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\begin{document}

\title{Hyperinsulinemia/euglycemia therapy (HIET) for the management of severe
amlodipine toxicosis in a cat}



\author[1]{Audrey Tinsman}%
\author[2]{Tara Bellis}%
\affil[1]{Bluepearl Veterinary Partners}%
\affil[2]{BluePearl Veterinary Specialists}%


\vspace{-1em}



  
  \date{June 07, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Calcium channel blocker overdose is encountered in human and veterinary
medicine. At toxic levels these medications alter glucose metabolism,
vascular tone, and cardiac function. Hyperinsulinemia/euglycemia therapy
is a cardioprotective treatment used in human medicine, but rarely
documented in veterinary medicine. This is the first report of HIET in a
cat.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Calcium-channel blockers (CCBs) have been used for over 40 years in
veterinary medicine as both anti-hypertensive and anti-arrhythmic
medications\textsuperscript{1}. 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 muscle\textsuperscript{1}.
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
reticulum\textsuperscript{2}. 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 vessels\textsuperscript{3}. Other
tissues affected by CCBs include the pancreas, pulmonary parenchyma, and
central nervous system\textsuperscript{1}. Blockade of L-type calcium
channels in the pancreas causes decreased insulin release by the \selectlanguage{greek}β-\selectlanguage{english}islet
cells and restricts tissue uptake of glucose by altering sensitivity to
insulin\textsuperscript{1}. 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
dysfunction\textsuperscript{4}.

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 seizures\textsuperscript{1}. 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
pacing\textsuperscript{1}.

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 infusion\textsuperscript{6}.
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 handling\textsuperscript{2}. Additional benefits of
HIET include increased cyclic AMP levels through phosphodiesterase III
inhibition, resulting in increased calcium influx\textsuperscript{6}.
There is evidence that HIET increases endothelial nitric oxide synthase
(eNOS) activity which in turn decreases capillary resistance and
improves overall tissue perfusion\textsuperscript{5}. 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
toxicosis\textsuperscript{7}. To the authors' knowledge this is the
first case report describing the use of HIET for the treatment of CCB
toxicosis in a cat.

\textbf{Case summary}

A 15-year-old female spayed Siamese cat presented for amlodipine
toxicosis. Two months prior, the cat was treated by her primary
veterinarian for a urinary tract infection and diagnosed with
hypertension. She was started on telmisartan 6.5mg PO q24h (Semintra,
Boehringer Ingelheim Vetmedica, Inc., St. Joseph, MO) and transitioned
onto amlodipine 2 weeks prior to hospitalization. For the 5 days leading
up to presentation the cat received 2.5mg instead of 0.625mg per os
every 24 hours. The cat had known pre-existing renal disease which was
managed with a prescription diet and stool softener (Miralax, Bayer
Healthcare LLC, Whippany, NJ; 1/8tsp per os ever 12 hours).

The cat presented to the authors' hospital for decreased appetite and
water intake for 24 hours and lethargy for several days. The owner
reported a single episode of vomiting the night before. Amlodipine was
last given that morning. Upon presentation (day one), the cat was
dehydrated with a prolonged skin tent and weak femoral pulses. She had a
decreased axillary temperature (35.5\selectlanguage{ngerman}°C;
38.1-39.2°C)\textsuperscript{8}and borderline bradycardia (160 beats per
minute). She was weakly ambulatory and quiet. Systolic blood pressure
(SBP) as measured by Doppler ultrasonography (Doppler flow detector
model 811-B, Parks Medical Electronics) was low at 70mmHg
(110-132mHg)\textsuperscript{9}. An intravenous (IV) catheter was
placed, and a minimum database was performed, which identified mild
anemia and hyperproteinemia (see Table 1). Spot blood glucose (sBG),
(AlphaTRAK 2, Abbott Animal Health, Abbott Park, IL) was high at
14.37mmol;/L (259mg/dl; RI {[}3.72-9.32mmol/L{]})\textsuperscript{10}. A
venous blood gas (vBG; RAPIDPoint 500 System, Siemens Healthineers,
Malvern, PA) revealed a metabolic acidosis with hyperlactatemia (see
Table 1). A chemistry panel (Catalyst One, IDEXX Laboratories Inc,
Westbrook, ME) revealed azotemia and hyperamylasemia (see Table 2). A
10ml/kg IV crystalloid bolus of LRS (Lactated Ringer's Solution; Dechra
Veterinary Products, Overland Park, KS) was administered. Systolic BP
improved to 92mmHg. A 90mg/kg calcium gluconate (Calcium Gluconate
Injection USP 100mg per mL, HF Acquisition Co LLC, DBA HealthFirst)
bolus diluted 1:1 with NaCl 0.9\% (0.9\% Sodium Chloride Injection USP,
B.Braun Medical, Irvine, CA) was given intravenously over 20 minutes.
The cat was started on intravenous fluid therapy with NaCl 0.9\% and was
administered maropitant citrate (Cerenia 10mg/ml, Zoetis Inc, Kalamazoo,
MI; 1 mg/kg IV q24h).

