Keeping a Pace on Diltiazem Toxicity With Bradycardia

Calcium channel blockers (CCBs) are frequently prescribed medications for both human and animal patients, and knowledge of how to treat a toxic exposure is critical for veterinarians. Learn from Erika Loftin, DVM, DACVECC, about symptoms, supportive therapies, and treatment options.

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A 12-year-old neutered male Chihuahua weighing 3.8 kg was presented for evaluation of weakness following suspected ingestion of any of a variety of medications, potentially including extended release diltiazem, ibuprofen, aspirin, trazodone, simvastatin, pramipexole, losartan and tamsulosin. On initial examination, the dog was noted to be hypothermic (rectal temperature was 93.8 degrees Fahrenheit) and severely bradycardic (heart rate was 38 beats per minute). His mucous membranes were light pink with a capillary refill time of less than two seconds. He was breathing spontaneously at 30 breaths per minute but was comatose. A doppler blood pressure could not be obtained. A lead II electrocardiogram (ECG) showed sinus bradycardia. Initial bloodwork (see Table 1 for values) revealed hyperlactatemia, elevated blood urea nitrogen (BUN) with a normal creatinine, mild hypermagnesemia and moderate hyperglycemia.

Due to the dog’s severe bradycardia and cardiovascular shock, diltiazem toxicity was determined to most likely be the reason for his clinical signs. His estimated ingested dose was approximately 47 mg/kg, well above the recommended therapeutic dose. An intravenous (IV) catheter was placed and the dog was administered a warm 80 mL Normosol-R bolus and atropine 0.054 mg IV for vagolytic effect with initial mild improvement of his heart rate to approximately 60 beats per minute. However, shortly thereafter, he again became severely bradycardic and suffered sinus arrest. Manual cardiac compressions were started and he was administered two sequential doses of 0.27 mg atropine IV, along with 200 mg calcium gluconate IV. He was also administered epinephrine 0.1 mg IV with return of spontaneous circulation noted.

Due to the severity of his clinical presentation, intravenous lipid therapy (Intralipid 20%) was started with a 5 mL slow IV bolus followed by an infusion at 0.1 mL/kg/min over 30 minutes. At the start of the infusion, his heart rate was noted to decrease and he once again entered sinus arrest. Cardiac compressions were started and atropine, epinephrine, calcium gluconate and crystalloid fluid boluses were repeated, and he was again noted to regain a spontaneous cardiac rhythm and respirations. An emergency blood panel was repeated 30 minutes post-admission (see Table 1) revealing a normal ionized calcium, progressive hyperglycemia, continued hyperlactatemia, and persistent elevations in BUN and ionized magnesium.

Following an additional dose of IV lipids, the dog had a sustained heart rate around 60 beats per minute with a doppler blood pressure of 60 mmHg. Bloodwork was repeated 60 minutes post-admission (see Table 1) with progressive hyperglycemia noted and nearly unchanged elevations in BUN and lactate. His heart rate was noted to decrease back to approximately 30 beats per minute, and transthoracic pacing was recommended. The dog was started on a fentanyl continuous rate infusion (CRI) at 5 mcg/kg/hr after a 5 mcg/kg bolus for analgesia given anticipated discomfort associated with transthoracic pacing. He was induced with propofol IV to effect, and intubated and maintained on a propofol CRI at 0.1 mg/kg/minute and 100 percent oxygen via his endotracheal tube. Transthoracic pacing pads were placed on either side of his thorax, and he was started on external pacing at 70 beats per minute using 30 milliamperes (mA) current initially, with adequate capture achieved.

The dog was hospitalized in the intensive care unit for continued aggressive therapy. Due to persistent hypotension (systolic 60 mmHg), his paced heart rate was increased to 80 beats per minute and the current was increased to 50 mA. He was started on Normosol-R at 10 mL/hr for volume support, as well as a dobutamine CRI which was titrated up to 7 mcg/kg/min. His pulse oximetry reading (SpO2) was noted to drop rather precipitously to around 85 to 88 percent, and temporary manual ventilation was started. A single dorsoventral radiograph was obtained, which revealed mild to moderate cardiac enlargement with no discrete evidence of heart failure and a region of pulmonary infiltrate in the left caudal lung lobe potentially consistent with atelectasis (with pneumonia or hemorrhage considered less likely). He was positioned in sternal recumbency to help promote respiratory excursions, with rapid improvement in his SpO2 and no further need for assisted ventilation. His blood pressure normalized to systolic 110 mmHg, and his other vitals remained stable during external pacing.

Repeat bloodwork 3.5 hours post-admission (Table 1) showed persistently lipemic serum, so further lipid therapy was not indicated. Additional results showed continued hyperglycemia, an improved lactate, a moderately elevated BUN, and a normal ionized calcium. A urinary catheter was placed for hygiene and urine output monitoring given prolonged hypoperfusion and possible nonsteroidal anti-inflammatory drug (NSAID) ingestion. Recumbent care was also performed, including ocular lubrication, rotation of body position and endotracheal tube adjustments. Poison control was contacted to discuss any additional recommendations, and they suggested use of an insulin and dextrose protocol to attempt to further ameliorate the diltiazem toxicity. The dog was administered regular insulin 1u intramuscularly (IM) initially. An insulin CRI was planned but could not be immediately instituted due to multiple concurrent infusions and lack of additional vascular access. Approximately five hours following initial presentation, the dog was noted to have a heart rate of 96 with spontaneous (non-paced) beats occurring. Transthoracic pacing was discontinued and the heart rate remained normal with no return of the previously noted severe bradycardia.

