Title: Incidence, Pathophysiology, and Treatment of Complications During Dobutamine-Atropine Stress Echocardiography
Abstract: HomeCirculationVol. 121, No. 15Incidence, Pathophysiology, and Treatment of Complications During Dobutamine-Atropine Stress Echocardiography Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBIncidence, Pathophysiology, and Treatment of Complications During Dobutamine-Atropine Stress Echocardiography Marcel L. Geleijnse, MD, PhD, Boudewijn J. Krenning, MD, PhD, Attila Nemes, MD, PhD, Bas M. van Dalen, MD, PhD, Osama I.I. Soliman, MD, PhD, Folkert J. ten Cate, MD, PhD, Arend F.L. Schinkel, MD, PhD, Eric Boersma, MD, PhD and Maarten L. Simoons, MD, PhD Marcel L. GeleijnseMarcel L. Geleijnse From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Boudewijn J. KrenningBoudewijn J. Krenning From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Attila NemesAttila Nemes From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Bas M. van DalenBas M. van Dalen From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Osama I.I. SolimanOsama I.I. Soliman From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Folkert J. ten CateFolkert J. ten Cate From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Arend F.L. SchinkelArend F.L. Schinkel From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author , Eric BoersmaEric Boersma From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author and Maarten L. SimoonsMaarten L. Simoons From the Erasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, the Netherlands. Search for more papers by this author Originally published20 Apr 2010https://doi.org/10.1161/CIRCULATIONAHA.109.859264Circulation. 2010;121:1756–1767Dobutamine stress echocardiography was clinically introduced in the mid-1980s.1,2 Indications for this stress modality rapidly expanded from diagnosing coronary artery disease (CAD) to risk stratification of patients undergoing vascular surgery; risk stratification of patients with chronic CAD, unstable angina, acute or chronic myocardial infarction (MI), or valvular heart disease; and the assessment of myocardial viability in patients with severe left ventricular (LV) dysfunction. Thus, dobutamine stress has been applied to progressively more complex, older, and higher-risk patients. Additionally, stress protocols became more aggressive, with higher dobutamine doses and the addition of atropine.3 Although generally regarded as a safe stress modality, serious complications do occur. In this review, we will describe the incidence, pathophysiology, and treatment of complications during dobutamine-atropine stress echocardiography (DASE). Data on incidence of complications were obtained from 26 studies including >400 patients that reported at least the major complications of mortality, acute MI, ventricular fibrillation, and sustained ventricular tachycardia,4–29 for a total of 55 071 patients (Table 1). In addition, references are given to case reports and studies dealing specifically with a particular complication. Table 1. DASE Safety Reports in >400 PatientsMertes4Picano5Pellikka*6Zahn7Hiro8Lamisse9Pinton10Hennessy11Secknus12Bremer*13Year of publication1993199419951996199719971997199719971998Stress protocol40/1†40/150/2†50/140/140/150/050/140/240/2No. of patients111829491000100073260073547430111035History of MI, %33.569.0NA21.5NA21.2NA40.915.825.8Mean age, y60566959626257596669Complications, % Death0000000000 Cardiac rupture0000000000 MI00.070.10000000.030 Cerebrovascular accident000.10000000.030 Atropine intoxication00.1700000000 Asystole0000000000 Atrioventricular block0.63NANA0.10NANA0.68NANANA Ventricular arrhythmias Ventricular fibrillation00.0700.10000000.10 Ventricular tachycardia Sustained00.070.40000.5400.210.170.10 Nonsustained3.6NA5.61.8NA1.10.51.72.37.3 Premature ventricular complex15.4NA18.97.1NA8.011.8NA8.0NA Supraventricular arrhythmias Supraventricular tachycardia3.4NA7.00.3NA0.40.03.01.7NA Atrial fibrillation or flutter0.7NA2.21.0NA1.10.31.11.11.9 Premature atrial complex7.7NANANANA5.63.8NANANAOther end points, % Hypotension3.22.12.92.53.60.30.80.23.71.6 Hypertension0.90.81.31.0NA2.63.50.20.80.9 Side effects3.22.43.04.4NA1.03.101.55.1 Wall motion abnormalities2.9NA10.610.0NA09.0NA0.96.3Pezzano14Plonska15Mathias16Takeuchi17Poldermans18Chenzbraun19Hirano20Cortigiani21Rodriguez Garcia22Year of publication199819991999199919991999200120012001Stress protocol40/140/140/140/1†40/150/140/040/1†40/0No. of patients30415824033109016594008976366832History of MI, %63.00.022.750.442.5NANANANAMean age, y585256636267NA60NAComplications, % Death000000000.01 Cardiac rupture000000000.01 MI000.020.090.090000.06 Cerebrovascular accident000000000.01 Atropine intoxication000.12000000 Asystole0.0300000000 Atrioventricular block0.030.170.400.28NA0.25NANA0.03 Ventricular arrhythmias Ventricular fibrillation0.0700.0200.180000.04(Continued)Table 1. ContinuedPezzano14Plonska15Mathias16Takeuchi17Poldermans18Chenzbraun19Hirano20Cortigiani21Rodriguez Garcia22NA indicates not available.