Diagnostics

electrocardiographic abnormalities associated with poisoning

Christopher Delk MD^a,*, Christopher P. Holstege MD^a,b, William J. Brady MD^a

^aDepartment of Emergency Medicine, University of Virginia, Charlottesville, VA 22911, USA

^bDivision of Medical Toxicology, Department of Emergency Medicine, University of Virginia, Charlottesville, VA 22911, USA

Received 27 October 2006; revised 27 October 2006; accepted 2 November 2006

Abstract This article will review the cardiovascular toxicities of various medications, stressing the electrocardiographic presentation-both rhythm and morphological issues-and emphasizing recogni- tion and management issues. cardiovascular toxins are grouped into categories causing similar Electrocardiographic effects, including the potassium efflux blockers, Sodium channel blockers, sodium- potassium adenosine triphosphatase blockers (ie, digitalis compounds), calcium channel blockers, and b-adrenergic blockers. This article reviews the various electrocardiographic abnormalities associated with these 5 classes of agents, ranging from morphological abnormalities and conduction blocks to brady- and tachyarrhythmias.

D 2007

Introduction

The emergency physician frequently evaluates the poisoned patient. Each year, more than 2 million human exposure cases are reported to poison centers in the United States [1]. Of these, one fifth presented to the emergency department (ED) for evaluation. Among these Poisoned patients, cardiovascular medications represented the 15 most frequently encountered drug category and the fifth leading cause of poisoning deaths; furthermore, if one adds the noncardiovascular agents such as antidepressants, antipsy- chotics, and antihistamines-noncardiovascular medications with potential cardiovascular effect-to this list of frequent offending drugs, the frequency of cardiovascular poisoning events only increases.

* Corresponding author.

E-mail address: [email protected] (C. Delk).

Numerous authorities have studied electrocardiographic changes encountered in patients with specific toxicity. For example, multiple reports have been published describing the ECG changes encountered in either tricyclic antidepressant (TCA) poisoning or digoxin exposure. Little clinical information, however, is found in the literature to address the general use of the ECG in the poisoned patient. A study [2] of the ECG in the poisoned patient revealed that the ECG is, in fact, frequently abnormal in the poisoned patient. In this study, it was noted that approx- imately 70% of patients demonstrated an Abnormal ECG; of the abnormal findings, 62% had a rhythm abnormality, whereas 38% had morphological abnormality. Rhythm disturbances included sinus tachycardia (51%), Sinus bradycardia (7%), atrioventricular (AV) block (7%), non- sinus atrial tachycardia (3%), and nodal bradycardia (3%); morphological abnormality included abnormal QRS con- figuration (35%), QRS complex widening (33%), QT interval prolongation (33%), PR interval prolongation

0735-6757/$ - see front matter D 2007 doi:10.1016/j.ajem.2006.11.038

(12%), ST segment abnormality (9% elevated, 25% depressed), and T wave inversion (20%). Interestingly, the degree of abnormality was directly related to the number of toxins ingested; yet, the cardiovascular agents (b-adrener- gic blockers or calcium channel antagonists) were no more likely to produce ECG abnormality when compared with the noncardiovascular substances (sedative-hypnotic medi- cations or stimulants). Importantly, this analysis did not include patients who underwent ECG Rhythm analysis via the monitor; this study would have likely missed the more malignant rhythm presentations, such as ventricular tachy- cardia or complete AV block.

This article will review the cardiovascular toxicities of various medications, stressing the ECG presentation-both rhythm and morphological issues-and stressing recognition and management issues. Cardiovascular toxins are grouped into categories causing similar ECG effects, including the potassium efflux blockers, sodium channel blockers, sodi- um-potassium adenosine triphosphatase (Na/K-ATPase) blockers (ie, digitalis compounds), calcium channel blockers (CCB), and b-adrenergic blockers. This article reviews the various ECG abnormalities associated with these 5 classes of agents, ranging from morphological abnormalities and conduction blocks to brady- and tachyarrhythmias.

