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Cardiovascular Anesthesiology: Case Report

Treatment of Serious Calcium Channel Blocker Overdose With Levosimendan, a Calcium Sensitizer

Varpula, Tero MD, PhD*; Rapola, Janne MD, PhD; Sallisalmi, Marko MD; Kurola, Jouni MD, PhD§

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doi: 10.1213/ane.0b013e3181931737
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Severe calcium channel blocker (CCB) overdose has a high mortality rate.1 More than one third of deaths from cardiovascular drug overdose are related to CCBs.2 Overdose of CCBs causes cardiovascular depression, which is often refractory to standard resuscitation methods. Therapy in severe intoxication includes high doses of catecholamines, glucagon and measures to inhibit further ingestion and absorption of the drug.3,4 Ventricular pacing is often needed because of severe bradycardia, but problems with pacing capture are common. Mechanical support of the circulation with intraaortic balloon pulsation (IABP) or extracorporeal circulation have also been reported.4,5

A new inotropic drug, levosimendan, has pharmacological properties which, in theory, could be beneficial in treating the hemodynamic compromise of severe CCB overdose. Levosimendan is a calcium sensitizer and its mechanism differs from other inotropes. Levosimendan enhances cardiac contraction by improving the use of available cytosolic calcium, rather than by flooding the cell with excessive calcium.6,7 To our knowledge, its use in CCB overdose has not been reported. We report two cases in which cardiovascular collapse after massive CCB overdose were successfully treated with levosimendan together with traditional treatment measures.


Patient 1

Paramedics were called for a 47-yr-old female who had taken 16 g of verapamil 1 h previously. Her mean arterial blood pressure (MAP) was 160/100 mm Hg and heart rate 100 bpm. She was given 50 g of activated charcoal solution orally and an IV infusion was initiated. Because of severe overdose, the patient was directly admitted to the intensive care unit. Upon arrival 30 min later, she was unconscious, her MAP was not measurable, but a carotid pulse was palpable. Her heart rate was 50 bpm in sinus rhythm and oxygen saturation was 99%. Norepinephrine (NE) infusion of 0.2 μg · kg−1 · min−1 was initiated and calcium (4 g) and atropine boluses (2 mg) were given. An arterial catheter was inserted and a MAP of 65/40 mm Hg was measured. Fifteen minutes after arrival, the patient convulsed and went pulseless. She was tracheally intubated and resuscitation was begun. Her primary rhythm was a slow idioventricular rhythm and after few minutes she went into asystole. Calcium (2 g every 30 min), glucagon (5 mg), and epinephrine-boluses (0.5-1 mg) were given, and a ventricular pacing lead was inserted via the internal jugular vein during continuous resuscitation. With ventricular pacing, circulation was achieved within 10 min. NE infusion was increased to 1 μg · kg−1 · min−1 and epinephrine infusion with an infusion rate up to 0.26 μg · kg−1 · min−1 was started. Vasopressin (5 IU/h), insulin (20 IU/h) together with dextrose (2 g/h) and glucagon (5 mg/h) infusion were also introduced. Despite very high doses of vasopressors, her MAP tended to decrease below 50 mm Hg and frequent epinephrine boluses were given. Arterial blood showed severe metabolic acidosis (pH 7.0, base excess [BE] −16) and lactatemia (15 mmol/L) and serum ionized calcium levels were low (1.10 mmol/L). Because of her dependence of ventricular pacing, a pulmonary artery catheter was not introduced. Extracorporeal perfusion techniques were not available in the hospital and the patient was considered too unstable for transfer.

A cardiologist was consulted and an IABP was inserted. Despite IABP and NE (1.5 μg · kg−1 · min−1), epinephrine (0.26 μg · kg−1 · min−1), and vasopressin (3 IU/h) infusions, MAP remained below 50 mm Hg and lactate remained high (12.8 mmol/L). With epinephrine boluses, MAP increased up to 60 mm Hg and the patient’s level of consciousness improved and she opened her eyes on request. The effect of the repeated epinephrine boluses wore-off in a few minutes.

Because of refractory shock, additional treatment was needed. In the hope of improving cardiac systolic function, levosimendan was initiated. Dosing was adopted from use in heart failure.6 A initial loading dose of 2 μg/kg followed by an infusion of 0.2 μg · kg−1 · h−1 was given. Two hours from initiation of levosimendan treatment a MAP of 60 mm Hg could be maintained without epinephrine boluses. Simultaneously, the patient’s lactatemia started to resolve. After 6 h of levosimendan infusion, the doses of vasopressors could gradually be decreased. The patient gained full consciousness 24 h after cardiac arrest and was sedated with propofol (0.5-2 mg · kg−1 · h−1). Because of anuria, intravascular volume overload and deteriorating gas exchange, continuous venovenous hemofiltration was started on Day 2.

Levosimendan infusion was continued for 30 h. Epinephrine infusion was tapered off after 35 h, vasopressin after 45 h, and NE after 52 h. Sinus rhythm was restored on Day 2. IABP could be discontinued on Day 3. Continuous venovenous hemofiltration was continued for 2 days after which the patient’s spontaneous diuresis was satisfactory. Sedation could be discontinued on Day 4 and she was tracheally extubated on Day 5. Upon discharge to the ward her neurological status was normal.

