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.