Fig. 1 A, Electrocardiographic rhythm strip with NSR and long QT interval. B, Twelve-lead ECG with NSR, inverted T waves in leads V₂ and V₃, and a single premature ventricular contraction. Importantly, the QT interval is prolonged to approximately 500 milliseconds. C, Polymorphic ventricular tachycardia is noted in this patient. This form of PVT is suggestive of Torsade de pointes, a subtype of PVT seen in patients with abnormal repolarization-as manifested by the prolonged QT interval on the sinus rhythm ECGs in panels A and B.

Illustrative cases

Case 1

A 46-year-old woman with a history of hypertension, myocardial infarction, congestive heart failure, and bipolar disorder presented to the ED with palpitations and syncope. She noted the onset of the complaints approximately 12 hours before arrival. The patient was taking multiple medications,

including furosemide, atenolol, enalapril, risperidone, and sertraline. The examination demonstrated an alert woman in no apparent distress with blood pressure of 145/80 mm Hg, pulse rate of 60 beats per minute (bpm), and R-R of 16/min. The remainder of the examination was unremarkable. The rhythm strip demonstrated sinus rhythm with a Long QT interval (Fig. 1A). The 12-lead ECG (Fig. 1B) revealed normal sinus rhythm (NSR) at a rate of approximately 60 bpm with a prolonged QT interval (520 milliseconds).

Fig. 2 A, Normal sinus rhythm with widened QRS complex. The QRS complex is approximately 0.12 second in width. B, This 12-lead ECG demonstrates significant additional widening of the QRS complex with the development of a prominent RV wave in Lead aVR. C, Marked widening of the QRS complex is seen here with prominent RV wave in lead aVR. These findings result from significant Sodium channel blockade. D, Coarse ventricular fibrillation.

Fig. 2 (continued)

additional laboratory studies were significant for low serum potassium and magnesium values.

Within 30 minutes of ED arrival, the patient developed a recurrent syncopal episode; the ECG monitor demonstrated polymorphic ventricular tachycardia (PVT; Fig. 1C). The dysrhythmia resolved spontaneously. Electrolyte replace- ment therapy was initiated. The patient was admitted to the hospital without recurrence of the dysrhythmia. Her ultimate diagnosis was Long QT syndrome; the syndrome developed because of the medication use (risperidone) and coexisting electrolyte abnormalities in a patient with a familial tendency for long QT syndrome.

Case 2

A 31-year-old woman presented to the ED via ambulance with lethargy. Friends had found her at home with confusion. Her medical history was unknown at the time of presentation. Basic life support emergency medical service found the patient minimally lethargic. She was transported to the ED. On arrival in the ED, the examination revealed lethargy. The ECG rhythm strip demonstrated a wide QRS complex rhythm at a rate of 70 bpm; the initial 12-lead ECG (Fig. 2A) revealed similar findings. A rapid

review of her medical history revealed systemic lupus erythematosus managed with hydroxychloroquine. Based upon her medical history and clinical presentation, hydrox- ychloroquine poisoning was considered. The patient was managed with endotracheal intubation, intravenous sodium bicarbonate, and admission to the intensive care unit. Before administration of the bicarbonate, the ECG monitor demonstrated several changes, including increased rate and further widening of he QRS complex; a second 12-lead ECG (Fig. 2B) revealed significant additional widening of the QRS complex with a prominent R’ wave in lead aVR. Ultimately, the rhythm diagnosis was a Wide complex tachycardia due to sodium channel blockade. After arrival in the intensive care unit, the ECG (Fig. 2C) demonstrated continued deterioration of the rhythm with the development of a Wide QRS complex tachycardia. Minutes later, the patient developed ventricular fibrillation (Fig. 2D) that did not respond to therapy; she died.

Case 3

A 67-year-old female patient presented to the ED with weakness and confusion. The patient had noted significant vomiting and diarrhea over the past week. Her family also

Fig. 3 A, Rhythm strip with markedly wide QRS complex. P waves remain evident, indicating a sinus mechanism. B, Twelve-lead ECG with wide QRS complex in a sinusoidal configuration. These findings are consistent with hyperkalemia. In a patient with digoxin therapy, strong consideration must be given to a digoxin-related hyperkalemia.

