Poisoning by Cardiovascular Drugs

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Chapter 81 Poisoning by Cardiovascular Drugs

Aaron B. Skolnik, MD , Susan R. Wilcox, MD

1 What are the clinical effects of digoxin toxicity?

Although all nodal agents such as digoxin, β-blockers, and calcium channel blockers delay conduction through the atrioventricular node, each has distinct properties that can help distinguish one from the other in a poisoning or overdose. Because digoxin stimulates automaticity in addition to delaying nodal conduction, frequent junctional or ventricular ectopy may be seen. The appearance of regularized atrial fibrillation, actually an accelerated junctional rhythm, is classic for digoxin poisoning. Bidirectional ventricular tachycardia, though rare, is pathognomonic for digoxin toxicity. Patients poisoned with digoxin may also have characteristic noncardiac symptoms, including scotomata, color aberrancy, confusion, hallucinosis, vomiting, and diarrhea.

2 What is the role of potassium in digoxin overdose?

Digoxin exerts its effects in part by binding to the sodium-potassium–adenosine triphosphatase (Na+, K+–ATPase) pump on cardiac cell membranes, competing with potassium for binding sites. When a patient taking digoxin has hypokalemia, the low serum potassium level decreases the competition for binding, leading to increased effects of digoxin and potentiating toxicity.

Conversely, once a patient is digoxin toxic, the Na+, K+–ATPase pumps are thoroughly bound and inhibited. This leads to decreased uptake of potassium into the cells, with resultant increases in the serum potassium concentration. Therefore hypokalemia can potentiate toxic effects of digoxin, and hyperkalemia is a marker for digoxin toxicity.

3 Should you avoid giving calcium to digoxin-poisoned patients?

Historically, the administration of calcium to treat hyperkalemia in patients with digoxin toxicity was contraindicated. The concern, based on case reports and animal models, was that resulting high levels of myocardial calcium could produce a stone heart by impairing diastolic relaxation and precipitate ventricular dysrhythmias. In recent years, a retrospective study suggests that patients who (possibly inadvertently) received intravenous calcium while digoxin toxic had no increase in mortality or any life-threatening dysrhythmias within 1 hour of administration, a finding supported by more recent animal models. Currently, avoiding calcium in suspected digoxin overdose is still recommended, although this may change in the future as data continue to emerge.

4 What is digoxin immune Fab, and how is it used as an antidote?

Digoxin immune Fab is a preparation of antibody fragments with specificity for digoxin. It is produced by preparing monoclonal antibodies to digoxin and then chemically cleaving off the immunogenic Fc portion. Digoxin immune Fab binds to digoxin, as well as a number of naturally occurring cardiac glycosides, and neutralizes their effects on the myocardium and other end-organs. Dosing of Fab fragments is based on the amount required to neutralize the total body burden of digoxin, which can be estimated on the basis of the amount ingested or on the serum digoxin level, if available. In patients who have chronic toxicity, a smaller dose is sometimes administered initially to avoid fully reversing the therapeutic effects of digoxin while treating toxicity.

5 How can the clinician distinguish between β-blocker and calcium channel blocker poisoning?

β-Blockers and calcium channel blockers may be difficult to distinguish clinically from one another in poisoning. Both classes have similar negative effects on cardiac conduction, inotropy, and blood pressure. Also, many patients with cardiovascular disease are taking medications of both types. However, serum blood glucose determination can help tell the two drug classes apart. β-Blockers may cause and/or mask hypoglycemia by blocking stimulation of hepatic glycogenolysis and the release of pancreatic glucagon in response to falling serum glucose levels. Calcium channel blockers may prevent the release of insulin from the pancreas, a process normally mediated by influx of calcium through voltage-gated calcium channels. The ensuing hypoinsulinemia can lead to impressive hyperglycemia in patients without diabetes.