The following morning (day 2), the cat was transferred to the Critical
Care service. Systolic blood pressure was 80mmHg and rectal temperature
was 32.9°C (38.1-39.2°C)\textsuperscript{8}. Repeat bloodwork revealed
persistent hyperglycemia with a sBG of 23.87mmol/L (430mg/dl; RI
{[}3.72-9.32{]})\textsuperscript{10}. Serum ketones were negative
(Precision Xtra, Abbott Animal Health, Abbott Park, IL). A vBG showed a
worsening metabolic acidosis with improving hyperlactatemia (see Table
1). A CBC (Procyte Dx Hematology Analyzer, IDEXX Laboratories Inc,
Westbrook, ME) showed a non-regenerative anemia and neutrophilia (see
Table 2). One unit (1U) regular insulin (HumulinR, Lilly USA LLC,
Indianapolis, IN) was administered IV. Two further doses (90mg/kg and
150mg/kg respectively) of calcium gluconate diluted 1:1 with NaCl 0.9\%
were given IV. Bradycardia worsened to 90 beats per minute and a single
dose of atropine sulfate (Atropine Sulfate Injection 1/120 Grain,
Med-Pharmex, Pomona, CA) 0.04mg/kg IV was given with no effect. A
calcium gluconate continuous rate infusion (CRI) was started at
0.05mcg/kg/h. Bradycardia persisted and an electrocardiogram (cECG;
MD9000vet, Meditech Equipment Co., Ltd) identified intermittent absence
of P-waves. A point-of-care thoracic ultrasound showed scant pleural
effusion and markedly decreased cardiac contractility. Intravenous fluid
therapy was discontinued and a dobutamine CRI (2.5-3.75mcg/kg/min;
DOBUTamine Injection USP, Hospira Inc., Lake Forrest IL) was started;
calcium gluconate was discontinued. Intralipid emulsion therapy (ILE;
Intralipid 20\% Baxter Healthcare Corporation, Deerfield, IL) was
administered: 0.5mls/kg IV bolus followed by 0.25mls/kg/min for 1 hour.
Hypothermia worsened to 33.2°C (38.1-39.2°C)\textsuperscript{8} despite
heat support and the cat's mentation deteriorated to dull. Serial vBGs
showed a worsening metabolic acidosis and hypokalemia (see Table 1).
Crystalloid fluid therapy was restarted at a rate of 5 ml/hr with
potassium supplementation (Potassium Chloride injection 2mEq/ml, Hospira
Inc Lake Forest, IL) at 80 meq/L. High-dose insulin/euglycemia therapy
(HIET) was initiated with a bolus of 1U/kg IV regular insulin and a
bolus of 1g/kg dextrose (50\% dextrose injection, USP 25g/50ml Hospira
Inc., Lake Forest IL) IV followed by a regular insulin CRI at 1U/kg/h
for the first hour with a rate decrease to 0.5 U/kg/h as of the second
hour. A 5\% dextrose CRI was administered concurrently. Within 5-10
minutes of starting HIET, there was a notable improvement in the
patient's blood pressure, heart rate and temperature. After 2 hours of
therapy, blood pressure was 112 mmHg, heart rate was 140 beats per
minute with normal sinus rhythm, and temperature was 36.7°C. Serum
potassium increased (see Table 1) and potassium supplementation was
decreased from 80 to 60mEq/L. Hypoglycemia (BG \textless{}3.72mmol/L)
was identified five times during HIET; and was treated with intermittent
dextrose boluses (0.5 g/kg IV) and an increase in dextrose
supplementation to 7.5\%. Insulin therapy was discontinued after
approximately 3 hours due to persistent hypoglycemia. At that time the
cat was ambulatory and interactive. Point-of-care ultrasound showed a
marked improvement in cardiac contractility. Overnight dextrose
supplementation was decreased then discontinued as euglycemia was
maintained. Crystalloid fluids were continued at 5 mls/hr with 60 mEq
KCl/L supplementation. Temperature normalized and heat support was
discontinued. Heart rate remained \textgreater{} 150 beats per minute
and blood pressure remained between 90 mmHg and 132 mmHg on a dobutamine
CRI at 3.75mcg/kg/min.

