

• Methylene blue has been reported to stabilize some patients with refractory vasodilatory shock due to CCBs.(30598720, 33299766)
  • CCBs may increase nitric oxide synthesis, so the use of methylene blue in CCB overdose makes sense.
• A reasonable dose of methylene blue might be a loading bolus of ~2 mg/kg administered over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour.
• Methylene blue infusions can have side effects, including hemolytic anemia (in G6PD deficiency), aberrant pulse oximetry signals, promotion of serotonin syndrome, and methemoglobinemia. Consider monitoring methemoglobin levels serially.

ECMO

• This is an attractive strategy to support patients until drug metabolism occurs.
• VA ECMO will be most effective in patients with cardiogenic shock (not patients with vasodilatory shock).
• The primary limitation is availability of ECMO.

hemodialysis

• Dialysis may be considered for hydrophilic beta-blockers (nadolol, sotalol, acebutolol, atenolol, timolol).

transvenous pacemaker

• This may be considered in patients with refractory bradycardia, particularly if they have preserved contractility. However, results tend to be disappointing.
• Problems with transvenous pacing:
  • (1) Capturing the myocardium is often difficult. These patients have a myocardium problem, not a conduction system problem – so they may be refractory to pacing.
  • (2) Transvenous pacing results in a loss of the atrial kick. It also causes a transition from the patient's native conduction system (which produces a coordinated contraction of the myocardium) to initiation of beats within the myocardium (causing a prolonged QRS interval with uncoordinated contraction of the myocardium). Overall, transvenous pacing may increase the heart rate, but result in less effective contraction of the myocardium (with little overall benefit).
• Transcutaneous pacing might be tried as well, but this is even less likely to be successful than transvenous pacing.

20% lipid emulsion therapy (e.g., Intralipid)

• The popularity of this intervention is decreasing, due to concerns that lipid could increase drug transport out of the intestine (thereby worsening intoxication).
• Lipid emulsion therapy is unlikely to work with more hydrophilic beta-blockers (nadolol, sotalol, acebutolol, atenolol).
• Adverse reactions may include hypertriglyceridemia, pancreatitis, difficulty measuring some labs, and adherence to ECMO circuits.
• Nuts and bolts of lipid administration:
  • Newer guidelines recommend a revised dosing scheme with a reduced maintenance infusion, which could optimize the risk/benefit balance. These recommend the following dosing scheme for 20% lipid emulsion (e.g., Intralipid):
  • (1) Start with a bolus of 1.5 mL/kg over ~2-3 minutes (e.g., ~100 mL). Repeat bolus may be considered if no response to the first bolus.
  • (2) Give an additional 0.75 mL/kg over three minutes (e.g., ~50 mL).
  • (3) Start a maintenance infusion rate of 0.025 mL/kg/min.
  • (4) If there is an initial response to the bolus followed by re-emergence of instability during the maintenance infusion, consider re-bolusing and/or increasing the infusion rate. There is no known maximal dose, but it may be best to limit the dose to ~10 mL/kg/day total.
  • More information: Full text PDF of the ACMT 2016 Lipid Emulsion Position Statement

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other issues that may require treatment

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hypoglycemia

• Follow glucose and replete as necessary (this is primarily an issue with BBl poisoning).

sodium channel blockade

• Sodium channels may be blocked by certain beta-blockers (acebutolol, betaxolol, carvedilol, oxprenolol, pindolol, propranolol).
• Clinically, sodium channel blockade manifests as widening of the QRS, which may lead to monomorphic VT.
• Management involves IV hypertonic bicarbonate, similar to a tricyclic overdose. Indications for hypertonic bicarbonate may include QRS prolongation, ventricular dysrhythmias, or severe hypotension.

potassium channel blockade (acebutolol, sotalol)

• These may prolong the QTc interval and cause torsade de pointes.
• QTc prolongation may be treated with IV magnesium boluses, whereas torsade may warrant more aggressive treatment with a magnesium infusion (more on this in the chapter on torsade).

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Delayed initiation of high-dose insulin.
• Reliance on therapies that are unlikely to work (e.g., atropine, IV calcium, and glucagon).
• Early focus on placing a transvenous pacemaker (this wastes time, often doesn't capture the myocardium). Note that traditional algorithms for bradycardia don't work for these patients.

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