Imaging

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.