*Completely or partially supervised by trained registered nurses.†Patients within an early, initial time frame underwent DASE without atropine. Stress protocol is displayed as follows: dobutamine dose in μg/kg per minute; atropine dose in mg.‡Obtained by a prior smaller safety study from the same author.60§Accelerated protocol.∥Contrast-enhanced imaging in 59%25 and 56%26 of patients, respectively. Ventricular tachycardia Sustained000.200.090.780.2500.310.13 Nonsustained2.11.03.50.82.7NANA1.3NA Premature ventricular complex33.74.631.243.6NANA34.1NANA Supraventricular arrhythmias Supraventricular tachycardia1.600.90.2NANANANANA Atrial fibrillation or flutter0.50.50.80.61.50.5NA0.3NA Premature atrial complex8.61.29.527.8NANANANANAOther end points, % Hypotension0.27.60.40.40.367.0NA0.8NA Hypertension0.42.61.5NA0.23.5NA0.6NA Side effects0.50.7NANA0.24.0NANANA Wall motion abnormalitiesNA19.8NA32.00.2‡0NANANATsutsui23Abreu24Tsutsui25Timperley26San Roman27Aggeli28Kane*29Year of publication2004200520052005200820082008Stress protocol40/2§40/250/2∥40/1∥40/1§40/1∥40/2No. of patients16645467249875196252506755History of MI, %20.0NA13.2NA27.336.216.0Mean age, y60606264646569Complications, % Death0000000 Cardiac rupture0000000 MI0000001 Cerebrovascular accident0000000 Atropine intoxication0000000 Asystole0000000 Atrioventricular blockNANANANANANANA Ventricular arrhythmias Ventricular fibrillation0.060.040000.020.03 Ventricular tachycardia Sustained0.3000.320.270.100.180.06 Nonsustained1.50.21.10.30.70.34NA Premature ventricular complex22.8NA24.33.32.24.0NA Supraventricular arrhythmias Supraventricular tachycardiaNANA1.6NA1.20.1NA Atrial fibrillation or flutter1.2NA1.7NA0.60.5NA Premature atrial complex5.1NA4.80.80.7NANAOther end points, % Hypotension1.9NANANA0.7NANA Hypertension5.5NA1.70.31.52.1NA Side effectsNANANANA1.8NANA Wall motion abnormalitiesNANANANA0.9NA4.0Potentially Life-Threatening ComplicationsMortalityIncidenceIncidence is <0.01% (0.002%; range, 0.00% to 0.01%). Case reports are available.30–33PathophysiologyIn DASE safety studies, mortality as a result of ventricular fibrillation was reported only once.22 In 4 case reports, lethal cases of cardiac rupture were described (see next section).30–33TreatmentSee other specific sections for treatment of potentially fatal complications.Cardiac RuptureIncidenceIncidence is <0.01% (0.002%; range, 0.00% to 0.01%). Case reports are available.30–35PathophysiologyCardiac rupture was reported in 7 patients undergoing DASE with akinetic or dyskinetic inferior myocardium resulting from a recent (4- to 12-day-old) inferior MI. In all cases, the patient suddenly developed (atypical) chest pain and lost consciousness with pulseless electromechanical dissociation. In 4 patients, cardiac rupture was fatal.30–33 Strong inotropic stimulation of necrotic and thinned myocardium may increase wall stress to such an extent that rupture results in that part of the myocardial wall with the least resistance. Of note, low-dose dobutamine provides strong inotropic stimulation, as was shown in 2 case reports with ruptured myocardium at doses of only 10 μg/kg per minute.30,34 Whether the inferior myocardial wall is more prone to rupture is controversial.36,37 Diagnosis should be based on the detection of sudden development of pericardial effusion. Of note, in 1 patient mild pericardial effusion was seen on the rest echocardiogram.31 It may be good practice to exclude cardiac pseudoaneurysm or rupture first in patients after an acute MI.TreatmentDiscontinue dobutamine infusion. Emergency pericardiocentesis and surgery should be performed.Myocardial InfarctionIncidenceIncidence is 0.02% (range, 0.00% to 0.10%). Case reports are available.38–43PathophysiologyDobutamine-atropine stress may cause an acute MI through different hypothetical mechanisms. In a coronary artery with an unstable atherosclerotic plaque, increment of heart rate and contractility may mechanically increase shear forces, resulting in plaque disruption and thrombosis. Additionally, dobutamine has been shown to induce platelet activation and aggregation44 and α1-mediated coronary vasoconstriction, which may paradoxically be exacerbated by administration of a nonselective β-blocker (see section on coronary spasm). Dobutamine stress–induced expansion of a sinus of Valsalva aneurysm, with compression of a coronary artery, was once reported as