Fig. 4 A, A narrow complex, regular bradycardia consistent with a junctional rhythm. B, Junctional rhythm on a 12-lead ECG.

Fig. 5 Cardiac action potential with corresponding ECG. Note the sodium, potassium, and Calcium channels and the primary action of sodium and potassium blockade. The insert in the upper right area demonstrates the normal ECG P-QRS-T cycle.

described progressive lethargy with confusion. The medical history was remarkable for diabetes mellitus, hypertension, and congestive heart failure; medications were numerous including insulin, glipizide, captopril, and digoxin. The patient was awake yet confused; the vital signs were

significant for a blood pressure of 90 mm Hg by palpation, pulse rate of 76 bpm, and respiratory rate of 24/min. The ECG monitor demonstrated a wide QRS complex rhythm at a rate of approximately 80/min (Fig. 3A); the 12-lead ECG revealed a similar rhythm (Fig. 3B). The ECG findings were

Fig. 6 Blockade of the potassium efflux channels delays the termination of Phase 2 and prolongs the QT interval. The insert in the upper left area demonstrates the ECG P-QRS-T cycle with the effect of a potassium efflux blocking agent-QT interval prolongation.

Case 4

Table 1 K⁺ efflux channel blocking agents Antihistamines

Astemizole

Clarithromycin Diphenhydramine Loratidine Terfenadine Antipsychotics Chlorpromazine Droperidol Mesoridazine Pimozide Quetiapine Risperidone Thioridazine Ziprasidone Arsenic trioxide Bepridil Chloroquine Cisapride Citalopram Clarithromycin

Class IA antiarrhythmics Disopyramide Quinidine Procainamide

Class IC antiarrhythmics Encainide

Flecainide Moricizine Propafenone

Class III antiarrhythmics Amiodarone

Dofetilide Ibutilide Sotalol

Cyclic antidepressants Erythomycin Fluoroquinolones Halofantrine Hydroxychloroquine Methadone Pentamidine

Quinine Venlafaxine

A 38-year-old man presented to the ED after a purposeful ingestion of diltiazem in a suicide attempt. The patient was found by family with altered mental status; a newly filled prescription bottle of diltiazem was found empty in the home. Emergency medical service discovered a middle-aged man with confusion and noted a blood pressure of 70 mm Hg by palpation with a pulse rate of 50 bpm. The ECG revealed a regular, narrow QRS complex rhythm consistent with a junctional rhythm. The patient received a total of 3 mg of atropine during transport as well as 1 L of intravenous isotonic sodium chloride solution. The examination was unchanged on ED arrival. The ECG rhythm (Fig. 4A) and 12-lead ECG (Fig. 4B) were significant for a regular, narrow QRS complex rhythm consistent with a junctional rhythm. The patient received intravenous atropine, calcium, glucagon, and insulin; a dopamine infusion was also started. Progressive hypotension occurred with continued brady- cardia. Within 5 minutes of ED arrival, the patient was orotracheally intubated with etomidate. Approximately

consistent with pronounced hyperkalemia, likely due to Digitalis poisoning. These findings included the sinoven- tricular rhythm with a sinusoidal QRS complex and no evidence of P wave activity. Laboratory studies confirmed hyperkalemia with a serum potassium level of 8.1 mEq/dL;

Table 2 Na⁺ channel blocking drugs Amantadine

Carbamazepine

Chloroquine

Class IA antiarrhythmics Disopyramide Quinidine Procainamide

Class IC antiarrhythmics Encainide

Flecainide Propafenone Citalopram Cocaine

Cyclic antidepressants Amitriptyline Amoxapine Desipramine Doxepin

Imipramine Nortriptyline Maprotiline Diltiazem Diphenhydramine Hydroxychloroquine Loxapine Orphenadrine Phenothiazines Medoridazine Thioridazine Propranolol Propoxyphene Quinine

Verapamil

additional findings included elevated serum creatinine and blood urea nitrogen levels. The patient received initial treatment for hyperkalemia followed by digoxin Antibody fragments. The ECG demonstrated significant improvement over the next 60 minutes with increased rate and narrowing of the QRS complex. She was diagnosed with digoxin toxicity manifested by hyperkalemia.

