Introduction
Calcium-channel blockers (CCBs) have been used for over 40 years in veterinary medicine as both anti-hypertensive and anti-arrhythmic medications1. Three main categories of CCBs are commercially available in the United States for veterinary use: phenylalkylamines such as verapamil, benzothiazepines such as diltiazem, and dihydropyridines such as amlodipine. All are defined by their ability to block the long-lasting L-type calcium channels found primarily in the cardiac, smooth and skeletal muscle1. Calcium channels are vital for conduction of electric impulses across the sinoatrial and atrioventricular nodes of the heart. By inhibiting calcium influx, CCBs decrease atrioventricular conduction and slow the heart rate. In contractile cells such as vascular smooth muscle cells and myocytes, calcium channel blockade reduces cytosolic calcium levels and calcium-induced calcium release from the sarcoplasmic reticulum2. This leads to reduced cardiac inotropy and vasodilation, particularly in vascular beds with a high resting tone such as arteries. In addition, there is a dose-dependent response to CCBs within the systemic resistance vessels3. Other tissues affected by CCBs include the pancreas, pulmonary parenchyma, and central nervous system1. Blockade of L-type calcium channels in the pancreas causes decreased insulin release by the β-islet cells and restricts tissue uptake of glucose by altering sensitivity to insulin1. Under normal aerobic conditions, myocardial cells oxidize free fatty acids as the main energy substrate. In hypoperfused or hypoxic states, myocardial cells utilize glucose as their main substrate. In patients with CCB toxicosis, hypoinsulinemia, insulin resistance, and hypotension lead to reduced glucose delivery. That combined with an increased tissue demand causes a relative negative glucose balance leading to impaired inotropy and myocardial dysfunction4.
Calcium channel blocker toxicity causes an exaggeration of therapeutic effects including hypotension, bradycardia and bradyarrhythmias. Additional clinical signs include gastrointestinal upset, hypothermia, central nervous system depression, noncardiogenic pulmonary edema, hyperglycemia, hypokalemia, hyponatremia, metabolic acidosis, often coupled with hyperlactatemia, and, rarely, stimulatory signs such as agitation or seizures1. First-line treatments for CCB toxicosis include decontamination and supportive care; second-line treatments include calcium supplementation, insulin-glucose infusions, vasopressors/catecholamines, glucagon, intralipid therapy, and external pacing1.
Hyperinsulinemia/euglycemia therapy (HIET) is described in the human literature and infrequently described in the veterinary literature as a therapy for CCB toxicity. It consists of a high-dose regular insulin infusion coupled with a glucose infusion6. Intracellular transport of glucose in cardiac and skeletal muscle is greatly enhanced by insulin providing an ongoing source of energy for cardiac contraction. In high concentrations, insulin affects several intracellular pathways that increase the inotropy of cardiac myocytes and alter calcium handling2. Additional benefits of HIET include increased cyclic AMP levels through phosphodiesterase III inhibition, resulting in increased calcium influx6. There is evidence that HIET increases endothelial nitric oxide synthase (eNOS) activity which in turn decreases capillary resistance and improves overall tissue perfusion5. There is one published case report in the veterinary literature describing HIET for the treatment of CCB toxicosis in a dog. Maton et al describe the successful use of HIET in the treatment of diltiazem toxicosis7. To the authors’ knowledge this is the first case report describing the use of HIET for the treatment of CCB toxicosis in a cat.