The Brady Bunch: Overdoses that cause bradycardia and hypotension

Transcription

1 EM:RAP Essay March 2011 The Brady Bunch: Overdoses that cause bradycardia and hypotension Part I: Calcium Channel Blockers and Beta Blockers Over the past several months, we have featured a series of interviews with our resident toxicologist, Dr. Sean Nordt, on the common overdoses that cause bradycardia and hypotension: calcium channel blockers, beta blockers, digoxin and clonidine. All of these drugs can be fatal in overdose and all of them appear on the list of single tablets that can kill a child. The differential diagnosis of hypotension and bradycardia is broad. There are cardiac causes such as myocardial infarction with cardiogenic shock, metabolic causes such hyperkalemia and neurologic causes such as spinal cord injury. However, when an overdose is suspected, these four agents are at the top of the list. All of these big four agents can result in altered mental status either because of their specific neurologic toxicity or simply on account of circulatory collapse with poor cerebral perfusion. As is often the case in toxicology, drug levels are either unavailable or, as is the case with digoxin, may be misleading. In acutely decompensating patients, empiric treatment must begin immediately. Although much of our approach to these patients follows along common ACLS and GI decontamination guidelines, important clues in the presentation may help direct us toward a specific cause and increase the likelihood of more directed and successful therapy. Calcium channel blockers, which only came into widespread use in the past three decades, have proven to be one of the most feared and lethal overdoses. In addition to bradycardia and hypotension, one key clue to the diagnosis may be hyperglycemia, because calcium channel blockers inhibit insulin secretion. Although treatment with atropine and high doses of intravenous calcium and glucagon are indicated, these are often ineffective at restoring effective circulation. It is often necessary to proceed rapidly to vasopressors, such as dopamine and norepinephrine. Another important therapy for these patients is high dose insulin infusion, which appears to enable the myocardium to switch its energy source to carbohydrates from free fatty acids and mitigate the effects of the calcium blockade. Sufficient glucose must be administered to prevent hypoglycemia. Beta blockers can cause a similar syndrome, but in contrast to calcium channel blockers, they may actually present with hypoglycemia, especially in diabetics or children. This is because beta blockers inhibit glycogenolysis. In addition, because

2 of the direct effects of beta blockade on the central nervous system, profound coma and seizures may be present. Treatment is similar, but high doses of glucagon tend to be more successful in beta blocker overdose, as they are able to bypass the site of action of the of toxin, increasing levels of intracellular cyclic adenosine monophosphate (camp) through non-adrenergic pathways. In patients recalcitrant to glucagon, therapy with calcium, vasopressors and high dose insulin is also indicated. Seizures should be treated with benzodiazepines. In both calcium channel and beta blocker overdoses, if effective circulation can be restored quickly enough, patients can often make a complete recovery. Thus, after medical therapies have been exhausted, invasive attempts to restore circulation, including transvenous electrical pacing and extracorporeal membrane oxygenation can be utilized. This may bridge the patient beyond the duration of action of the drug in question. An exciting new potential therapy for both calcium channel and beta blocker overdoses is intravenous fat emulsion or intralipid infusion. Because many of these agents are fat soluble, it is possible to trap them in fat globules in plasma, so that they are unable to reach the myocardium. This new therapy may also prove beneficial in other deadly overdoses, such as tricyclic antidepressants. In next month s piece, we will continue our discussion with the other two agents, digoxin and clonidine. Dr. Swadron is currently Vice-Chair for Education in the Department of Emergency Medicine at the Los Angeles County/USC Medical Center in Los Angeles. He is an Associate Professor of Clinical Emergency Medicine at the Keck School of Medicine of the University of Southern California. EM:RAP (Emergency Medicine: Reviews and Perspectives) is a monthly audio program that can be found at