Early the next day (Day 3), the cat became hypotensive with a decrease
in SBP to 80 mmHg. A CRI of norepinephrine (Levophed TM, Norepinephrine
Bitartrate Injection USP, Hospira Inc., Lake Forest, IL) was started at
0.1mcg/kg/min and titrated up to 0.2mcg/kg/min. Mild respiratory effort
was noted and oxygen therapy at FiO2 0.4 (Snyder MFG.CO Intensive Care
Unit) was provided. Point-of-care ultrasound revealed an increase in the
volume of pleural effusion. Based on progression of clinical signs and
financial constraints, the owners elected humane euthanasia.

\textbf{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
ingestion\textsuperscript{10}. Amlodipine has the highest
bioavailability and volume of distribution in its
class\textsuperscript{11}, 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 cat\textsuperscript{1}. 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 CCB\textsuperscript{1}. 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
2017\textsuperscript{1}. The clearance of CCBs is likely prolonged in
disease states such as congestive heart failure, cardiomyopathy, or
hypotensive overdose which result in altered hepatic
perfusion\textsuperscript{12}. Standard dosage is typically 0.625-1.25mg
per cat\textsuperscript{8}. 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\%\textsuperscript{13}.

Decontamination and limitation of toxin absorption is the first line of
treatment if ingestion occurred within 2 hours of
presentation\textsuperscript{1}. 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
contents\textsuperscript{1}. Calcium gluconate is recommended to
overcome inhibited calcium channels and promote inotropy, but response
to treatment is inconsistent in severe intoxications\textsuperscript{5}.
An exact dose of calcium is not described but a CRI titratable to a
desirable blood pressure and heart rate has been
suggested\textsuperscript{10}. 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 transient\textsuperscript{2}. Furthermore, the resulting
increase in myocardial oxygen demand can lead to myocardial injury when
systemic and coronary hypotension are present\textsuperscript{14}.
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
beds\textsuperscript{5}. Treatment with adrenergic drugs may yield a
poor response in patients with moderate to severe
overdoses\textsuperscript{10}. Glucagon is a pancreatic peptide and
cardiac inotrope\textsuperscript{1}. It increases cardiac output, lowers
pulmonary arterial pressure, and pulmonary vascular resistance without
any systemic vascular effects\textsuperscript{15}. 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 observed\textsuperscript{10}. 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
solubility\textsuperscript{16}, including CCBs\textsuperscript{7}. 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 chylomicrons\textsuperscript{16}. 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 substrate\textsuperscript{16}. Furthermore, long
chain fatty acids may activate myocyte calcium channels resulting in
increased calcium influx\textsuperscript{16}. The inhibition of
amlodipine-induced cardiomyoblast apoptosis using ILE has been
demonstrated in a murine model\textsuperscript{17}. 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 infusion\textsuperscript{16}. 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)
vasodilation\textsuperscript{5}. High-dose insulin increases coronary
blood flow without increasing oxygen demands, contrary to
catecholamines\textsuperscript{6}\emph{.} Insulin also increases eNOS
activity leading to systemic, coronary, and pulmonary
vasodilation\textsuperscript{5}. 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
output\textsuperscript{5}. 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 effects\textsuperscript{5}.

