Discussion:
This is the first case report describing hyperinsulinemia/euglycemia
therapy for the treatment of amlodipine toxicosis in a cat. Calcium
channel blockers are rapidly and completely absorbed after
ingestion10. Amlodipine has the highest
bioavailability and volume of distribution in its
class11, is highly protein bound and hepatically
metabolized prior to renal excretion. The elimination half-life is
potentially the longest of any CCB at 30 hours in the dog, with a range
of 30-60 hours reported in the cat1. Time to peak
plasma concentration for immediate release forms is 20-45 minutes. The
minimum toxic dose has not been established in humans or animals,
however signs of toxicosis at therapeutic doses have been noted in all
classes of CCB1. Amlodipine toxicosis is the most
commonly reported dihydropyridine toxicosis in animals, accounting for
83.2% of the cases reported to the ASPCA APCC from 2000 to
20171. The clearance of CCBs is likely prolonged in
disease states such as congestive heart failure, cardiomyopathy, or
hypotensive overdose which result in altered hepatic
perfusion12. Standard dosage is typically 0.625-1.25mg
per cat8. Little is known about the cumulative effects
of amlodipine, but signs of toxicosis in people may persist for up to 10
days, with mortality in symptomatic cases as high as
21%13.
Decontamination and limitation of toxin absorption is the first line of
treatment if ingestion occurred within 2 hours of
presentation1. Emesis was not attempted in the cat
reported here due to the chronicity of the exposure. Activated charcoal
was not administered due to the concern for aspiration. A warm water
enema could have been performed to facilitate evacuation of intestinal
contents1. Calcium gluconate is recommended to
overcome inhibited calcium channels and promote inotropy, but response
to treatment is inconsistent in severe intoxications5.
An exact dose of calcium is not described but a CRI titratable to a
desirable blood pressure and heart rate has been
suggested10. The administration of calcium gluconate
in this case led to ionized hypercalcemia without any clear benefit.
Atropine may increase heart rate and improve cardiac output, however the
effect is often transient2. Furthermore, the resulting
increase in myocardial oxygen demand can lead to myocardial injury when
systemic and coronary hypotension are present14.
Atropine had no positive effect in the present case. Vasopressors can
increase SBP by overriding the vasodilatory effects of amlodipine, but
the resulting increase in systemic vascular resistance can lead to
decreased cardiac output and altered perfusion of vascular
beds5. Treatment with adrenergic drugs may yield a
poor response in patients with moderate to severe
overdoses10. Glucagon is a pancreatic peptide and
cardiac inotrope1. It increases cardiac output, lowers
pulmonary arterial pressure, and pulmonary vascular resistance without
any systemic vascular effects15. Several animal models
evaluating glucagon for the treatment of CCB toxicosis have shown an
increase in HR and cardiac output, as well as AV block reversal, however
no effect on MAP or survival was observed10. Glucagon
was not used in the case reported here due to lack of availability, and
associated cost.
The use of lipid emulsion therapy (ILE) has been described in the
treatment of toxicities from substances with a high lipid
solubility16, including CCBs7. The
mechanism of action of ILE is incompletely understood. One theory is
that ILE sequesters the lipophilic drug in a ‘lipid sink’ reducing
availability and promoting clearance through metabolism of
drug-containing chylomicrons16. Another theory for the
benefit of ILE in cardiotoxic drugs is that increased availability of
free fatty acids may prevent the myocardium from switching to glucose as
its preferred energy substrate16. Furthermore, long
chain fatty acids may activate myocyte calcium channels resulting in
increased calcium influx16. The inhibition of
amlodipine-induced cardiomyoblast apoptosis using ILE has been
demonstrated in a murine model17. Complications
associated with ILE are infrequent but include microbial or particulate
contamination of the lipid product, pancreatitis, hyperlipidemia, or an
allergic-type reaction to the infusion16. For the cat
reported here HIET was started shortly after ILE so the role of ILE
alone cannot be evaluated. No complications were observed.
There are three major mechanisms by which HIET is believed to improve
survival following CCB overdose: (1) increased inotropy, (2) increased
intracellular glucose transport, and (3)
vasodilation5. High-dose insulin increases coronary
blood flow without increasing oxygen demands, contrary to
catecholamines6. Insulin also increases eNOS
activity leading to systemic, coronary, and pulmonary
vasodilation5. Cardiogenic shock is characterized by
altered microvascular perfusion and a failure to supply capillary beds
and the surrounding tissues with metabolic substrate. By increasing eNOS
activity, insulin enhances microvascular hemodynamics improving tissue
perfusion, decreasing afterload, and increasing cardiac
output5. In cell cultures, supraphysiologic doses of
insulin are required to increase eNOS activity above basal
concentrations, which may explain why hyperinsulinemia is needed to
elicit these beneficial vascular effects5.
A study by Kline et al compared normal saline, epinephrine, glucagon,
calcium chloride and HIET for the treatment of verapamil toxicosis in
dogs. Dogs that received HIET had an increased survival rate, improved
maximum elastance, left ventricular end diastolic pressure, ventricular
relaxation, and coronary artery blood flow18. An
experimental study by Kerns et al showed that insulin-treated
anesthetized dogs following propranolol-induced cardiomyopathy had
improved cardiodynamics and hemodynamics, as well as increased
myocardial glucose uptake compared to dogs treated with glucagon or
epinephrine. Survival was significantly higher in the insulin group
compared with the glucagon and epinephrine groups15.
Krukenkamp et al. induced myocardial depression in dogs using
propranolol and found 80% reversal following HIET, as well as a
statistically significant increase in peak blood pressure without
changing myocardial oxygen consumption19. Beta-blocker
overdose is often used in experimental models to extrapolate data which
can then be applied to clinical CCB and beta-blocker toxicities as both
drug classes result in blockade of calcium flux through the L-type
calcium channels20. Two experimental porcine models
evaluated the use of vasopressors and HIET in propranolol-induced
cardiogenic shock21,22. The first study found that
pigs treated with insulin and dextrose had a consistent improvement in
cardiac output over the duration of treatment compared with the pigs
treated with vasopressors alone, which had a progressive worsening of
cardiac output21. The authors concluded that higher
insulin doses may be required in the presence of vasopressors to
overcome increased SVR and decreased cardiac output21.
The second study found that patients treated with norepinephrine after
maximizing high-dose insulin therapy had improved brain tissue
oxygenation compared to HIET alone22 and that patients
with profound hypotension (<55mmHg) could benefit from
vasopressors after maximizing HIET.
There is strong evidence supporting the benefits of HIET in humans with
CCB toxicosis, however there is little clinical evidence in the
veterinary literature to support its use. One case report by Maton et al
describes the use of HIET in conjunction with ILE to treat diltiazem
toxicosis in a dog. In that case, HIET was initiated after clinical
signs did not improve despite decontamination, calcium gluconate,
dopamine CRI, glucagon, insulin pulse therapy with dextrose
supplementation at 5% and ILE. Dextrose supplementation was increased
to 10% at initiation of HIET and a regular insulin CRI was started at 1
U/kg/h. Within one hour of starting the insulin CRI clinical signs
improved. The dog received a total of 20 hours of ILE therapy and 17
hours of insulin CRI and dextrose CRI which were slowly weaned. The
patient was discharged without long-term
complications7