15 minutes later, the patient developed ventricular fibrillation that did not respond to therapy.

Discussion

The clinician approaches the poisoned patient with numerous important diagnostic tools, including the history of the ingestion, the physical examination, and selected investigations-each of these tools yields important diag- nostic information that, when considered as a whole, can suggest the diagnosis and appropriate therapy. One of these investigative tools is the ECG-both the ECG rhythm strip and the 12-lead ECG. The ECG is used here not only to establish the diagnosis but also to assess for end-organ toxicity and to direct management. These individuals presenting with significant cardiotoxicity manifested by dysrhythmia will be assessed with the ECG monitor; further diagnostic and management decisions will be suggested based upon the bedside interpretation of the ECG rhythm strip. In the stable patient, the 12-lead ECG is performed. In addition to the rhythm interpretation issue, the ECG is reviewed for abnormalities of the various structures, intervals, complexes, and axes; beyond rhythm consider- ations, the primary ECG determinants of impending or established cardiotoxicity include the PR interval, the QRS complex, the T wave, the ST segment, and the QT interval. In that the various cardiovascular toxins affect the ECG cycle in many different fashions, a thorough knowledge of not only the genesis of the waveform but also the normal

ECG is required for the appropriate interpretation in the poisoned patient.

Myocardial cell physiology

When exploring cardiotoxic medications and their mechanisms of poisoning, a discussion of the physiology of the cardiac cycle, action potential, and myocardial cell function is necessary. Sodium, potassium, and calcium are the most important ions that play a role in the cardiac cycle. In addition, the Na/K-ATPase pump is also actively involved in the cardiac action potential. The medications most likely to cause cardiotoxicity involve disruptions of the normal metabolism of these ions and membrane pumps. From a mechanistic perspective, the cardiotoxic agents of concern include the potassium efflux blockers, sodium channel blockers, CCB, b-adrenergic blockers, and Na/K- ATPase blockers (cardiac glycosides).

In the resting state (phase 4), the myocardial cell membrane is not permeable to the positively charged sodium ions (Fig. 5) [3]. The electrical resting potential of the myocyte is approximately -90 mV. This electrical potential is maintained in the resting state by the Na/K- ATPase pump, which actively pumps 3 sodium ions out of the cardiac cell and pumps 2 potassium ions into the cell. With depolarization of the cell membrane, the sodium channels are rapidly opened and there is an influx of sodium ions. This influx of sodium ions is termed phase 0 of the cardiac action potential. With the influx of sodium

Fig. 7 Blockade of the sodium channel prolongs phase 0, producing a widening of the QRS complex. The insert in the upper left area demonstrates the ECG P-QRS-T cycle with the effect of a sodium channel blocking agent-QRS complex widening.

cardiovascular toxicity“>ions, there is an upstroke of the cardiac action potential that is conducted through the ventricles. The ventricular conduction of this action potential corresponds to the QRS interval on the ECG.

At the peak of the action potential, there are closure of the sodium channels and activation of the potassium efflux channels (Phase 1). After the opening of potassium ef- flux channels, there is also an activation of the calcium influx channels. The calcium channel activation allows for the plateau phase (phase 2) of the action potential and for continued contraction. The end of the cardiac cycle is marked by the closure of the calcium channels and the activation of the potassium efflux channels, which allow the action potential to return to its resting potential of -90 mV (phase 3), from which it can depolarize again-manifested on the ECG by the QT interval. Refer to Fig. 5 for a

demonstration of the myocardial action potential and the various effects of blocking agents on the action potential and the ECG.