Patient 2

A 38-yr-old male with no history of psychiatric illness was found in his bed deeply comatose. From empty medicine packages, it was suspected that he had taken 630 mg of amlodipine, 300 mg of zopiclone, and an uncertain amount of citalopram and acetaminophen at least 4 h earlier. At the emergency department, the patient was comatose, his peripheral pulses were not palpable and his MAP was not measurable. His heart rate was 90 bpm with sinus rhythm and normal conduction. The patient was tracheally intubated and he received activated charcoal through an orogastric tube. IV fluid resuscitation was started and IV boluses of glucagon (10 mg), calcium (4 g) as well as a dopamine infusion up to 29 μg · kg−1 · min−1 were given. After initial treatment, a radial artery pulse was found and an arterial catheter could be placed. Dopamine infusion was replaced by a NE infusion at 0.3 μg · kg−1 · min−1 with a target MAP of 50 mm Hg. Blood gas analysis showed a pH of 7.37, BE −1.0, and plasma lactate 2.1 mmol/L. To achieve the target MAP, the dose of NE had to be increased to 0.7 μg · kg−1 · min−1 and a continuous IV infusion of calcium (1 g/h) was initiated. Glucagon (5 mg/h) and insulin (10 IU/h), together with dextrose (2 g/h), infusions were also given.

The patient was transferred from the emergency room to the intensive care unit where a transthoracic echocardiography (TTE) showed a left ventricular ejection fraction (LVEF) of 50%. To support ventricular function a dobutamine infusion was initiated at 3.8 μg · kg−1 · min−1. To keep his MAP target, NE had to be increased up to 1.5 μg · kg−1 · min−1. A continuous vasopressin infusion 1 IU/h was added to the treatment. Despite treatment, his acidosis worsened: pH 7.25, BE −9.5 mmol/L, and plasma lactate 4.7 mmol/L. At this point, a pulmonary artery catheter was inserted. Mixed venous oxygen saturation was satisfactory at 74% and the mean pulmonary wedge pressure was satisfactory at 16 mm Hg.

His acidosis continued worsening with pH 7.22, BE −12.5 and plasma lactate 6.5 mmol/L. TTE revealed right ventricular dilation, septal shift, and decreased ejection fraction of the left ventricle (LVEF 38%). Because of the signs of tissue hypoperfusion, persistent hypotension, and echocardiographic signs of heart failure, additional treatment was needed. Levosimendan was given and dobutamine was discontinued. After 90 min of levosimendan infusion at a rate of 0.1 μg · kg−1 · min−1, TTE showed improved left-sided heart function (LVEF 72%).

The levosimendan infusion was increased to 0.2 μg · kg−1 · min−1 and continued for 24 h. The vasopressin infusion was discontinued after 12 h. His lactic acidosis resolved after 24 h. Sedation was discontinued and the patient was tracheally extubated on Day 2. The patient developed bilateral pneumonia and moderate hypotension necessitating the use of NE until Day 3. After recovery from pneumonia, the patient was discharged on Day 11.


We report two cases of severe CCB overdose, which resulted in life-threatening cardiovascular collapse. Our patients received extensive conventional treatment of CCB overdose, but their circulatory state and tissue perfusion remained unsatisfactory. Initiation of levosimendan was associated with improvement and stabilization of hemodynamics. Both patients survived with an overdose of CCB, which was nearly fatal.1

CCBs inhibit the movement of calcium into cells by interfering with the action of the voltage-gated calcium channels.2 As calcium entry into cardiac myocytes is reduced, the result is negative inotropy, chronotropy, and dromotropy. Impaired impulse generation and conduction in the sinoatrial and atrioventricular nodes slow heart rate and may cause atrioventricular block.2 The basic treatment principle is to increase the availability of calcium with high IV doses.3 Doses of catecholamines needed in severe CCB overdose can be very high and arrhythmias may occur.3

Levosimendan is a myocardial calcium sensitizer, which binds to cardiac troponin-C and improves the availability of calcium to actin and myosin fibers6–8Figure 1. It seems that levosimendan is active even in prolonged shock with severe acidosis.9 With severe CCB overdose, inhibition of calcium influx may cause myocardial stunning without myocardial ischemia.10 Levosimendan may act as a cardioprotective drug via mitochondrial adenosine triphosphate-sensitive potassium channels and it may reverse myocardial stunning.10

Figure 1.:
Intracytosolic actions of levosimendan.

Levosimendan has been investigated in several experimental models of cardiovascular collapse. In ropivacaine-induced myocardial depression, levosimendan was effective in improving cardiac function.11 In experimental ventricular fibrillation, the administration of levosimendan has been shown to facilitate resuscitation and significantly lessen postresuscitation myocardial dysfunction, and to improve postresuscitation survival.12,13 Recently, the possible benefit of levosimendan in verpamil overdose using a rodent model was investigated.14 In this study, levosimendan increased cardiac output and improved survival. However, levosimendan did not improve MAP if verapamil concentrations were very high. Investigators concluded that vasodilation induced by levosimendan’s agonism on peripheral vascular K(+)(ATP)-channel could offset the overall hemodynamic improvement.14 Levosimendan has few side effects. In the largest clinical trial of levosimendan the most common finding was sinus tachycardia.15

We used several recommended treatments of CCB overdose including glucagon, insulin, and vasopressin. Data to support the benefit of these treatment options of CCB overdose are limited and based mainly on experimental data, physiological rationale, and clinical experience.16–18 Randomized, controlled trials are unlikely to be conducted with such severely ill patients.

These two cases cannot be considered as direct evidence of a beneficial effect of levosimendan. Both patients received intensive conventional treatment for severe CCB overdose. However, reversal of shock in both was observed shortly after administration of levosimendan.

In conclusion, levosimendan, a calcium sensitizer, may be useful in severe CCB overdose.


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