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 flow\textsuperscript{18}. 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 groups\textsuperscript{15}.
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 consumption\textsuperscript{19}. 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 channels\textsuperscript{20}. Two experimental porcine models
evaluated the use of vasopressors and HIET in propranolol-induced
cardiogenic shock\textsuperscript{21,22}. 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 output\textsuperscript{21}. The authors concluded that higher
insulin doses may be required in the presence of vasopressors to
overcome increased SVR and decreased cardiac output\textsuperscript{21}.
The second study found that patients treated with norepinephrine after
maximizing high-dose insulin therapy had improved brain tissue
oxygenation compared to HIET alone\textsuperscript{22} and that patients
with profound hypotension (\textless{}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
complications\textsuperscript{7}

\textbf{Conclusion}

In the cat reported here, a notable response to HIET was appreciated as
evidenced by an increase in temperature, heart rate, blood pressure and
contractility within 15 minutes of initiating therapy. The dosing
recommendation for animals is a 1 U/kg insulin bolus followed by a
1U/kg/h CRI for 1 hour, followed by 0.5 U/kg/hr until resolution of
clinical signs\textsuperscript{10} . There is no set protocol for timing
of discontinuation of HIET, however the goal of therapy is hemodynamic
stability. Based on previous reports and human guidelines, prolonged
therapy may be needed. The primary complications associated with HIET
are hypoglycemia and hypokalemia; both of which can be anticipated,
monitored and addressed. The initiation of vasopressor therapy in the
context of amlodipine toxicosis should be approached with caution and
considered after initiation and optimization of HIET. The authors also
recommend monitoring of magnesium and phosphorus, which have a complex
interplay with insulin and are vital for myocardial cellular activity.
The wide availability of insulin and dextrose, low expense, and minimal
adverse event profile make HIET an attractive therapeutic option for CCB
toxicosis. Although the outcome was unsatisfactory in this case, the
authors feel that the response to HIET supports the use of this therapy
in cats with CCB toxicosis.

1. Hayes CL. An Update on Calcium Channel Blocker Toxicity in Dogs and
Cats. \emph{Vet Clin North Am Small Anim Pract} . 2018;48(6):943-957.

2. Kittleson, Mark D K Richard D. \emph{Small Animal Cardiovascular
Medicine} .

3. Costello M, Syring RS. Calcium channel blocker toxicity. \emph{J Vet
Emerg Crit Care} . 2008;18(1):54-60.

4. Depre Christophe, Vanoverschelde Jean-Louis J., Taegtmeyer Heinrich.
Glucose for the Heart. \emph{Circulation} . 1999;99(4):578-588.

5. Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin
therapy in beta-blocker and calcium channel-blocker poisoning.\emph{Clin
Toxicol Phila Pa} . 2011;49(4):277-283.

6. Lheureux PE, Zahir S, Gris M, Derrey A-S, Penaloza A.
Bench-to-bedside review: Hyperinsulinaemia/euglycaemia therapy in the
management of overdose of calcium-channel blockers. \emph{Crit Care} .
2006;10(3):212.

7. 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. \emph{J Vet Emerg Crit Care San
Antonio Tex 2001} . 2013;23(3):321-327.

8. Kahn CM, ed. \emph{The Merck Veterinary Manual} . 9. Aufl. Merck;
2005.

9. Payne JR, Brodbelt DC, Luis Fuentes V. Blood Pressure Measurements in
780 Apparently Healthy Cats. \emph{J Vet Intern Med} . 2017;31(1):15-21.