6 What vasopressor(s) should be used in patients with hypotension poisoned by β-blockers or calcium channel blockers?

No good prospective comparisons of the various vasopressors in these patients exist, but, in general, direct-acting mixed sympathetic agonists such as norepinephrine and epinephrine are preferred over dopamine. Part of dopamine’s effect on blood pressure is exerted via the presynaptic release of norepinephrine and epinephrine, a calcium-mediated process that may be impaired in the setting of calcium channel antagonism. Furthermore, patients with either β-blocker or calcium channel blocker poisoning may be depleted of endogenous catecholamines by the time that treatment is initiated, and this may lead to a lack of response or tachyphylaxis to dopamine’s indirect vasopressor effects.

7 Is glucagon useful in poisoning with cardiovascular drugs?

Glucagon is a first-line therapy in treatment of β-blocker toxicity. Glucagon works by stimulating increases in intracellular cyclic adenosine monophosphate, independent of the β-receptors. This, in turn, leads to activation of phosphokinase A (PKA), which phosphorylates a number of intracellular targets important to increase cardiac inotropy and chronotropy. Evidence also exists to support glucagon’s use in cases of calcium channel blocker poisoning, as PKA activation also leads to increases in influx of calcium into poisoned myocytes. One dosing regimen consists of a 2- to 10-mg bolus, followed by continuous infusion at 1 to 5 mg/hour, intravenously.

8 What is hyperinsulinemia-euglycemia therapy?

Hyperinsulinemia-euglycemia therapy involves administration of high doses of insulin while maintaining a normal serum glucose level. It has become a widely used therapy in calcium channel blocker poisoning. Insulin is a positive inotrope but is obviously not used as such under normal circumstances given the high risk for hypoglycemia. In addition, stunned heart seems to develop some acute insulin resistance and prefers carbohydrate to its normal free fatty acid fuel. By offering large amounts of insulin with accompanying appropriate amounts of dextrose, it is thought that carbohydrate is directed to the energy-starved cardiac myocytes. Furthermore, insulin or glucose administration leads to shifts of potassium into the cells. The resulting relative hypokalemia prolongs phase II of the cardiac action potential, during which calcium influx occurs. This may also be beneficial in raising intracellular calcium levels and stimulating calcium release from the sarcoplasmic reticulum with subsequent increases in inotropy. This therapy may also benefit patients poisoned with β-blockers; however, additional caution against acute hypoglycemia must be exercised as those patients lack the hyperglycemia seen from calcium channel blockade.

9 How does intravenous lipid emulsion (ILE) therapy work?

ILE therapy uses intravenous administration of a 20% lipid emulsion as a polyvalent antidote to poisoning by lipophilic drugs. The emulsion, originally developed for parenteral nutrition, may act as a “sink” within the plasma for lipophilic drugs. In various animal models and human case reports, it appears that the drugs are sequestered within this lipid phase and thus prevented from acting at potential target organs, such as the brain and the heart. Other theoretical mechanisms of action include the provision of free fatty acid fuel to starving cardiac mitochondria and increasing cardiac myocyte calcium influx. A large and growing body of data demonstrates benefit of ILE for several types of cardiotoxic drugs, including sodium channel blockers, calcium channel blockers, and some β-blockers. Consider giving lipid emulsion to any poisoned patient who has ingested a highly lipid-soluble drug and has significant hemodynamic instability.

10 What else can be done for the patient with cardiovascular collapse in whom other medical therapies are failing?

Several heroic options are described for patients in whom maximal medical therapies are failing, though none have been validated prospectively. Potential therapies include intraaortic balloon counterpulsation, left ventricular assist, cardiopulmonary bypass, and extracorporeal membrane oxygenation.

Key Points Poisoning by Cardiovascular Drugsimage

1. Distinguishing among digoxin, β-blocker, and calcium channel blocker toxicity may be difficult, but digoxin toxicity is often associated with other systemic symptoms, such as nausea, weakness, and visual changes.

2. If digitalis toxicity is suspected, prompt administration of digoxin immune Fab is indicated.

3. Glucagon remains a first-line treatment for β-blocker toxicity.

4. The treatments of choice for calcium channel blocker toxicity include high-dose, direct-acting vasopressors and hyperinsulinemia-euglycemia therapy.

5. ILE has shown benefit in treatment of poisonings for several types of cardiotoxic drugs and should be considered for any poisoned patient who has ingested a highly lipid-soluble drug with significant hemodynamic instability.