a potential mechanism for MI.42TreatmentDiscontinue dobutamine infusion. Consider thrombolysis or immediate coronary angiography followed by angioplasty.45Cerebrovascular AccidentIncidenceIncidence is <0.01% (0.005%; range, 0.00% to 0.10%). A complication-specific publication is available.46PathophysiologyDobutamine-atropine stress may cause a cerebrovascular accident through different mechanisms. Increment of heart rate and blood pressure may mechanically increase shear forces across an aneurysmal arterial wall, leading to hemorrhagic stroke, although in a series of 40 patients with at least 1 intracranial aneurysm, no evidence of aneurysm instability was seen.46 Ischemic stroke (including transient ischemic attack) may be caused by the same mechanisms as described in the previous section on MI. Additionally, ischemic stroke may occur in the setting of dobutamine stress–induced hypotension (see later) as a result of high-grade carotid artery stenosis6 or LV thrombus. However, in 1 study no thromboembolic complications were seen in patients with LV thrombus.47TreatmentDiscontinue dobutamine infusion. Hospitalization in a stroke unit should occur. Consider immediate imaging with magnetic resonance imaging or computed tomography and thrombolysis.48Cardiac AsystoleIncidenceIncidence is <0.01% (0.002%; range, 0.00% to 0.03%). Case reports are available.49–51PathophysiologyThe syndrome of sinus bradycardia with or without hypotension is well known during DASE. Eventually, this may lead to asystole lasting for 6 to 8 seconds.14,49 Although, in an early report, sinus node deceleration was linked to ischemia in the inferior myocardial wall,52 a powerful cardioinhibitory vagal reflex seems a more likely mechanism.53 This reflex, known as the Bezold-Jarisch reflex, is a neurally mediated mechanism in which vigorous myocardial contraction stimulates intramyocardial mechanoreceptors, resulting in sympathetic withdrawal and enhanced parasympathetic activity.54 Alternatively, it was suggested that prohibition of oral intake before DASE may lead to volume depletion, and experimental data have demonstrated that in the presence of reduced cardiac volume, β1-adrenergic stimulation can elicit paradoxical bradycardia.55 In contradiction to the earlier described life-threatening complications, patients with asystole usually had good baseline LV function with a hyperdynamic response to dobutamine and usually an absence of myocardial ischemia.49–51TreatmentDiscontinue dobutamine infusion. Administer intravenous bolus of atropine (0.5 to 2 mg).Ventricular FibrillationIncidenceIncidence is 0.04% (range, 0.00% to 0.18%). Case reports are available.43,56–59PathophysiologyAll but 3 patients16,43,59 with ventricular fibrillation and available data had impaired LV function, and all had evidence of (usually severe) myocardial ischemia on DASE.5,7,16,28,56–60 Furthermore, except for 1 patient with ST-segment elevation, nonsignificant CAD, and suspected coronary spasm,58 all patients who underwent coronary angiography showed left main, severe proximal left anterior descending, or 3-vessel CAD.5,7,13,24,28,43,59 Therefore, ventricular fibrillation seems to occur mainly in patients with structural heart disease (presence of persistent factors such as scar tissue) in combination with inducible, dynamic factors such as severe and/or extensive myocardial ischemia and possibly electrolyte disturbances (see also the next section on other ventricular arrhythmias).TreatmentDiscontinue dobutamine infusion. Cardiopulmonary resuscitation was successful in all but 1 patient.22Sustained Ventricular TachycardiaIncidenceIncidence is 0.15% (range, 0.00% to 0.78%). Complication-specific publications are available.61–63 Case reports are available.64–66PathophysiologyDobutamine may provoke ventricular arrhythmias by several mechanisms. Dobutamine has differential effects on action potential duration,67 QRS duration, and QTc interval68 in normal and ischemic myocardium. The abnormal dispersion of conduction in adjacent areas of ischemic and nonischemic myocardium thus created may be important in β-receptor–mediated (reentry) arrhythmogenesis. Additionally, dobutamine may increase intracellular calcium concentration by second messenger cyclic AMP.69 Increased intracellular calcium has been shown to increase automaticity in ventricular myocardium and provoke triggered activity in the form of delayed afterdepolarizations.70 Finally, β-receptor stimulation reduces plasma potassium level, which may temporarily predispose patients to ventricular arrhythmias.71 In many safety studies, clinical predictors for these arrhythmias were analyzed. Ventricular arrhythmias have quite consistently been