By Christian Tomaszewski, MD
Introduction
As the U.S. population ages, increasing prescriptions for cardiovascular drugs are being written. Not only does this make these potentially lethal drugs more available for intentional overdose, but can also lead to more accidental ingestions, especially in children, with potentially devastating consequences. Second only to cocaine in mortality, the most dangerous cardiovascular drugs are the calcium channel antagonists (CCA). Calcium channel antagonist poisonings are also one of the most challenging to treat in toxicology because of their metabolic effects, which may require consideration of novel antidotes such as insulin and lipid therapy.
Case presentation
A 17-year-old female presented three hours after taking at least ten of her grandmother’s sustained-release verapamil 200 mg tablets. She presented to an emergency department, lethargic with a systolic blood pressure of 80 mm/Hg and a regular weak pulse of 56 bpm. Her pupils were 3 mm equal and reactive bilaterally. The bedside glucose was 340 mg/dl. She was placed on a cardiac monitor and an ECG obtained that showed a narrow bradycardic rhythm at a rate of 52, but with no consistent P waves with the ventricular complexes: she was in third degree heart block. As per ACLS algorithm, she was given atropine 2 mg IV and placed on an external pacemaker. An ampoule of 10% calcium gluconate was infused IV. None of these treatments resulted in an improvement in blood pressure. A second ampoule of 10% calcium gluconate was infused without improved hemodynamic status. Poison Control was contacted for further treatment recommendations.
Questions
- What is the initial approach to stabilization and decontamination of a potentially lethal CCA overdose?
- What are the mechanisms for CCA toxicity?
- What other antidotes are available to treat calcium channel antagonist toxicity?
Epidemiology
Calcium channel antagonists in overdose are among the most dangerous cardiovascular drugs. Over 10,000 exposures were reported to the American Association of Poison Control Centers in 2008 regarding these agents, 74 of which resulted in major toxicity, with an additional 17 resulting in death. In fact, just one nifedipine capsule has resulted in the death of a 14 month old child in spite of aggressive care .
Pathophysiology
Calcium channel antagonists cause cardiovascular collapse through blockage of calcium channels. In the heart, such channels are responsible both for excitation-contraction coupling and generation of the action potential in the sino-atrial node. This combination results in CCAs being both negative inotropic and chronotropic agents. Additional insult comes from the necessity of calcium in maintaining peripheral vascular tone. Peripheral blockade of calcium channel channels interferes with vasoconstriction, further contributing to hypotension.
More recent data shows that CCAs are also metabolic poisons. The heart is typically dependent on free fatty acids for energy. In CCA toxicity, as in other forms of cardiovascular stress, the heart becomes more dependent on carbohydrates for energy. Unfortunately, in spite of increased need, insulin release from the pancreas is blocked by CCAs, thereby exacerbating the ability of the heart to use the preferred energy substrate efficiently. The end result is hypodynamic cardiac function.
Clinical presentation
The hallmark of CCA toxicity is hypotension with bradycardia. This bradycardia can develop into various forms of heart block, including sinus arrest with a ventricular escape rhythm. Moderate ingestions, particularly of the dihyrdropyridines (e.g. nifedipine, amlodipine) may actually cause reflexive tachycardia early in the poisoning in response to peripheral vasodilatation.
Additional clinical manifestations of CCA toxicity include metabolic acidosis and altered mental status commensurate with the degree of shock. Because of the diabetic effect of CCAs, there usually is some hyperglycemia. Extreme cases may be accompanied by seizures or pulmonary edema.
Diagnosis
There are no readily available laboratory drug levels for CCAs. The differential diagnosis for bradycardia and hypotension associated with poisoning includes beta blockers; clonidine; organic phosphorus and carbamate pesticides; and cardiac glycosides such as digitalis and digoxin. Typically in acute digoxin toxicity, serum potassium will be elevated with normoglycemia. Except for digoxin, most hospital labs can not provide timely levels of any of these agents. Because poisoning by CCAs causes inhibition of insulin secretion, another clue to the diagnosis may be the presence of hyperglycemia, however the absence of this finding does not definitely exclude the diagnosis.