10. Silverstein DC, Hopper K, eds. \emph{Small Animal Critical Care
Medicine} . 2. ed. Saunders, Elsevier; 2015.

11. Stopher DA, Beresford AP, Macrae PV, Humphrey MJ. The metabolism and
pharmacokinetics of amlodipine in humans and animals. \emph{J Cardiovasc
Pharmacol} . 1988;12 Suppl 7:S55-59.

12. Holder T. Calcium channel blocker toxicosis. :4.

13. Zahed N-S, Hassanian-Moghaddam H, Zamani N. A Fatal Case of
Amlodipine Toxicity Following Iatrogenic Hypercalcemia. \emph{Cardiovasc
Toxicol} . 2018;18(3):290-293.

14. Monteiro ER, Campagnol D, Parrilha LR, Furlan LZ. Evaluation of
cardiorespiratory effects of combinations of dexmedetomidine and
atropine in cats. \emph{J Feline Med Surg} . 2009;11(10):783-792.

15. Kerns W, Schroeder D, Williams C, Tomaszewski C, Raymond R. Insulin
Improves Survival in a Canine Model of Acute \selectlanguage{greek}β-\selectlanguage{english}Blocker
Toxicity.\emph{Ann Emerg Med} . 1997;29(6):748-757.

16. Fernandez AL, Lee JA, Rahilly L, Hovda L, Brutlag AG, Engebretsen K.
The use of intravenous lipid emulsion as an antidote in veterinary
toxicology. \emph{J Vet Emerg Crit Care} . 2011;21(4):309-320.

17. Ok S-H, Ahn SH, Kim H-J, et al. Lipid emulsion attenuates extrinsic
apoptosis induced by amlodipine toxicity in rat
cardiomyoblasts.\emph{Hum Exp Toxicol} . Published online October 8,
2020:960327120964551.

18. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a
superior antidote for cardiovascular toxicity induced by verapamil in
the anesthetized canine. \emph{J Pharmacol Exp Ther} .
1993;267(2):744-750.

19. Krukenkamp I, S\selectlanguage{ngerman}ørlie D, Silverman N, Pridjian A, Levitsky S. Direct
effect of high-dose insulin on the depressed heart after beta-blockade
or ischemia. \emph{Thorac Cardiovasc Surg} . 1986;34(5):305-309.

20. Woodward C, Pourmand A, Mazer-Amirshahi M. High dose insulin
therapy, an evidence based approach to beta blocker/calcium channel
blocker toxicity. \emph{DARU J Pharm Sci} . 2014;22(1):36.

21. Holger JS, Engebretsen KM, Fritzlar SJ, Patten LC, Harris CR,
Flottemesch TJ. Insulin versus vasopressin and epinephrine to treat
\selectlanguage{greek}β-\selectlanguage{english}blocker toxicity. \emph{Clin Toxicol} . 2007;45(4):396-401.

22. Katzung KG, Leroy JM, Boley SP, Stellpflug SJ, Holger JS,
Engebretsen KM. A randomized controlled study comparing high-dose
insulin to vasopressors or combination therapy in a porcine model of
refractory propranolol-induced cardiogenic shock. \emph{Clin Toxicol} .
2019;57(11):1073-1079.

23. Lindeman E, \selectlanguage{ngerman}Ålebring J, Johansson A, Ahlner J, Kugelberg FC,
Nordmark Grass J. The unknown known: non-cardiogenic pulmonary edema in
amlodipine poisoning, a cohort study. \emph{Clin Toxicol Phila Pa} .
2020;58(11):1042-1049.

24. Paige CF, Abbott JA, Elvinger F, Pyle RL. Prevalence of
cardiomyopathy in apparently healthy cats. \emph{J Am Vet Med Assoc} .
2009;234(11):1398-1403.

25. Bachmann K, Kutter AP, Schefer RJ, Marly-Voquer C, Sigrist N.
Determination of reference intervals and comparison of venous blood gas
parameters using standard and non-standard collection methods in 24
cats. \emph{J Feline Med Surg} . 2017;19(8):831-840.

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