related to impaired LV function17,18,28,29,60–63,72,73 and a history of ventricular arrhythmias60,62,72 but not to atropine addition12,22,60,62,63 or myocardial ischemia.12,14,18,19,22,60–63,73,74 However, in most of these studies a distinction between nonsustained and sustained ventricular arrhythmias was not made (probably because of the small number of the latter), and the incidence of ventricular tachycardias may be overestimated because of difficulties in differentiation with supraventricular tachycardia with aberration.61 Nonsustained ventricular tachycardias do not seem to be related to long-term adverse outcome.61,73TreatmentDobutamine infusion should be discontinued (ventricular arrhythmias are usually brief and self-terminating). Administer intravenous β-blocker as a natural dobutamine antagonist (metoprolol 5 to 10 mg over a 5-minute period). Administer intravenous procainamide (10 mg/kg body weight over a 5-minute period) or amiodarone (150- to 300-mg bolus) in β-blocker–resistant sustained ventricular tachycardia. Cardiovert if the patient is hemodynamically unstable or persistent.Other Rhythm and Conduction DisturbancesSupraventricular ArrhythmiasIncidenceIncidence of premature atrial complex is 7.8% (range, 0.7% to 27.8%). Incidence of supraventricular tachycardia is 1.3% (range, 0.0% to 7.0%). Incidence of atrial fibrillation is 0.9% (range, 0.3% to 2.2%). A complication-specific publication is available.63PathophysiologyLittle is known about the mechanism of dobutamine stress in the induction of supraventricular arrhythmias. In 1 study,63 supraventricular arrhythmias occurred more frequently in patients with more extensive impairment of LV function. The associated increases in left atrial size and pressure in such patients are well-known predictors of these arrhythmias. In another study,9 supraventricular arrhythmias occurred more frequently in elderly patients.TreatmentIn the case of sustained supraventricular arrhythmias, dobutamine infusion should be discontinued (supraventricular arrhythmias are usually brief and self-terminating). Administer an intravenous β-blocker (metoprolol 5 to 10 mg; dose may be increased in case of existing maintenance dose), verapamil (10 mg over 10 minutes; dose may be reduced in case of previous use of a β-blocking drug or hypotension), or digoxin (bolus of 0.5 mg). Digoxin effects may take several hours and are therefore less useful for rapid rate control75 but may be preferred in patients with LV dysfunction. In regular supraventricular tachycardias, adenosine (intravenous bolus of 6 or 12 mg) may be helpful for diagnosis by induction of atrioventricular block and may actually end circus movement tachycardias. Adenosine has a half-life of only 2 seconds, and therefore adverse reactions (facial flushing, dyspnea) last only a short time.76 Cardiovert if the patient is hemodynamically unstable.Atrioventricular BlockIncidenceIncidence is 0.23% (range, 0.03% to 0.68%). A complication-specific publication is available.77PathophysiologyTransient second- or third-degree atrioventricular block may be induced by several mechanisms such as myocardial ischemia (the conduction system is supplied mainly by the right coronary artery and also more distally by the left anterior descending artery), the Bezold-Jarisch reflex, and latent abnormalities in the His-Purkinje system. In a detailed study in patients with dobutamine stress–induced second-degree atrioventricular block by Hung et al,77 the incidence of atrioventricular block was 4.0% (12 of 302 patients), indicating a higher incidence than that reported in the safety studies. All 6 patients with second-degree atrioventricular block Mobitz type II (usually located in the His bundle or bundle branches) had CAD (usually left anterior descending artery or 2-vessel CAD). In all but 1 patient, atrioventricular block occurred concomitantly with the onset of new wall motion abnormalities. After successful coronary revascularization, AV block could not be induced by repeat DASE. In the 6 patients with second-degree atrioventricular block Mobitz type I (Wenckebach block, usually located in the atrioventricular node), the relation with CAD and myocardial ischemia was less clear. Vagal-mediated effects by the aforementioned Bezold-Jarisch reflex (see section on asystole) could be a contributing factor is these patients. This assumption was supported by positive head-up tilt testing in all 3 patients with second-degree atrioventricular block Mobitz type I without CAD. Atrioventricular block is less common during this vagal reflex than sinus bradycardia, sinoatrial block, or sinus arrest, probably because these sinus node problems protect the atrioventricular