3 EM:RAP Essay March 2011 The Brady Bunch: Overdoses that cause bradycardia and hypotension Part II: Clonidine Over the past several months, we have featured a series of interviews with our resident toxicologist, Dr. Sean Nordt, on the common overdoses that cause bradycardia and hypotension: calcium channel blockers, beta blockers, clonidine and digoxin. All of these drugs can be fatal in overdose and all of them appear on the list of single tablets that can kill a child. Last month we discussed calcium channel blockers and beta blockers. This month we continue the discussion with clonidine. Clonidine is very interesting. It is unlike any other antihypertensive medication because it is actually a receptor agonist. By stimulating pre-synaptic alpha-2 adrenergic receptors that are found in the medulla oblongata, clonidine causes a decrease in central sympathetic outflow throughout the body. Although its most familiar indication is as an antihypertensive agent, its central action has led to its use for a variety of behavioral indications, including attention deficit disorder, smoking cessation and opioid withdrawal. Moreover, clonidine can be considered a drug of abuse - it is bought and sold on the street. Dr. Nordt also highlighted the fact that dosing errors in pediatric patients is of particular concern as a cause of overdose. The clinical picture of a clonidine overdose can be indistinguishable from that of an opioid overdose. Bradycardia, hypotension, respiratory depression, miosis and a decreased level of consciousness can all be seen. Although it may be a subtle finding, patients with clonidine overdose are more likely to respond transiently to painful stimuli before falling back to a state of unresponsiveness. Moreover, although patients may appear to respond to an opiate antagonist such as nalaxone, this response is only partial at best and often transient. Patients with an opiate-like toxidrome who fail to reverse with naloxone should raise suspicion for a clonidine overdose. The treatment of clonidine overdose is generally supportive. Airway protection via endotracheal intubation may be necessary in some cases. Volume infusion with crystalloid, atropine and dopamine can all be used to support the patient s hemodynamic status. Clonidine is not dialyzable, so patients need to be supported through their toxidrome in the intensive care unit. GI decontamination is an option in the patient who presents early, before any depression of consciousness occurs

4 and the risk of aspiration ensues. In the intubated patient, activated charcoal may also be given through a gastric tube. Interestingly, many common over-the-counter eye drops and nasal sprays are closely related to clonidine. When used topically as directed, alpha agonists such as tetrahydrozoline (Visine ) and Oxymetazoline (Afrin ), stimulate alpha-1 receptors and result in vasoconstriction, decreasing eye redness and nasal congestion. However, if ingested their action on the central alpha-2 receptors may predominate, and a syndrome resembling a clonidine overdose may occur. Clonidine sustained release patches are relatively common and have also been implicated in overdose. Because these patches contain many times the amount of medication found in tablets, patch ingestion can cause a particularly prolonged and severe toxidrome. Whole bowel irrigation with polyethylene glycol is indicated in these cases. Finally, clonidine withdrawal is another phenomenon which emergency physicians encounter not infrequently. Clinically it can mimic alcohol withdrawal and can similarly be treated with benzodiazepines. In next month s piece, we will finish our discussion with the last of the four cardinal agents causing bradycardia in overdose, digoxin. Dr. Swadron is currently Vice-Chair for Education in the Department of Emergency Medicine at the Los Angeles County/USC Medical Center in Los Angeles. He is an Associate Professor of Clinical Emergency Medicine at the Keck School of Medicine of the University of Southern California. EM:RAP (Emergency Medicine: Reviews and Perspectives) is a monthly audio program that can be found at