Cardiovascular toxicity

Potassium efflux blocker toxicity

Blockade of the Outward potassium currents by certain medications may prolong the action potential [4]. This prolongation of the action potential results in the lengthen- ing of the repolarization phase of the ECG cycle. Electrocardiographically, this blockade of the potassium efflux channels is manifested by QT interval prolongation (Figs. 1 and 6) and the appearance of T or U wave abnormalities. This prolongation of repolarization causes the

Fig. 8 Sodium channel blockade along with other toxic effects from TCA agents. A, Sinus tachycardia, primarily resulting from anticholinergic properties of the drug class. B, Wide QRS complex tachycardia. C, Prolonged QT interval. D, Large S wave in lead I and Prominent R wave in lead aVR, an indication of impending sodium channel blocker toxicity. This ECG finding is indicative of a far rightward axis deviation.

Fig. 9 A, A wide complex tachycardia that is easily confused with ventricular tachycardia. This rhythm is likely supraventricular in origin with a markedly widened QRS complex due to the sodium channel poisoning and tachycardia due to the anticholinergic effects of the drug. Note also the prominent RV wave in lead aVR as well as the Deep S wave in lead I, both findings of TCA cardiotoxicity. B, With sodium bicarbonate therapy, the patient improves with both a slowing of the rate and a narrowing of the QRS complex. C, Subsequently, the ECG normalizes approximately 24 hours after the initiation of therapy.

Fig. 9 (continued)

myocardial cell to have less charge difference across its membrane that may subsequently result in the activation of the inward depolarization current (early after depolarization) that may, in turn, promote triggered activity. Triggered activity, as noted above, can produce reentry and subsequent PVT-in this case, torsade de pointes (Fig. 1C).

Certain medications, such as sotalol, are marketed specifically for their ability to inhibit the delayed rectifier current [5]. Other medications possess this activity as an unwelcome adverse effect at Therapeutic doses. A number of medications, such as terfenadine and cisapride, have been removed from the market in various countries because of reports of associated torsade de pointes and sudden death in patients taking these drugs [6,7]. Most medications have been reported to cause QT prolongation when taken in massive overdose. For a listing of agents associated with QT prolongation, see Table 1.

The QT interval is noted on the ECG, starting at the Q wave of the QRS complex, preceding through the ST segment and T wave, and culminating at the end of the T wave. A more correct physiologic determination of the repolarization phase of the ECG cycles is the JT interval. This interval starts at the J point, the terminus of the QRS complex, and extends through to the end of the T wave. Despite the ECG purity of the JT interval, most clinicians use the QT interval. When measuring the QT interval, the emergency physician must realize that there is lead-to-lead variation of the QT interval; in general, the longest

measurable QT interval on an ECG is considered the representative QT interval for that patient.

The QT interval is influenced by the patient’s age, sex, and heart rate-among many other variables. Although standard reference texts list the appropriate ranges for both age and sex, the clinician can apply several bedside methods to determine the appropriate maximum QT interval for an individual patient’s current heart rate. A rapid determination can be made for patients in sinus rhythm with rates between 60 and 100 bpm. To be considered normal for a particular rate, the QT interval must be less than one half the corresponding R-R interval.

A more complex method of calculation of the Corrected QT interval (QTc) is made using the Bazett formula (QTc = QT / RR^1/2). QT interval prolongation is considered to occur when the QTc interval is greater than 0.450 second. In the toxic setting, PVT is most commonly associated with QTc interval values greater than 0.500 second, although the potential for arrhythmia for a given QT interval depends upon both the individual patient and the agent ingested. Patient issues include current electrolyte status as well as any congenital tendency for QTc interval prolongation. Various congenital syndromes are described that encompass the long QT syndrome; it is theorized that certain patients who develop symptomatic QT interval prolongation after modest exposure to an offending agent likely have a partial tendency toward long QT syndrome-the exposure to the particular agent unmasks this tendency. Furthermore, a

direct relationship between the degree of drug-induced QT interval prolongation and the potential for the occurrence of torsade de pointes is not found. In fact, drug-induced torsade de pointes can occur without substantial prolongation of the QT interval.