node. Finally, dobutamine enhances atrioventricular nodal conduction and may thus unravel latent abnormalities in the more distal His-Purkinje system.TreatmentIn Mobitz type II, discontinuation of dobutamine infusion is indicated (of note, atropine may actually worsen subnodal block78). In Mobitz type I (Wenckebach) block, administer an intravenous bolus of atropine (0.5 mg; may be repeated up to 2.0 mg) if necessary.Coronary SpasmIncidenceTrue incidence is unknown but is 0.14% in 1 safety study.9 Case reports are available.58,79–86 A complication-specific publication is available.87PathophysiologyCoronary spasm during dobutamine stress is believed to result from α1-receptor–mediated coronary vasoconstriction,88 particularly in patients with endothelial dysfunction due to smoking, hypertension, or diabetes mellitus.89,90 Systolic “spasm” (or better compression) during dobutamine stress may be caused by myocardial bridging.86 In 1 study,87 including 51 patients with angina at rest accompanied with electrocardiographic ST-segment elevation, nonsignificant CAD, and proven spasm (induced with acetylcholine), dobutamine stress provoked ST-segment elevation in 7 patients (14%). In another study,80 ST-segment elevation and wall motion abnormalities became evident only after dobutamine stress after the administration of propranolol, and it has been suggested that nonselective β-blockers may paradoxically exacerbate spasm by blocking the β2-receptor–mediated coronary vasodilatory effects of dobutamine. Alternatively, coronary spasm may be caused by hyperventilation in an anxious patient.91 Coronary spasm should be suspected in patients with dobutamine stress–induced ST-segment elevation in noninfarct leads and severe new wall motion abnormalities, although these may be absent in distal spasm,85 in combination with nonsignificant lesions on coronary angiography. ST-segment elevation in noninfarct leads has also been linked to transmural myocardial ischemia due to severe CAD.92–97 The final diagnosis of coronary spasm can only be confirmed on coronary angiography with ergonovine, acetylcholine, or dobutamine provocation.85,87TreatmentSublingual nitroglycerin should be administered first rather than β-blocking agents83,84 because of a small risk of exacerbation of spasm with a β-blocker.80 Long-term treatment with calcium channel blockers should be considered, as well as risk factor modulation.Disturbances in Blood PressureHypotensionIncidenceAs test end point, incidence is 1.7% (range, 0.2% to 7.6%). Dependent on definition, the overall incidence is much higher; a decrease of >20 mm Hg is noted in ≈20% of patients.98,99 Complication-specific publications are available.98–106PathophysiologyHypotension may result from an inadequate increase in cardiac output to compensate for an expected decrease in systemic vascular resistance and/or a disproportionate decrease in systemic vascular resistance. An inadequate increase in cardiac output may be due to inadequate contractile reserve, severe ischemic LV dysfunction, or fixed or dynamic left-sided obstructive heart disease. Dynamic LV cavity obliteration due to strong inotropic stimulation was proposed as an important cause for reduced cardiac output and hypotension,103 but in later studies conflicting results have been reported for this mechanism as an important cause of hypotension.101,104–106 The second mechanism, a disproportionate decrease in systemic vascular resistance, may be due to the aforementioned Bezold-Jarisch reflex or, rarely, an allergic reaction to dobutamine (see later section on dobutamine hypersensitivity). The consistent absence of histories of prior MI or congestive heart failure,98,99 ischemia,17,98–102 or CAD17,98,99,102 in studies with heterogeneous patients is indirect evidence of a dobutamine-induced hypotension mechanism that is based primarily on an excessive decrease in systemic vascular resistance instead of a mechanism principally involving inadequate cardiac output in most patients. In patients with impaired LV function (and thus a lesser role for the Bezold-Jarisch reflex), there is some evidence that contractile reserve plays a more important role in the pathogenesis of hypotension72,107,108 and that hypotension has adverse prognostic value.107TreatmentDiscontinue dobutamine infusion in symptomatic, severe (≥40 mm Hg) hypotension. Trendelenburg position should be considered. Rapid fluid infusion should be started if the patient is symptomatic. In combination with sinus bradycardia, exclude inferior wall ischemia and consider an intravenous bolus of atropine (0.5 to 2 mg).HypertensionIncidenceAs test end point, incidence is 1.3% (range, 0.2% to 5.5%). A complication-specific