On the morning of the third day of hospitalization, blood pressure had improved to 110 mm Hg and the norepinephrine CRI was able to be discontinued. A hypoglycemic seizure occurred approximately 22 hours after initiation of HIET, with a blood glucose of 34 (Table 1, hour 36). The seizure was terminated with the administration of a 0.5 ml/kg 50% dextrose (VetOne) bolus diluted 1:1 with 0.9% saline (Vetivex; Dechra Pharmaceuticals). Due to the continued improvement in electrolyte abnormalities on serial blood gas analysis as well as the hypoglycemic seizure, the decision was made to discontinue the insulin CRI and wean the dextrose solution. This was accomplished over the following 4 hours as the dog rapidly became hyperglycemic. At discontinuation, the dog’s weight had decreased to 15.3 kg from 16.2 kg approximately 24 hours prior. Due to the persistent tachypnea and B-lines on point of care ultrasound, a 6-hour furosemide (Salix; Merck Animal Health) CRI at 0.5 mg/kg/hr was initiated, followed by bolus therapy at 1 mg/kg IV q6. An echocardiogram after completion of the CRI revealed no evidence of structural heart disease or congestive heart failure, and the observed fluid intolerance was believed to be most likely secondary to the bradycardia and hypotension associated with amlodipine toxicity.
The dog was hospitalized for 3 additional days and continued to improve daily. Furosemide was discontinued on the 4th day of hospitalization, and supplemental oxygen was discontinued on the 5th day of hospitalization. Capromorelin (Entyce®, Elanco) was instituted on the 5th day of hospitalization due to mild intermittent hyporexia, with improvement in appetite observed afterwards, avoiding nasogastric tube placement. The dog was discharged on day 6 with near complete resolution of biochemical abnormalities, and oral capromorelin (Entyce®, Elanco) for ongoing hyporexia. Follow up after approximately 9 months revealed that the dog was doing well with no reported long-term adverse effects, although no repeated bloodwork was available for review.
Discussion
To the authors’ knowledge, this is the first case report describing the use of HIET therapy to treat amlodipine toxicosis in a dog. As reported in the human literature, this case report suggests that HIET is an effective means of controlling the cardiovascular collapse associated with amlodipine toxicosis in the dog. Current dosing of HIET has as of yet not been well defined in human literature, with recommendations for initial dose ranging from 0.3-1.0 U/kg/hr in various reports and a generally acknowledged ceiling of 10 U/kg/hr, although a report of a dose of 21.8 U/kg/hr secondary to an administration error was tolerated by the patient and led to survival to discharge18,19. Similarly, response times are variable. One report identified improvements in blood pressure approximately 30 minutes after starting HIET, but other reports have shown times up to four hours7,10,18. As the decision to initiate HIET in this dog was based on the azotemia and fluid intolerance noted on the morning of the second day of hospitalization as opposed to refractory hypotension as previously described in canine patients, response to therapy is harder to define, especially given the dog’s development of hypotension during therapy14. However, as noted by serial blood gas analysis, the azotemia and lactate concentrations improved during HIET, suggestive of improved cardiac output. Similarly, the dog experienced a reduction in weight on HIET, suggestive of mobilization of previously administered fluids. In this sense, the authors’ goals for usage of HIET are in line with a human toxicology group recommending the use of HIET to maintain cardiac output and tissue perfusion as defined by clinical parameters such as mental status and urinary output as opposed to a target MAP20. The dog’s development of hypotension is unexpected but may be reflective of an ineffective insulin dose, and more aggressive titration may be required. However, insulin has also been shown to enhance the expression of endothelial nitric oxide synthase causing vasodilation, and it is not uncommon for patients with CCB toxicosis to still require vasoactive medications18,21. Indications for discontinuation of HIET are also not well defined, but generally the recommendation is to discontinue once the patient is hemodynamically stable18. This factored into the decision to discontinue HIET in this dog, as HIET was discontinued when the patient was normotensive without norepinephrine; although part of the reason for discontinuation was the development of a hypoglycemic seizure.
