“HOUSTON, WE HAVE A PROBLEM.”
High-dose insulin euglycemic therapy (HIET) was first recognized as an apparently miraculous rescue therapy for Calcium Channel Blocker (CCB) overdose about two decades ago. Since then, it has become standard therapy for CCB overdose, but without the necessary regard for differences between the two major classes of these drugs, Dihydropyridines (DHP) and non-DHPs. HIET works well for some patients, but not for others. Why? The recently published literature was coalesced to answer this key question.
Amlodipine is the most common CCB agent seen in overdose, and HIET may be preventing amlodipine-overdose patients from recovering. In these patients, high-dose insulin may exacerbate shock and render it less responsive to vasopressors. This is in contrast to overdoses with diltiazem and verapamil, which usually respond well to HIET.
Based on the recent literature, the Missouri Poison Center has made a major change in its recommendations for the use of HIET in overdose of amlodipine and related dihydropyridines (felodipine, isradipine, levamlodipine, nicardipine, nifedipine, nimodipine, and nisoldipine):
HIET is no longer considered first-line therapy, AND is no longer routinely recommended for poisoning with amlodipine and other Dihydropyridine Calcium Channel Blocker agents.
CRITICAL DIFFERENCES IN CCB ACTION ON THE CARDIOVASCULAR SYSTEM
Not all CCB overdoses are the same. Understanding the mechanism of toxicity for amlodipine and other DHPs compared to verapamil and diltiazem is essential to understanding why HIET can make amlodipine overdoses worse.
The overall picture of verapamil toxicity is pacemaker failure and shock of cardiogenic origin. Verapamil preferentially blocks voltage-dependent slow calcium channels in the heart, producing bradycardia, slowed cardiac conduction, and decreased myocardial contractility, resulting in hypotension. Diltiazem-induced shock has both cardiogenic and peripheral vasodilatory components because it blocks calcium channels in both heart and peripheral vasculature. The commonality of verapamil and diltiazem poisoning is cardiogenic shock.
In contrast, the overall picture of amlodipine toxicity is profound vasoplegic shock due to peripheral vascular failure caused by the preferential block of voltage-dependent slow calcium channels in the vascular muscle. In addition, there is another mechanism of vasodilation that is of utmost importance and consequence – amlodipine and most other DHPs also increase production of endogenous nitric oxide in the vasculature. This means that there are two mechanisms driving peripheral vascular relaxation to the point of vasoplegia, which does not respond well to norepinephrine.
In amlodipine poisoning, the myocardium itself is little affected and may even be hyperdynamic with reflex tachycardia. It is hypothesized that only in massive overdose are the calcium channels also blocked in the heart, producing a cardiogenic component to shock.
INSULIN’S ACTION ON THE CARDIOVASCULAR SYSTEM
High-dose Insulin Euglycemic Therapy as a treatment for CCB overdose helps cardiogenic shock, but not vasodilatory shock. Insulin is characterized as an “inodilator,” which has two distinct actions. It is a potent inotrope that increases cardiac output through increased stroke volume. This has beneficial effects only in patients with drug-induced myocardial dysfunction, such as that caused by verapamil and diltiazem overdose. It does not improve hypotension caused by peripheral vascular failure that is typical of amlodipine toxicity. In fact, it may make vascular shock worse by its other mechanism.
Insulin’s second action is vasodilation by enhancing the synthesis of endothelial nitric oxide. Adding increased nitric oxide generation and vasodilation (insulin) to the cardiogenic shock of verapamil and diltiazem-poisoned patients may improve the shock state by reducing afterload and enhancing organ perfusion.
However, adding increased nitric oxide generation and vasodilation (insulin) to amlodipine-induced peripheral vascular failure worsens hypotension/shock. This triple mechanism (calcium channel blockade and two sources that increase nitric oxide) drives the refractory nature of shock that is seen clinically, unresponsive to maximum doses of four or five vasopressors. The patient may remain in shock for days despite intensive treatment, long after the amlodipine overdose effect has receded, because shock is being perpetuated by the treatment.
WHEN TO WITHHOLD HIET AND WHEN TO CONSIDER IT FOR AMLODIPINE-POISONED PATIENTS
HIET is no longer considered first-line therapy and is no longer routinely recommended for poisoning with amlodipine and other Dihydropyridine Calcium Channel Blocker agents. There must be a specific indication for its use, so that there is potential benefit to balance out the risk.
When would its use be considered? The key clinical parameter is the presence of significant cardiogenic shock, because this may respond positively to the inodilator action of high-dose insulin therapy.
If the shock is largely vasoplegic in origin, as expected in most amlodipine overdoses, HIET has a substantial risk of making the patient worse and the hypotension more difficult to treat.
How can cardiogenic vs. vasodilatory shock be known? The best way is by employing a formal or bedside echocardiogram to diagnose cardiac involvement before considering HIET. Furthermore, since the clinical course evolves, serial echocardiograms throughout the course of significant toxicity are useful. They can assess the changing relative roles of myocardial dysfunction and vasoplegia in causing shock, guide therapy, and monitor recovery of cardiac function. Repeated echocardiogram is particularly important if the patient is not improving or is getting worse. Therapy may need adjustment.
Also consider that co-ingestants are common in intentional overdoses. Beta blockers, ACE inhibitors, Angiotensin Receptor blockers, or other agents with action in the cardiovascular system can exacerbate symptoms or add additional ones.
PATIENT MANAGEMENT IN CCB OVERDOSE
Diltiazem and verapamil differ from amlodipine and other DHPs in overdose primarily because of the etiology of shock, and we suggest the use or omission of HIET be based on the presence or absence of significant cardiogenic shock. However, many of the other management strategies are similar across all CCB agents.
Many interventions concurrently may be needed in severely ill patients, including IV fluids, multiple inotropes or vasopressors, IV calcium, sodium bicarbonate, atropine, and pacing for bradycardia, intubation and ventilation, etc. Rescue therapies include intravenous methylene blue for vasoplegic shock or lipid emulsion. VA-ECMO should be considered, if available, for patients who are failing to respond to standard treatment. Patients who ingested ≥ 400 mg amlodipine should be considered for transfer to an ECMO-capable facility early after ingestion while the patient is still relatively stable.
It is important to recognize that amlodipine has been responsible for more poisonings and poisoning deaths in the US than diltiazem and verapamil combined. With better-targeted use of HIET only for patients who have significant cardiogenic shock, treatment for amlodipine poisoning may be more successful in the future.
The Missouri Poison Center is available around the clock to assist in the expert management of exposures to amlodipine and other Calcium Channel Blockers. Our specially trained nurses, pharmacists, and physician toxicologist can provide consultation regarding exposures and treatment. For patient-specific guidance, please contact the poison center’s dedicated line for healthcare professionals at 1-888-268-4195.
References
- Cole JB, et al. Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: A comparison of amlodipine versus non-dihydropyridines. Clin Tox, 2022,60(11): 1205-1213.
- Isoardi KZ, Chan B, Chiew AL. High dose insulin is an inodilator, not an antidote in the poisoned patient! Emerg Med Australasia, 2025;37: e70035.
- Isbister GK, et al. Calcium channel blocker overdose: Not all the same toxicity. Br J Clin Pharmacol, 2025;91: 740-747.