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