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
  • Hemodialysis
  • Methylene blue
  • ECMO
  • (Transvenous pacemaker)
  • (Lipid emulsion therapy)
• Other issues that may require treatment
  • Hypoglycemia
  • Sodium channel blockade
  • Potassium channel blockade
• Related topics
  • Glucagon pharmacology

---

clinical presentation

(back to contents)

---

general

• Onset of symptoms depends on the medication and formulation:
  • 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 moreso than vasodilation.
  • Presentation is marked by early development of hypotension and bradycardia.
• Dihydropyridine CCBs (e.g., nifedipine, isradipine, amlodipine, felodipine, nimodipine)
  • Lower doses: can cause a primarily vasodilatory shock state (hypotension with reflex tachycardia).
  • Higher doses will lose selectivity and affect the heart as well (vasodilation combined with bradycardia).

specific features of various BBl

• Lipophilic agents:
  • Agents: Propranolol.
  • More likely to enter the brain and cause delirium or seizure.
• Cardiac sodium channel blockade:
  • Agents: Acebutolol, betaxolol, carvedilol, oxprenolol, pindolol, propranolol.
  • May cause QRS widening and monomorphic VT. ECGs may also reveal a Brugada pattern. Hypotension can be more severe than one would expect, based solely on the degree of bradycardia.
• Cardiac potassium channel blockade:
  • Agents: Acebutolol, sotalol.
  • May prolong the QTc and cause torsade de pointes (the combination of bradycardia and QT prolongation will synergistically promote torsade).
• Peripheral vasodilators:
  • Agents: Bbetaxolol, bucindolol, carteolol, carvedilol, celiprolol, labetalol, nebivolol.
  • May cause hypotension due partially to peripheral vasodilation.

---

differential diagnosis and evaluation

(back to contents)

---

ECG

• 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/or a Brugada pattern.
• BBl with potassium channel blockade activity may prolong the QTc interval.

POCUS

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

labs

• Glucose level (hyperglycemia suggests CCB toxicity).
• Chemistries (including Ca, Phos, & Mg).
• Additional evaluation:
  • Digoxin level, for patients taking digoxin.
  • Consider checking TSH, Lyme serology (if no definite history of medication ingestion).
  • Check acetaminophen and salicylate levels if coingestion is possible.

related topics

• The approach to a poisoned patient is discussed here.
• Differential diagnosis of bradycardia is listed here.

---

decontamination

(back to contents)

---

single-dose activated charcoal

• The usual indications apply.
• (Discussed further here.)

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.
• (Discussed further here.)

---

airway control & vascular access

(back to contents)

---

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).

---

basic hemodynamic interventions

(back to contents)

---

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).
• Dobutamine may be used for inotropic or chronotropic effects. (37976176)
• 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.
• (Isoproterenol is theoretically a rational agent for beta-blocker intoxication with refractory bradycardia, since isoproterenol serves as a pure beta-agonist. Consequently, up-titration of isoproterenol could allow for directed stimulation of beta-agonist receptors, without unintended activity on alpha-receptors (which could cause excessive vasoconstriction). Note that isoproterenol also stimulates beta-2 agonists, leading to hypokalemia and lactic acidosis. There is no data to support the use of isoproterenol, and it is generally not utilized for logistic reasons.)

---

glucagon or milrinone

(back to contents)

---

glucagon

• Glucagon is most useful for patients with beta-blocker intoxication, bradycardia, and cardiogenic shock.
  • Glucagon might be attempted in a patient with CCB intoxication, bradycardia, and shock.
  • Glucagon is unlikely to help in patients with CCB intoxication and predominantly vasodilatory shock.
• ⚠️ Glucagon often induces emesis, so be cautious in patients at risk of aspiration (e.g., patients with borderline mental status who are not intubated).
• ⚠️ Guidelines recommend against the use of glucagon for calcium channel blocker intoxication. (27749343)
• (Further discussion of glucagon is below.)

milrinone

• Milrinone use is supported by less evidence than glucagon. There is a risk 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 that 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.

(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.

---

IV calcium

(back to contents)

---

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.

---

atropine

(back to contents)

---

• Atropine is listed here because it's technically a front-line therapy for bradycardia.
• Trialing atropine is reasonable, 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).
• (Atropine pharmacology discussed here.)

---

HyperInsulinemic Euglycemia (HIE)

(back to contents)

---

indications

• HIE seems to work best in patients with myocardial dysfunction (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).
  • ⚠️ Insulin-mediated vasodilation may be counterproductive in patients with profound vasoplegia as the primary driver of their shock state. (37976176)
• 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. Doses over ~5 units/kg/hour might be excessive (since lower doses will likely saturate the insulin receptors).
  • Exactly what to target with an insulin infusion is unclear. Ideally, the insulin infusion will cause a substantial reduction in vasopressor requirement and improvement in the systolic BP. However, since insulin causes both vasodilation and inotropic effects, titrating insulin against blood pressure may not be rational or safe. It might be ideal to titrate insulin against a perfusion or ejection fraction target. (37976176)
• 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 or D70W, using high-dextrose solutions that are used to formulate TPN. If the pharmacy is unable to provide D50W or D70W, 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 levels and replete as needed to achieve a target potassium level >3 mM. (30141827)
  • Note that when insulin is withdrawn, potassium will shift back out of the cells. Thus, overaggressive potassium supplementation could 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