Sodium channel blocker toxicity

Numerous reports are found throughout the literature describing sodium channel blocking agents; the impact of these agents has been described using numerous phrases, including membrane stabilizing effect, local anesthetic effect, and quinidine-like effect [3]. Refer to Table 2 for a list of agents with sodium channel blocking ability.

Voltage-gated sodium channels in cardiac tissue are located in the cell membrane and are opened in response to depolarization of the cell. Sodium channel blocking agents bind to the transmembrane channels and decrease the number of channels available for depolarization. The effect produced on the cell is a delay in the entry of sodium ions into the cardiac myocyte, which occurs during phase 0 of depolarization. As a result of this delayed entry, the upslope of depolarization is slowed and the QRS complex widens (Figs. 2 and 7).

Multiple ECG abnormalities are seen in patients with blockade of the cardiac sodium channels. The primary manifestation of blockade, as mentioned above, is the slowing of the upslope of phase 0 depolarization and thus a widening of the QRS complex (Figs. 2 and 8). With continued progression of the QRS prolongation, then there may be difficulty distinguishing between ventricular and supraventricular rhythms; and ultimately, this pro- gression may continue to a Sine wave pattern or, in the extreme, asystole.

In addition, sodium channel blockade may produce ventricular tachycardia through the development of a reentrant circuit after slowed intraventricular conduction and unidirectional conduction block. Ultimately, this ven- tricular tachycardia can degenerate into ventricular fibrilla- tion that could be fatal to the patient. Bradydysrhythmias are rare in sodium channel blocking agents because many of these also possess anticholinergic or sympathomimetic properties. These agents can, however, affect the pacemaker cells that are dependent on sodium entry, thus causing bradycardia. In Severe poisoning, the combination of a wide QRS complex and bradycardia is a sign of overwhelming sodium channel blockade of all channels, including the pacemaker cells.

Fig. 9 demonstrates the profound ECG abnormalities that can be encountered in patients with sodium channel block- ing toxicity. Fig. 9A, obtained in a young adult female patient who overdosed on a large amount of amitriptyline, reveals a wide complex tachycardia that can be easily confused with ventricular tachycardia. This rhythm is likely supraventricular in origin with a markedly widened QRS complex due to the sodium channel poisoning and tachy-

cardia due to the anticholinergic effects of the drug. Note also the prominent RV wave in lead aVR as well as the deep S wave in lead I, both findings of TCA cardiotoxicity. With sodium bicarbonate therapy, the patient improves with both a slowing of the rate and a narrowing of the QRS complex (Fig. 9B); subsequently, the ECG (Fig. 9C) normalizes approximately 24 hours after the initiation of therapy.

Calcium channel blocker toxicity

Calcium channel blockers are widely used medications that are prescribed for the management of hypertension and tachyarrhythmias (Table 3). These medications may, how- ever, have life-threatening Cardiovascular effects in over- dose and therapeutic dosing or with drug-Drug interactions. Calcium channel blockers exert these effects by the blockade of slow, voltage-sensitive bL-typeQ calcium chan- nels that are located in vascular smooth muscle and cardiac tissue [3]. The L-type channels are important for the conduction of the electrical impulse through cardiac tissues such as the sinoatrial (SA) and AV nodes; phase 4 depolarization in the cardiac cycle is also adversely affected by the blockade of these channels.

The blockade of calcium channels results in the relaxation of vascular smooth muscle, decreased contractility, slowed cardiac impulse propagation, and the inhibition of sponta- neous SA and AV node depolarization. Relaxation in the vascular smooth muscle has the clinical effect of vasodila- tion. The effect of decreased contractility with the vasodi- lation that occurs causes decreased cardiac output and, ultimately, profound hypotension. Other clinical effects that may be present include bradycardia and conduction blocks. Many different ECG presentations are possible with CCB toxicity (Fig. 10). Initially, toxicity from CCBs usually presents as a sinus bradycardia on the ECG. Some agents, however, have an initial effect of reflex tachycardia due to the peripheral vasodilation and resulting hypotension. With increasing CCB effect, various degrees of AV block as well as junctional and ventricular bradydysrhythmias are seen. First-, second-, and third-degree AV blocks are all possible because of the blockade of calcium channels in AV nodal