Bibliography

1 Bauman J.L., Didomenico R.J., Galanter W.L. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs. 2006;6:77–86.

2 Cave G., Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med. 2009;16:815–824.

3 Engebretsen K.M., Kaczmarek K.M., Morgan J., et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011;49:277–283.

4 Levine M., Nikkanen H., Pallin D.J. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011;40:41–46.

5 Manini A.F., Nelson L.S., Hoffman R.S. Prognostic utility of serum potassium in chronic digoxin toxicity: a case–control study. Am J Cardiovasc Drugs. 2011;11:173–178.

6 Page C., Hacket L.P., Isbister G.K. The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report. J Med Toxicol. 2009;5:139–143.

7 Patel N.P., Pugh M.E., Goldberg S., et al. Hyperinsulinemic euglycemia therapy for verapamil poisoning: a review. Am J Crit Care. 2007;16:498–503.

8 Rothschild L., Bern S., Oswald S., et al. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010;5:51.

9 Vivo R.P., Krim S.R., Perez J., et al. Digoxin: current use and approach to toxicity. Am J Med Sci. 2008;336:423–428.

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Chapter 81 Poisoning by Cardiovascular Drugs

Aaron B. Skolnik, MD , Susan R. Wilcox, MD

1 What are the clinical effects of digoxin toxicity?

Although all nodal agents such as digoxin, β-blockers, and calcium channel blockers delay conduction through the atrioventricular node, each has distinct properties that can help distinguish one from the other in a poisoning or overdose. Because digoxin stimulates automaticity in addition to delaying nodal conduction, frequent junctional or ventricular ectopy may be seen. The appearance of regularized atrial fibrillation, actually an accelerated junctional rhythm, is classic for digoxin poisoning. Bidirectional ventricular tachycardia, though rare, is pathognomonic for digoxin toxicity. Patients poisoned with digoxin may also have characteristic noncardiac symptoms, including scotomata, color aberrancy, confusion, hallucinosis, vomiting, and diarrhea.

2 What is the role of potassium in digoxin overdose?

Digoxin exerts its effects in part by binding to the sodium-potassium–adenosine triphosphatase (Na+, K+–ATPase) pump on cardiac cell membranes, competing with potassium for binding sites. When a patient taking digoxin has hypokalemia, the low serum potassium level decreases the competition for binding, leading to increased effects of digoxin and potentiating toxicity.

Conversely, once a patient is digoxin toxic, the Na+, K+–ATPase pumps are thoroughly bound and inhibited. This leads to decreased uptake of potassium into the cells, with resultant increases in the serum potassium concentration. Therefore hypokalemia can potentiate toxic effects of digoxin, and hyperkalemia is a marker for digoxin toxicity.

3 Should you avoid giving calcium to digoxin-poisoned patients?

Historically, the administration of calcium to treat hyperkalemia in patients with digoxin toxicity was contraindicated. The concern, based on case reports and animal models, was that resulting high levels of myocardial calcium could produce a stone heart by impairing diastolic relaxation and precipitate ventricular dysrhythmias. In recent years, a retrospective study suggests that patients who (possibly inadvertently) received intravenous calcium while digoxin toxic had no increase in mortality or any life-threatening dysrhythmias within 1 hour of administration, a finding supported by more recent animal models. Currently, avoiding calcium in suspected digoxin overdose is still recommended, although this may change in the future as data continue to emerge.

4 What is digoxin immune Fab, and how is it used as an antidote?

Digoxin immune Fab is a preparation of antibody fragments with specificity for digoxin. It is produced by preparing monoclonal antibodies to digoxin and then chemically cleaving off the immunogenic Fc portion. Digoxin immune Fab binds to digoxin, as well as a number of naturally occurring cardiac glycosides, and neutralizes their effects on the myocardium and other end-organs. Dosing of Fab fragments is based on the amount required to neutralize the total body burden of digoxin, which can be estimated on the basis of the amount ingested or on the serum digoxin level, if available. In patients who have chronic toxicity, a smaller dose is sometimes administered initially to avoid fully reversing the therapeutic effects of digoxin while treating toxicity.

5 How can the clinician distinguish between β-blocker and calcium channel blocker poisoning?

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