Later in the evening, an insulin CRI was started at 0.03 u/kg/hr and the dextrose CRI was titrated as needed up to 7.5 percent to maintain euglycemia. These infusions were discontinued after about four hours as the dog’s heart rate remained stable and hyperglycemia had resolved. Renal values and blood glucose normalized on sequential bloodwork. The dog remained hospitalized over the following three days for supportive therapies (including oxygen, gastroprotectants, analgesia and fluid diuresis due to potential NSAID exposure) and was then discharged home into the care of the owner. A follow-up phone call approximately three weeks later revealed that he was doing well with no apparent adverse effects from his toxicity.



Calcium channel blockers (CCBs) are frequently prescribed medications for both human and animal patients, and knowledge of how to treat a toxic exposure is critical for veterinarians. Calcium channels are physiologically essential for cardiac conduction, as well as contraction of both cardiac and smooth muscle tissue. Therapeutically, calcium channel blockers work by preventing activation of voltage sensitive calcium channels but have little to no effect on other types of calcium channels (stretch or receptor-operated channels). The currently available calcium channel blockers all have different clinical effects. For example, amlodipine (in the dihydropyridine class) has a significant effect on vascular smooth muscle tone but very little effect on cardiac condition or contraction. Because of this, amlodipine is therapeutically used to treat hypertension. In contrast, diltiazem (in the benzothiazepine class) has a much more pronounced effect on cardiac function and is typically used to treat supraventricular arrhythmias. The therapeutic dose of diltiazem in dogs is 0.5-1.5 mg/kg orally every eight hours. The lowest reported oral LD50 for diltiazem in dogs is 50 mg/kg. Sustained release products typically have a slower onset of action (within 4 to 12 hours) but a much longer duration, and this is further enhanced in overdose situations. One case report of a diltiazem overdose in a dog treated with temporary transvenous pacing showed an undetectable diltiazem serum level 48 hours post-ingestion3.

Within the cardiac conduction system, calcium channels are essential for allowing the initial action potential in the sinoatrial (SA) and atrioventricular (AV) nodes. In the presence of CCBs, this conduction slows, resulting in profound bradycardia. Within the myocytes, calcium channels allow initial influx of a small amount of calcium into the cytosol, which triggers release of a much larger amount of calcium, which then binds to troponin and leads to contraction of the myocyte. When CCBs prevent the initial influx of calcium, the force of myocardial contraction is reduced leading to decreased cardiac output. In vascular tissue, calcium channels allow an increase in cytosolic calcium levels, which directly leads to smooth muscle contraction and maintenance of vascular tone. In the presence of CCBs (particularly in toxic doses), there is loss of appropriate vascular tone and resulting hypotension. In addition to the above effects, CCBs lead to decreased release of insulin from the pancreas (due to blockage of calcium channels in the beta cells) and resulting hyperglycemia. Detection of significant hyperglycemia in a patient suspected of CCB toxicity can help confirm the diagnosis and potentially give insight into the severity of toxicity.

The diagnosis of diltiazem toxicity is typically made based on exposure history and physical examination showing profound bradycardia and hypotension. ECG changes can include sinus bradycardia, AV dissociation, variable heart block, junctional escape rhythms and asystole. Bloodwork can reveal hyperglycemia, metabolic acidosis and potentially azotemia secondary to decreased renal perfusion. Gastrointestinal signs, seizures and pulmonary edema have also been variably reported in both animal and human patients. The cause of the pulmonary edema is not entirely understood, but it may be due to an increase in pulmonary capillary permeability in combination with excessive fluid therapy to treat the hypotension, or alternatively to a massive surge in sympathetic output in response to vascular and cardiac collapse (leading to non-cardiogenic pulmonary edema).

Any diltiazem overdose should be taken very seriously, given the potentially lethal consequences. With recent ingestions, vomiting should be induced and activated charcoal administered. In patients already symptomatic, vomiting induction (or anesthesia for gastric lavage) is not recommended. As calcium channel blockers are extensively protein-bound, hemodialysis is not an effective decontamination method. However, diltiazem is lipid-soluble, and so intravenous lipid therapy is a viable decontamination method. The recommended protocol is to administer a 20% lipid emulsion as a 1.5 mL/kg IV bolus, followed by 0.25 mL/kg/min over 30 to 60 minutes. The treatment can be repeated as indicated based on clinical status, but once the patient’s serum is lipemic, it is likely that no further benefit will be achieved.