Table 3 Ca⁺⁺ channel blocking drugs Dihydropyridines

Nicardipine

Nifedipine Isradipine Amlodipine Felodipine Nimodipine Phenylalkylamine Verapamil Benzothiazepine Diltiazem

Diarylaminopropylamine ether Bepridil

Fig. 10 Rhythm disturbances seen in patients with both b-adrenergic and calcium channel blocking toxicities. atrioventricular blocks and bradycardias are commonly seen in these toxicities. A, Sinus bradycardia. B, Junctional rhythm. C, Idioventricular rhythm. D, Asystole, a not uncommon cardiac arrest rhythm; another common class of cardiac arrest rhythms is pulseless electrical activity.

tissues. Another ECG presentation is QRS complex widening that occurs because of ventricular escape rhythms or CCB-induced sodium channel blockade, which causes a delay in phase 0 of depolarization. With the presence of QRS complex widening, there is an increased risk for dysrhythmias, including asystole. In addition, ECG changes are seen reflective of cardiac ischemia due to hypotension and the decreased cardiac output that occurs.

b-Adrenergic blocker toxicity

b-Adrenergic blocking agents are Antiarrhythmic drugs that act by blocking the b-adrenergic receptor sites throughout the body (Table 4). These agents are commonly used to treat Cardiac conditions, including hypertension, angina, acute coronary syndrome, and tachydysrhythmias, as well as noncardiac conditions, such as glaucoma, anxiety, tremors, migraine headache, and pheochromocyto- ma. b-Adrenergic receptor sites are classified by 3 types, but b-1 and b-2 receptors are the most clinically relevant. b-1

receptors are located primarily within the myocardium, and b-2 receptors are found in the smooth muscle of bron- chioles, arterioles, and uterus [8]. b-Receptors function through the G protein-mediated activation of adenylate

Table 4 b-Blocking drugs Acebutolol

Atenolol

Betaxolol Bisoprolol Carvedilol Esmolol Labetalol Metoprolol Nadolol Pindolol Propranolol Sotalol Timolol

Table 5 Na⁺-K⁺ ATPase blocking agents Bufadienolides

Digoxin

Digitoxin

Digitalis purpurea (foxglove) Convallaria majalis (lily of the valley) Nerium oleander (oleander)

Thevetia peruviana (yellow oleander)

Urginea maritima (red squill)

cyclase, producing cyclic adenosine monophosphate and increasing intracellular and sarcoplasmic reticular calcium concentrations. Thus, the blockade of b-receptors decreases the concentrations of intracellular calcium.

The decrease in Intracellular calcium concentrations from b-blockade has various effects on the tissues contain- ing b-receptors. In the heart, where b-1 receptors are located, the result is decreased automaticity, contractility, and conduction velocity of the myocardial cells. These effects are often the desired Therapeutic effects of b- blocking agents. The blockade of b-2 receptors produces many of the adverse effects of the use of these agents, including bronchospasm, Peripheral vasoconstriction, in- creased Serum potassium concentrations, and decreased gluconeogenesis and glycogenolysis.

With acute toxicity from b-blocking agents, the most pronounced effects are seen on the cardiovascular system [3]. The hallmarks of toxicity include bradycardia, AV

block, and hypotension. The bradycardia that results from toxicity of b-blocking drugs is usually sinus bradycardia and is present because of the decreased SA node function, as well as decreased automaticity, contractility, and conduction velocity. These effects are also responsible for the hypotension that can be present with increased concentrations of the agents. Another notable ECG finding is AV block due to the prolonged AV conduction time. First-degree block is the most common type and is the most common finding in symptomatic overdose; but second- and third-degree blocks, junctional rhythms, and intraventricu- lar conduction delays can be present with increasing toxicity. electrocardiographic findings encountered in patients with b-adrenergic blocker toxicity are similar to those seen in poisoning with calcium antagonists and are depicted in Figs. 4 and 10.