The dog also experienced several less frequently identified adverse effects from the amlodipine overdose, including the development of hyponatremia, pleural effusion, and suspected non-cardiogenic pulmonary edema, but was able to make a full recovery. Due to the atypical clinical presentation, other differentials such as congenital or acquired cardiac disease were considered, but with a structurally normal heart and a drug bottle visibly damaged by teeth, amlodipine toxicosis was considered most likely. The remainder of the dog’s clinical and laboratory findings, such as hyperglycemia, mild ionized hypercalcemia, and hypotension, are associated with CCB toxicosis9. Hyponatremia has previously been reported to be associated with HIET in humans, but the development of hyponatremia preceded HIET in this case22. CCBs are natriuretic, with increased tubular excretion and inhibition of sodium reabsorption6. While the dog’s azotemia and hyperkalemia are not commonly associated with CCB toxicosis, they have been previously reported, likely secondary to prolonged hypotension and decreased renal perfusion6. Pleural effusion has been previously reported in association with amlodipine toxicosis at levels thought to be therapeutic, although the mechanism is unknown, and right sided heart failure secondary to a concomitant decrease in systolic function associated with CCB toxicosis cannot be ruled out5. While financial constraints prevented full evaluation of the extent of the dog’s pulmonary disease with radiographs, based on response to therapy and echocardiographic assessment, it is most likely that the dog’s respiratory changes were purely secondary to relative volume overload and decreased cardiac output associated with amlodipine toxicosis.
While relatively novel in veterinary medicine, HIET has the potential to significantly improve patient outcomes. In human medicine, published fatality rates for amlodipine toxicosis range from 38-50%11,23,24. Given the significant improvement in cardiovascular status associated with HIET therapy in the literature, it should be part of the standard of care for canine patients unresponsive to traditional therapeutic interventions or those patients who present with profound clinical signs18,20. The decision for a gradual increase in the insulin dose was made empirically to balance the potential for adverse effects of hyperinsulinemia with the improved cardiovascular status; however, this dog may have benefitted from more aggressive therapy. Therefore, the authors recommend initiating insulin at 0.3 U/kg/hr with titration up to 1 U/kg/hr as needed for improvement of hemodynamic status, which has been previously described in dogs14. Additionally, due to concern for the dog’s fluid intolerance, dextrose support was achieved using lower fluid rates but higher concentrations of dextrose, which may have predisposed to the development of hypoglycemia. The decision to use a continuous interstitial glucose monitor (FreeStyle Libre 2, Abbott) was made to ease technical demands during therapy but may have contributed to delayed recognition of the patient’s hypoglycemia and subsequent seizure. While frequently used for critically ill patients in human and veterinary medicine, continuous interstitial glucose monitors have a lag time of 15-20 minutes, and may not be the best choice for monitoring in patients receiving HIET25,26. Hypoglycemia was the primary indication for discontinuation of HIET in another veterinary case report15. As such, the authors recommend blood glucose monitoring during therapy on at least an hourly basis with consideration for repeated checking sooner after adjustments in insulin dosage, in line with human recommendations12,13,18.
Conclusion
This case report describes the use of HIET to treat cardiovascular abnormalities associated with amlodipine toxicosis. While the strongest indication for HIET is refractory hypotension in the presence of CCB toxicosis, this case shows that other adverse effects of CCB toxicosis may also show improvement due to the increased cardiovascular support provided by HIET.
Recommendations for the use of HIET for amlodipine toxicosis exist in both human and veterinary literature, but there are no currently published dose recommendations in the veterinary literature. This case describes the successful deployment of a protocol for HIET in dogs affected by amlodipine toxicosis. While potential complications may occur, HIET is an effective treatment for amlodipine toxicosis, and should be considered as first line therapy in patients with cardiovascular collapse or other severe adverse effects refractory to conventional therapy. Clinical trials are necessary to further evaluate the benefits of HIET, and further investigation into the optimal dosing and monitoring strategy for HIET is necessary to help minimize the risk of associated complications.
CRediT authorship statement:
Connor Ellis: Writing – original draft
Adesola Odunayo: Writing – review and editing, supervision
References
1.    Atkins CE. Digitalis, Positive Inotropes, and Vasodilators. In: Papich MG, Riviere JE, eds. Veterinary Pharmacology and Therapeutics. Wiley Blackwell; 2018:503-536.
2.    Burges R, Moisey D. Unique pharmacologic properties of amlodipine. Am J Cardiol. 1994;73(3):2A-9A. doi:10.1016/0002-9149(94)90268-2
3.    Thomason JD, Fallaw TL, Carmichael KP, Radlinsky MA, Calvert CA. Gingival hyperplasia associated with the administration of amlodipine to dogs with degenerative valvular disease (2004-2008). J Vet Intern Med. 2009;23(1):39-42. doi:10.1111/j.1939-1676.2008.0212.x
4.    Creevy KE, Scuderi MA, Ellis AE. Generalised peripheral oedema associated with amlodipine therapy in two dogs. J Small Anim Pract. 2013;54(11):601-604. doi:10.1111/jsap.12104
5.    Jang H-W, Park S-M, Hwang S-Y, et al. Unusual case of pleural effusion caused by amlodipine in a dog with systemic hypertension. Vet Med Sci. 2022;8(2):445-449. doi:10.1002/vms3.727
6.    Hayes CL. An update on calcium channel blocker toxicity in dogs and cats.Vet Clin North Am Small Anim Pract. 2018;48(6):943-957. doi:10.1016/j.cvsm.2018.06.002
7.    St-Onge M, Dubé PA, Gosselin S, et al. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014;52(9):926-944. doi:10.3109/15563650.2014.965827
8.    Rietjens SJ, de Lange DW, Donker DW, Meulenbelt J. Practical recommendations for calcium channel antagonist poisoning. Neth J Med. 2016;74(2):60-67.