Fluid therapy with a balanced isotonic crystalloid should be used as needed to maintain hydration and to provide initial support for hypotension, but care should be taken not to volume overload patients who have inadequate cardiac output to handle a high fluid load. Placement of a central line and monitoring of central venous pressures (CVP) can help guide fluid needs in these patients. Hypoxemic patients should have thoracic radiographs performed to monitor for the presence of pulmonary edema. Atropine can be tried for treatment of bradycardia but is not typically effective. Likewise, use of a variety of catecholamines and vasopressor medications has been reported (including epinephrine, norepinephrine, dopamine, dobutamine and isoproterenol) without consistent benefit.

Other therapeutic strategies for CCB toxicity have been investigated, including calcium infusions, glucagon, a combination of high-dose insulin and dextrose, and temporary cardiac pacing. IV calcium is commonly given early in the course of CCB toxicity, and it is a medication that is readily available to most veterinarians. This causes an increase in the amount of calcium available to the cells and may be effective for some patients, but in most cases additional therapies will be required. The dose of 10% calcium gluconate is 0.5-1.5 mL/kg and should be given slowly over 10 to 15 minutes while monitoring for ECG changes. It can also be used as a CRI at a recommended dose of 10 mg/kg/hr, but the patient should be monitored carefully for hypercalcemia. Calcium chloride could also be used with caution, but it has been reported to cause tissue necrosis with any extravasation.

Glucagon is a hormone that has a variety of physiologic effects, but, in the setting of diltiazem toxicity, it appears to bind to specific cardiac receptors that are not affected by CCBs. This interaction leads to increased intracellular influx of calcium and an increase in cardiac contractility and conduction. Glucagon is readily available from human pharmacies but is extremely expensive. Experimentally recommended protocols include a 0.04-0.25 mg/kg IV bolus followed by a CRI of 0.04-9 mg/kg/hr, which reportedly results in variable and transient improvement in bradycardia but no significant improvement in hypotension. Glucagon can also exacerbate hyperglycemia due to insulin-antagonistic effects.

High-dose insulin and dextrose infusions have been recommended as an adjunct treatment due to the inhibitory effects of CCBs on the beta cells in the pancreas. In a normal resting state, myocytes use free fatty acids to provide metabolic energy. When calcium channels are blocked, myocytes become more dependent on glucose for fuel, which is inhibited in the presence of reduced insulin secretion. Insulin has also been shown to improve cardiac contractility independent of the effects on glucose. As regular (short-acting) insulin and dextrose are commonly available to veterinarians, this may be a very useful therapy for CCB toxicity. However, at the recommended doses (regular insulin 1 u/kg IV bolus, then 1-10 u/kg/hr CRI and 10-20% IV dextrose), hypoglycemia and electrolyte derangements are very real risks, as well as phlebitis from longer-term infusions of concentrated dextrose. Placement of a central line and very close monitoring of pertinent blood values (blood glucose every 5 to 10 minutes during initial therapy, then every 30 to 60 minutes) is essential. A recent case report in the Journal of Veterinary Emergency and Critical Care2 described a dog that ingested 79 mg/kg extended release diltiazem and developed clinical signs of progressive hypotension and atrial standstill. The dog was refractory to multiple attempted treatments including atropine, calcium, glucagon and dopamine, but the clinical signs improved within one hour of starting high-dose insulin and glucose therapy. High-dose insulin therapy is considered a first-line treatment for CCB and beta blocker toxicity in human patients.

In cases of severe CCB toxicity with minimal response to other therapies, temporary cardiac pacing is sometimes required to resolve the bradycardia and improve cardiac output. Depending on the resources available, pacemaker support can be via a transvenous or transthoracic approach. Transthoracic pacing is technically easier (pads are placed on both sides of the thorax and electrical impulse provided via a properly equipped defibrillator), but the process is very uncomfortable and the patient must be heavily sedated to tolerate it. With either type of temporary pacing, an external pulse generator is used to set the preferred heart rate, and the strength of the current adjusted as needed to achieve capture. This therapy will only alter the heart rate and will have no direct impact on the strength of cardiac contraction or on vascular tone, so ancillary therapies are typically still needed as described above. The patient should be monitored closely for increase in spontaneous heart rhythm that would indicate resolution of the CCB toxicity and an appropriate time to discontinue pacing support.


Table 1 – Sequential laboratory values



30 minutes

60 minutes

3.5 hours

Lactate (0.5-2.0 mmol/L)





Glucose (77-125 g/dL)





BUN (7-27 mg/dL)





Creatinine (0.5-1.8 mg/dL)





Ionized calcium

(1.12-1.42 mmol/L)





Ionized magnesium

(0.44-0.58 mmol/L)





Packed cell volume/total solids (PCV/TS)



37/4.0, lipemic

34/5.0, lipemic



  1. Costello M, Syring RS. Calcium channel blocker toxicity. J Vet Emerg Crit Care 2008;18(1):54-60.
  2. 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 2013;23(3):321-327.
  3. Syring RS, Costello MF, Poppenga RH. Temporary transvenous cardiac pacing in a dog with diltiazem intoxication. J Vet Emerg Crit Care 2008;18(1):75-80.

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