In addition to the most common findings listed above, there are other ECG manifestations that are more specific to certain b-blocking agents. Some agents have been shown to possess membrane stabilizing activity that has been attrib- uted to blockade of sodium channels and which is shown on an ECG by QRS complex widening. Propranolol, labetalol, metoprolol, acebutolol, and pindolol have been shown to display this property, with propranolol exhibiting the most significant effects. Sotalol, another b-adrenergic blocker, has actions on the potassium channel as well and has been shown to prolong the action potential and lengthen repolarization (seen as a prolonged QT interval in ECG). Finally, both sotalol and propranolol have been associated

Fig. 11 Digoxin toxicity with atrial fibrillation and a slow ventricular response-likely a toxic response to the drug. Note the bdigoxin effectQ as seen in the ST segment depression seen in numerous leads. This ST segment depression, importantly not a toxic manifestation of the drug, is characterized by a gradual downsloping initial limb of the ST segment followed by a more abrupt return to the baseline in the terminal portion of the depressed segment.

Fig. 12 Digoxin toxicity with a junctional rhythm (regular, narrow QRS complex with an absence of P waves) and a slow ventricular response-likely a toxic response to the drug.

with ventricular dysrhythmias, including ventricular tachy- cardia and torsade de pointes.

Na/K-ATPase blocker toxicity (cardiac glycosides)

Cardiac glycosides, such as digoxin and other digitalis derivatives (Table 5), inhibit the Na/K-ATPase pump, which serves to maintain the electrochemical membrane potential

by concentrating sodium extracellularly and potassium intracellularly. When the Na/K-ATPase pump is inhibited, there is an increase in extracellular potassium and intracel- lular sodium [3]. With increased intracellular sodium concentrations, the transmembrane sodium gradient is reduced and there is an increase in the activity of the sodium-calcium exchanger to remove the excess intracellu- lar sodium. The net effect of this event is the increase in

Fig. 13 Digoxin toxicity with an idioventricular rhythm (regular, wide QRS complex with an absence of P waves) and a slow ventricular response-likely a toxic response to the drug.

intracellular calcium concentrations, resulting in a positive inotropic effect on cardiac myocytes. The positive inotropic effect is the therapeutic goal in the use of digitalis for patients with congestive heart failure, one of the primary indications for its use.

At therapeutic levels, there are a number of ECG changes that are associated with digitalis use. The earliest finding is labeled as the digitalis effect and includes abnormal inverted or flattened T waves, combined with ST segment depression, which is described as a scooped or sagging ST segment/T wave complex. Leads with tall R waves show this pattern most significantly. Other findings of therapeutic levels include QT interval shortening due to decreased ventricular repolarization time, lengthening of PR interval due to increased vagal activity, and increased U wave amplitude. Importantly, it must be stressed that these findings are not indicative of cardiotoxicity but of adequate bdigitalizationQ of the heart-cardiac tissue absorption of the drug.

The ECG changes that are associated with digitalis toxicity occur because of increased automaticity (secondary to increased intracellular calcium) and slowed conduction through the AV node. Premature ventricular contractions are the most common findings in acute intoxication, and a large number of dysrhythmias can result. The arrhythmias can be due to an excitatory effect (with premature contractions and tachyarrhythmias), a suppressant effect (bradycardia [Figs. 11 and 12]), bundle-branch blocks, AV conduction blocks), or any combination of the 2 effects. Paroxysmal atrial tachycardia with an associated block or accelerated

junctional rhythm is highly suggestive of digitalis toxicity. Another suggestive pattern for toxicity is a slowed ventricular response in a patient with atrial fibrillation on digoxin (Fig. 13). Finally, it is important to note that the typical ECG findings of hyperkalemia should be considered because this is often present with digitalis toxicity, including prominent T waves, QRS complex widening, and the sine wave QRS complex configuration (Fig. 3).

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