9.    Wright AM, King LG. Calcium Channel Blocker and β-Blocker Drug Overdose. In: Silverstein DC, Hopper K, eds. Small Animal Critical Care Medicine. 2nd ed. W. B. Saunders; 2015:407-414.
10.   Azendour H, Belyamani L, Atmani M, Balkhi H, Haimeur C. Severe amlodipine intoxication treated by hyperinsulinemia euglycemia therapy. J Emerg Med. 2010;38(1):33-35. doi:10.1016/j.jemermed.2007.11.077
11.   Koliastasis L, Lampadakis I, Milkas A, et al. Refractory Shock from Amlodipine Overdose Overcomed with Hyperinsulinemia. Cardiovasc Toxicol. 2022;22(1):63-66. doi:10.1007/s12012-021-09699-2
12.   Kumar K, Biyyam M, Bajantri B, Nayudu S. Critical management of severe hypotension caused by amlodipine toxicity managed with hyperinsulinemia/euglycemia therapy supplemented with calcium gluconate, intravenous glucagon and other vasopressor support: review of literature. Cardiol Res. 2018;9(1):46-49. doi:10.14740/cr646w
13.   Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011;49(4):277-283. doi:10.3109/15563650.2011.582471
14.   Maton BL, Simmonds EE, Lee JA, Alwood AJ. The use of high-dose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem toxicosis in a dog. J Vet Emerg Crit Care (San Antonio). 2013;23(3):321-327. doi:10.1111/vec.12053
15.   Tinsman AE, Bellis TJ. Hyperinsulinemia/euglycemia and intravenous lipid emulsion therapy for the management of severe amlodipine toxicosis in a cat.Clin Case Rep. 2021;9(12):e05175. doi:10.1002/ccr3.5175
16.   Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther. 1993;267(2):744-750.
17.   Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med. 1995;23(7):1251-1263.
18.   Krenz JR, Kaakeh Y. An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and β-blocker Overdose. Pharmacotherapy. 2018;38(11):1130-1142. doi:10.1002/phar.2177
19.   Stellpflug SJ, Harris CR, Engebretsen KM, Cole JB, Holger JS. Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. Clin Toxicol (Phila). 2010;48(3):227-229. doi:10.3109/15563650903555294
20.   Holger JS, Stellpflug SJ, Cole JB, Harris CR, Engebretsen KM. High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clin Toxicol (Phila). 2011;49(7):653-658. doi:10.3109/15563650.2011.593522
21.   Fisslthaler B, Benzing T, Busse R, Fleming I. Insulin enhances the expression of the endothelial nitric oxide synthase in native endothelial cells: a dual role for Akt and AP-1. Nitric Oxide. 2003;8(4):253-261. doi:10.1016/s1089-8603(03)00042-9
22.   Beavers JR, Stollings JL, Rice TW. Hyponatremia induced by hyperinsulinemia-euglycemia therapy. Am J Health Syst Pharm. 2017;74(14):1062-1066. doi:10.2146/ajhp160262
23.   Connor-Schuler RL, Carr JM, Reaven MS, Bridgman BT, Patel DM, Subramanian RM. The efficacy of albumin dialysis in the reversal of refractory vasoplegic shock due to amlodipine toxicity. Crit Care Explor. 2020;2(6):e0120. doi:10.1097/CCE.0000000000000120
24.   Warrick BJ, Tataru AP, Smolinske S. A systematic analysis of methylene blue for drug-induced shock. Clin Toxicol (Phila). 2016;54(7):547-555. doi:10.1080/15563650.2016.1180390
25.   Chen C, Zhao X-L, Li Z-H, Zhu Z-G, Qian S-H, Flewitt AJ. Current and emerging technology for continuous glucose monitoring. Sensors. 2017;17(1). doi:10.3390/s17010182
26.   Silva DD, Cecci GRM, Biz G, Chiaro FN, Zanutto MS. Evaluation of a flash glucose monitoring system in dogs with diabetic ketoacidosis. Domest Anim Endocrinol. 2021;74:106525. doi:10.1016/j.domaniend.2020.106525