Investigation of the heart using an electrocardiogram may confirm the ingestion of CCAs. On ECG there is usually bradycardia with variable degrees of heart block. The bedside ultrasound may show decreased cardiac contractility.
Treatment
Initial approach
For patients with bradycardia and hypotension, intravenous saline and atropine are good initial approaches. An epinephrine infusion may be started, but this often has variable effect. If the patient presents soon after the ingestion (within an hour) or the ingestion involves a sustained release preparation, then administration of activated charcoal may be useful. However, attention to the airway and avoidance of aspiration takes precedence. Adding whole bowel irrigation with polyethylene glycol solution may be useful for gastrointestinal decontamination in overdose of sustained-release preparations.
Specific antidotes
The initial antidote for CCA toxicity has traditionally been calcium bolus and infusion. Given either in a peripheral vein as calcium gluconate, or centrally as calcium chloride, these agents may competitively reverse some of the calcium channel blockade. A minimum of three to five 10 ml ampoules of 10% calcium gluconate (0.6 ml/kg), or 1-3 of 10% calcium chloride should be tried initially. The goal is a doubling of the ionized calcium level to 2-3 meq/L or targeting a corrected serum calcium of 15-18 meq/L. If the there is a response in blood pressure or heart rate, then a continuous infusion of calcium gluconate 10%, 1.0 ml/kg/hr (calcium chloride 10% 0.3 ml/kg/hr) may be started. Although calcium chloride is theoretically superior to the gluconate form because three times more free calcium is available, there should be caution in administering the chloride form peripherally, because of the danger of extravasation and tissue necrosis. Calcium chloride is preferably administered via central vascular access.
Glucagon, although more traditionally used in beta blocker toxicity, may also have a role in CCA toxicity. Bypassing both calcium and beta receptor in myocytes, glucagon has an independent pathway that stimulates adenyl cyclase in the cell. This results in positive inotropic and chronotropic effects. In dog models of verapamil toxicity, glucagon works as well as catecholamines and calcium. It is typically given at an initial dose of 2 to 10 mg (50 to 150 mcg/kg) for an adult. This can be followed by an infusion of 0.05 to 0.1 mg/kg/hr. One should be cautious in patients with hypotension and altered mental status because of the issue of aspiration from glucagon-induced vomiting.
Newer treatments
The most vexing issue with CCA toxicity is that it often does not respond to traditional ACLS intervention. In one series of CCA intoxicated patients, less than half of them responded to atropine, cardiac pacing or isoproterenol. In addition, many cases still fail to respond even with the addition of calcium and glucagon. Recent animal models of verapamil toxicity show promise with metabolic interventions, namely insulin and lipid emulsion.
Insulin-Euglycemia
Because CCAs are metabolic poisons in the heart, insulin was tested as an inotropic agent. With inhibition of pancreatic function, exogenous insulin allows the heart to utilize carbohydrates more efficiently, thereby helping to reverse the shock state. Multiple animal studies attest to its efficacy, showing superiority of insulin over catecholamines, glucagon and even calcium. In addition, multiple case series comprising over 60 patients in refractory shock from CCAs show its ability to act as a rescue agent when routine treatment was not working.
Because of insulin resistance and hyperglycemia, CCA toxic patients can tolerate high doses of insulin. The typical starting dose for regular insulin is a bolus of 1 IU/kg, followed by an infusion of 0.5 IU/kg/hr. Also, a bolus or 25 gm of dextrose is given initially, followed by an infusion of 0.5 gm/kg/hr. Regular glucose monitoring is done hourly to avoid hypoglycemia, which has been reported in 20% of cases treated in this fashion. If a dire case warrants insulin infusion, then it should be started early because there is usually a delay of an hour in onset of its effect.