• When to wean:
  • Following clinical improvement, insulin may be weaned off or discontinued with close monitoring of hemodynamics.
  • In CCB intoxication, the emergence of hypoglycemia may be an indicator of recovery.
• How to wean:
  • Insulin accumulates and continues working for hours to days after stopping the infusion. Thus, the insulin infusion can be weaned rapidly, because it will still persist for several hours and auto-taper on its own (especially in the context of renal dysfunction). (32656624) Of course, if hemodynamic deterioration occurs, insulin may be bolused, and the infusion can be increased or resumed.
  • The dextrose infusion should be continued and adjusted based on the patient's glucose levels (rather than, for example, arbitrarily shutting off the dextrose infusion when the insulin infusion is stopped).
  • Remain vigilant for hypoglycemia and hyperkalemia/hypokalemia, even after shutting off the insulin infusion (rebound hyperkalemia can occur).

---

Tier two therapies

(back to contents)

---

hemodialysis

• Dialysis may be considered for hydrophilic beta-blockers (nadolol, sotalol, acebutolol, atenolol, timolol).
• CRRT may be considered in patients with renal failure to avoid progressive volume overload.

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.
• (Further discussion of contraindications, dosing, etc, is here.)

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 the availability of ECMO.

(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.)

(lipid emulsion therapy)

• The popularity of this intervention is waning due to concerns that lipid could increase drug transport out of the intestine (thereby worsening intoxication). Lipid emulsion is reasonable for a patient in cardiac arrest or perhaps periarrest. Otherwise, lipid emulsion may be more likely to cause harm than benefit.
  • 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, ARDS, and difficulty with occluding ECMO circuits.
• (Further discussion of lipid emulsion therapy is here.)

---

other issues that may require treatment

(back to contents)

---

hypoglycemia

• This may be problematic, even in the absence of high-dose insulin.
• 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).

---

glucagon pharmacology

(back to contents)

---

---

contraindications, drug interactions, side effects 👎

contraindications

• [1] Unprotected airway: Glucagon often induces emesis, so be careful in patients at risk of aspiration (e.g., patients with borderline mental status who are not intubated).
• [2] Pheochromocytoma or insulinoma.

drug-drug interactions

• Glucagon is a protein, so there are no pharmacokinetic drug-drug interactions.

side effects

• Nausea/vomiting (common; ~15% of patients vomit following 1-mg dose).
• Headache.
• Hyperglycemia, or rebound hypoglycemia (especially in rare patients with insulinoma or glucagonoma).
• Elevation of heart rate and BP.

---

indications & dosing 👍

beta-blocker intoxication

• When to use glucacon?
  • The exact role of glucacon is unclear. Although glucagon is often quoted as the “antidote” to beta-blocker intoxication, in most cases beta-agonists are easier and safer to use (e.g., epinephrine or isoproterenol infusion). Glucagon should only be utilized for patients who are refractory to catecholamine inotrope infusion. (Wellington 3e)
  • Glucagon is generally safe, except that it may trigger emesis and aspiration. If aspiration isn't a concern (e.g., for patients who are either intubated or able to protect their airway), trialing glucagon may be reasonable in some situations.
• [#1/2] Glucagon test dose
  • Start with a loading dose of 5 mg IV over 5 minutes (may repeat if ineffective).
  • If there is no improvement following 10 mg of glucagon, then this treatment is ineffective and further administration is futile.
• [#2/2] 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 short half-life, 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. An alternative and more workable solution may be to start a milrinone infusion instead.

(hypoglycemia)

• Glucaon has minimal role in the treatment of hypoglycemia within a hospital.
• A commonly utilized dose is 1 mg IV/IM.

---

pharmacology

• Chemical properties:
  • Glucagon is a 29-amino acid peptide.
  • Molecular weight: 3483 g/mol.
  • LogP: Below -5 (extremely hydrophilic).
• Absorption:
  • IM administration: rapidly absorbed, with peak plasma concentration in 10-20 minutes.
• Distribution:
  • Vd is ~8-10 liters (~0.25 L/kg).
  • Glucagon receptors are expressed in the liver, kidney, heart, adipose tissues, and pancreas.
• Metabolism:
  • Metabolized primarily via proteolytic degradation (in the blood, liver, and kidneys).
• Elimination:
  • The kidney is the main site of elimination.
• Half-life & duration of action:
  • Half-life is 5-7 minutes.
  • Renal failure causes a reduced elimination of glucagon.
• Mechanism of action:
  • Glucagon increases myocardial cAMP levels, leading to positive inotropic and chronotropic effects (similar to milrinone).  Both glucagon and milrinone bypass the beta-receptor, making them particularly attractive for patients with BBl poisoning.

---

questions & discussion

(back to contents)

---

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

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.