- Cardiogenic shock due to beta-blocker (BB) or calcium channel blocker (CCB) toxicity is frequent and potentially lethal.
- The most common cause of poison-induced cardiogenic shock is beta-blocker toxicity. In 2012 alone, there were 24,465 beta-blocker exposures (Mowry 2013).
- Calcium channel blocker overdose is less frequent than that of beta-blockers, but has been associated with the highest mortality rates among the cardiovascular drug overdoses(Woodward 2014).
Mechanism of Toxicity (Kerns 2011):
- BBs and CCBs lead to decreased intracellular calcium within the myocardial cells. This can lead to vasodilation, decreased systemic vascular resistance, bradycardia, conduction delay, decreased contractility, hypotension and cardiogenic shock.
- As the myocardium becomes stressed, it switches from catabolizing free fatty acids to catabolizing carbohydrates. The liver responds to this increased demand by releasing glucose via gluconeogenesis, ultimately resulting in hyperglycemia.
- Blockade of calcium channels leads to effects outside the cardiovascular system as well.
- CCB inhibits insulin secretion from the beta-islet cells of the pancreas. As a result of lower insulin levels, glucose cannot move into the myocardial cells at a rate sufficient to respond to demand.
- CCB inhibits lactate oxidation resulting in lactic acidosis
- Traditional management includes fluid resuscitation, atropine, cardiac pacing, calcium, glucagon and vasopressors. When these fail care may escalate to ECMO.
High Dose Insulin – How it Works:
- Under normal physiologic conditions the heart prefers to use free fatty acids as its primary energy source.
- In a stressed state the heart turns to prefer carbohydrate and insulin appears to facilitate this preference.
- In vitro and in vivo evidence has shown insulin’s positive inotropic and chronotropic effects(Reikeras 1985, Kline 1995).
- Even in a CCB poisoned animal model insulin increases myocardial glucose uptake resulting in improved contractility.
Using Hyperinsulinemia Euglycemia Therapy(Lugassy 2015)
- Hyperinsulinemia Euglycemia Therapy (HIET) Initiation:
- Intravenous bolus of regular insulin at a dose of 1 unit/kg.
- If serum glucose <250 mg/dL, concurrently administer a bolus of dextrose 25-50 g (or 0.5-1 g/kg) IV.
- HIET Continuous Infusion
- Regular insulin: start 0.5 – 1 unit/kg/hr
- Dextrose: 0.5 g/kg/hr (titrate to maintain glucose 110 – 150 mg/dL
- If the fluid overload is a concern, the insulin can be concentrated to 10 U/mL
- If hypoglycemia does occur, bolus with dextrose and/or increase dextrose infusion first before considering a decrease or cessation of insulin infusion.
- Continuous Monitoring
- Serum glucose every 30 minutes for 1-2 hours until stable
- Potassium every 1 hour
- Insulin bolus infusion can take 20-30 minutes to induce clinical inotropic/chronotropic effect.
- You may increase insulin infusion by 0.5-1 unit/kg/hr every 30-60 minutes (similar to administration of a pressor to maintain desired hemodynamic effect.)
- A wide range of continuous maintenance infusion of insulin for inotropic/chronotropic support have been reported with apparent safe use in the range of 3-10 Units/kg/hr.
- In addition to monitoring glucose and electrolyte levels, it may be prudent to monitor ejection fraction. Obtain a bedside echocardiogram upon arrival to estimate the patient’s ejection fraction. Repeat after 30-60 hours of insulin therapy. An improvement in EF is a good sign the therapy is working.
- Most common adverse effects of HIET include hypoglycemia and electrolyte imbalances, especially hypokalemia. No irreversible adverse effects have been reported(Engebretsen 2011).
- In a case series of seven patients with severe calcium-channel blocker overdoses in which HIET was used, serum glucose and potassium levels were monitored closely (every thirty minutes until stabilized and then every 1-2 hours). One patient had a serum glucose concentration of <65 mg/dL that was rapidly corrected. Two patients had potassium concentrations <3.5 mEq/L, but neither had ECG signs of hypokalemia of arrhythmias. No patient had clinically significant hypoglycemia or hypokalemia(Greene 2007).
- Another case series examined twelve patients receiving HIET for drug-induced cardiogenic shock. Six patients developed a total of nineteen hypoglycemic effects and hypokalemia was seen in seven patients. No adverse arrhythmias were noted and no patients had adverse sequelae secondary to hypoglycemia or hypokalemia(Holger 2011).
- It is important to note that hypoglycemia may occur up to several hours after the insulin infusion has been completed.
Take Home Points
- HIET has been shown to be a safe and effective treatment for BB and CCB toxicity
- Although they have been rarely reported, hypoglycemia and hypokalemia are potential adverse events when using HIET. Monitor glucose and electrolytes closely while using this therapy.
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Greene SL et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med 2007: 33(11): 2019-2024. PMID: 17622512
Holger JS et al. High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clin Toxicol 2011; 49(7): 653-658. PMID: 21819291
Kerns, W. Antidotes in Depth (A18): Insulin-Euglycemia Therapy. Goldfrank’s Toxicologic Emergencies 2015, 10th e. L. S. Nelson, N. A. Lewin, M. Howland et al. New York, NY, McGraw-Hill. Hyperlink
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Reikeras O et al. Haemodynamic effects of high doses of insulin during acute left ventricular failure in dogs. Eur Heart J 1985; 6(5): 451-457. PMID: 3899650
Woodward C et al. High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity. Daru 2014; 22(1): 36. PMID: 24713415