Intravenous lipid emulsion
Another new metabolic therapy that can be used in addition to or in place of insulin in refractory CCA toxicity cases is intravenous lipid emulsion. Intravenous lipid emulsion (ILE) was discovered years ago to reverse cardio toxicity in rats and later dogs from bupivicaine, a long acting anesthetic. Although there are no randomized human trials to date, there are multiple case reports, including patients with cardiac arrest after bupivicaine, that have recovered after ILE with minimal or no neurological sequelae.
Intravenous lipid emulsion has since been shown to be possibly useful in other cardiotoxins. As opposed to the traditional antidote of sodium bicarbonate in tricyclic antidepressant toxicity, ILE was essentially 100% protective in a lethal rabbit model of clomipramine toxicity. An impressive lethal rat study of verapamil toxicity showed improved survival time and increased median lethal dose with the use of ILE. Recently, a patient with cardiac arrest from an acute ingestion of bupropion and lamotrigine showed return of spontaneous circulation after almost an hour of CPR, responding within minutes to the infusion of 100 ml of 20% Intralipid®.
Intravenous lipid emulsion therapy is readily available in most hospitals for hyperalimentation. Known as Intralipid ®, it consists mainly of soybean oil (20%) and egg yolk phospholipids (2.25%) emulsified in glycerin and water. Although hospital charges seem often random and inflated, currently a pack of ten 100 ml Intralipid 20% containers lists at $240.80 (Baxter Product Catalog, 2007) – relatively inexpensive for a potential life saving agent.
Whenever one considers a new antidote, potential risks must be weighed as well. Intravenous lipid emulsion does have a boxed warning regarding neonatal use because of the risk of fat overload syndrome with respiratory demise. In adults at the doses recommended above, this is highly unlikely and has not been reported in this scenario.
The manufacturer also recommends cautious use in acute pancreatitis. Although theoretically an allergic reaction to the soy or egg component could occur, hypersensitivity reactions to this agent are rare.
Lipids have been postulated to have various mechanisms in reversing drug-induced cardiac toxicity. These agents may simply function as a lipid sink, extracting or sequestering lipophilic drugs intravascularly, thereby making them less available to cardiac tissue. In addition, they may act as a metabolic antidote. Calcium channel antagonists are known to impair myocardial use of fatty acids, thereby shifting dependence to less efficient carbohydrates. In such a scenario, administration of free fatty acids actually can improve ischemic myocardial function by shifting energy sources back to fatty acids. Finally, the free fatty acids may directly reverse CCA toxicity by activating calcium channels in the heart.
When confronted with a case of refractory shock from CCAs, or other cardiotoxins, the California Poison Control System may recommend a starting dose of 100 ml rapid bolus of the 20% Intralipid® formulation. In children, typically one would start with 1.5 ml/kg. If there is minimal or no response initially, the bolus can be repeated twice every 5 min.
Discussion of case questions
- What is the initial approach to stabilization and decontamination of a potentially lethal CCA overdose?
Obviously attention to airway is the primary concern. Once that is secured, initial treatment of bradycardia and hypotension may benefit from atropine or external pacing. Instillation of activated charcoal may be useful in early or sustained release overdoses; with the latter also benefiting from whole bowel irrigation. - What are the mechanisms for CCA toxicity?
CCAs cause shock through their effect in lowering peripheral vascular resistance, cardiac contractility and cardiac rate. The net effect is a hypotensive, bradycardic patient. In addition, CCAs are a metabolic poison, increasing cardiac dependence on carbohydrates in the face of insulin resistance or deficiency. - What other antidotes are available to treat calcium channel antagonist toxicity?
The most common antidotes are calcium and glucagon. If a bolus of either agent does not have beneficial effect in reversing hypotension, one should quickly move to the newer metabolic antidotes. Either a bolus of insulin or intravenous lipid emulsion may be life-saving, provided they are given early enough in severe cases.