5 EM:RAP Essay May 2011 The Brady Bunch: Overdoses that cause bradycardia and hypotension Part III: Digitalis glycosides demystified This is the third and last installment in a series focusing on the common overdoses that cause bradycardia, hypotension and altered mental status. Over the past several months during interviews with toxicologist Dr. Sean Nordt, we have discussed calcium channel blockers, beta blockers, clonidine and digitalis glycosides. All four classes of drugs can be fatal in overdose and all of them appear on the list of single tablets that can kill a child. Digoxin is the most commonly encountered digitalis glycoside in the United States but, as Dr. Nordt reminded us, other prescribed forms exist such as digitoxin and ouabain. Digitalis glycosides are also found in the extracts of plants (foxglove, oleander and lily-of-the-valley among many others) and even on the skin of some toads! (see Figure) Digoxin is somewhat perplexing for many emergency physicians - it s one of the cardioactive drugs to grasp. At the center of its clinical effect is its direct inhibition of membrane-bound sodium-and potassium-activated adenosine triphosphatase (Na+/K+ ATPase), which leads to an increase in the intracellular concentration of calcium and hence an increase in cardiac contractility. Digoxin is unique among cardiac drugs in that it is both a positive inotrope and a atrioventricular nodal blocker. In addition, digoxin has an pro-arrhythmogenic effect on both the atria and the ventricles. This gives rise to the classic electrocardiographic findings of regularized, slow atrial fibrillation and paroxysmal atrial flutter with a high grade block. Unfortunately, these rhythms are seen only in some cases, with ventricular arrhythmias such as premature ventricular contractions and sustained ventricular tachycardia being more common, and more life-threatening, in chronic overdoses. Digoxin differs from the other three of the brady bunch in that it has measurable serum levels. However, serum levels in chronic toxicity may actually be within the normal range of standard reference laboratory values. Moreover, laboratory values may be spurious or erratic in cases involving the more exotic sources of cardiac glycosides, like plant extract ingestion. Therefore, it is the patient s clinical presentation that is paramount in determining toxicity and the need for therapy. Acute toxicities are less of a diagnostic challenge. Typically these are younger patients who overdose intentionally. Serum levels will be markedly elevated but because it may take up to six hours for the drug to distribute and levels to stabilize,

6 it is generally recommended that treatment decisions be based on clinical features rather than levels during this initial period. Hyperkalemia, an acute accumulation of extracellular potassium that results from sodium-potassium pump failure, is one of the most important indicators of a life-threatening overdose. Thus, a potassium above 5.0 or 5.5 meq/l is a key trigger for administration of expensive (yet effective) immunotherapy with intravenous digoxin-specific Fab fragments. Other indications for Fab fragments include hemodynamic instability and ventricular dysrhythmias. In patients with marked bradycardia due to nodal blockade, a trial of atropine may also be effective. While it is acceptable to lower elevated potassium levels with traditional shifting agents such as intravenous insulin and bicarbonate boluses, the use of calcium as a membrane stabilizer remains controversial because of historical case reports of cardiac arrest following its use in this setting. Electrical cardioversion is acceptable in patients with sustained ventricular arrhythmias, but much lower energy levels (e.g J) are recommended than in non-poisoned patients. Lastly, gastrointestinal decontamination with activated charcoal can be used to decrease further absorption of digoxin after oral ingestion provided that the patient is alert and not otherwise at risk for aspiration. In chronic overdoses, the extra-cardiac manifestations of digoxin toxicity may predominate. These include non-specific gastrointestinal symptoms, visual disturbances and altered mental status. It is thus not difficult to see why these cases are often missed the presentation can easily be confused with other conditions such as myocardial ischemia, hypothyroidism and uremia, which by itself often precipitates digoxin toxicity due to decreasing clearance. Potassium values are often low, reflecting the chronic wasting that occurs when potassium is unable to move into cells and over time is eliminated in the urine a process that is facilitated by concomitant diuretic therapy. Because digoxin toxicity is exacerbated in a low potassium state, repletion of potassium is a critical step in the management of these patients. As in other low potassium states, co-administration of magnesium is also often necessary. Dr. Swadron is currently Vice-Chair for Education in the Department of Emergency Medicine at the Los Angeles County/USC Medical Center in Los Angeles. He is an Associate Professor of Clinical Emergency Medicine at the Keck School of Medicine of the University of Southern California. EM:RAP (Emergency Medicine: Reviews and Perspectives) is a monthly audio program that can be found at