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