publication is available.109PathophysiologyStress-induced hypertension normally constitutes an end point for test termination because of safety concerns.110 The clinical characteristics of patients with a marked hypertensive response were analyzed in only 3 studies.12,27,109 Such patients more often had a history of systemic hypertension and higher resting blood pressure and were more often on treatment with β-blockers compared with patients without a hypertensive response. These findings underscore the importance of adequate blood pressure control before dobutamine-atropine stress to avoid nondiagnostic tests. Alternatively, the earlier use of atropine has been proposed109 in patients with a marked hypertensive response because of only a mild additional effect on blood pressure and a marked chronotropic effect.TreatmentDiscontinue dobutamine infusion; in the case of persistent hypertension, administer an intravenous β-blocker.Direct Side Effects of Dobutamine-AtropineAtropine IntoxicationIncidenceIncidence is 0.03% (range, 0.00% to 0.17%). No case reports are available.PathophysiologyAtropine intoxication is a central anticholinergic syndrome in which atropine acts on central nervous system cholinergic receptors, causing altered mental status (confusion, delirium, hallucinations) or prolonged sedation for several hours. This syndrome seems more common in elderly patients and generally requires a dose of atropine of several milligrams.111 Of note, the incidence rates reported in this review concern the total number of atropine intoxications divided by the total number of patients who underwent DASE published in reports that specifically provided information on atropine intoxication (Table 1). Because the number of patients who actually received atropine is much lower, the incidence in patients who received atropine may be ≈2 to 3 times higher.TreatmentPhysostigmine 1 to 2 mg intravenously can reverse central atropine effects. Its administration also acts as a diagnostic test; rapid improvement rules out other causes of confusion such as cerebral stroke. Alternatively, avoidance of atropine in the elderly and administration of glycopyrrolate, an anticholinergic drug that does not cross the blood-brain barrier and therefore cannot cause a central anticholinergic syndrome, have been proposed.112Dobutamine ExtravasationIncidenceDobutamine extravasation was reported only once in 2 patients in a safety study6 but is probably underreported. Case reports during continuous therapeutic infusion are available.113,114PathophysiologyDobutamine accumulation in subcutaneous tissue can cause local vasoconstriction by stimulation of α1-receptors, which may result in limb ischemia115 and during longer infusion may result in necrosis.113 Dobutamine accumulation in subcutaneous tissue may also cause a local hypersensitivity reaction (see next section).TreatmentDiscontinue dobutamine infusion. Elevate the involved extremity. Consider local injection of 5 to 10 mg phentolamine mesylate in 10 to 15 mL saline, which is a reversible, nonselective α-receptor antagonist.Dobutamine HypersensitivityIncidenceOnly 3 patients were described in safety studies.7,16 Case reports of local dermal lesions116–118 and asthma119 during continuous therapeutic infusion are available.PathophysiologyDobutamine solution contains sodium bisulfite, which may cause allergic-type reactions with systemic symptoms and/or signs such as bronchospasm, flushing, tingling, pruritus, urticaria, angioedema, and hypotension or local dermal lesions characterized by erythema, pruritus, cellulitis, and phlebitis with or without bullae formation at the side of the injection.120TreatmentDiscontinue dobutamine infusion. Administer antihistamine therapy.DiscussionToday’s aggressive DASE protocol and expanding indications with inclusion of sicker patients have raised concerns about the safety of this stress modality.121 In the present review, potentially life-threatening complications (cardiac rupture, acute MI, cerebrovascular accident, asystole, ventricular fibrillation, and sustained ventricular tachycardia) occurred in 116 patients, of whom 1 died, accounting for 1 complication in 475 tests (Table 2). This number is in reasonable agreement with the complication rate found in the recently published International Stress Echo Complication Registry (Table 2).122Table 2. Incidence of Major Complications in This Meta-Analysis and the International Stress Echo Complication Registry122ComplicationPresent Meta-Analysis (n=55 071)Complication Registry122 (n=35 103)No. of PatientsIncidence RateNo. of PatientsIncidence RateCauses of mortality were *ventricular fibrillation and †cardiac rupture in 3 and ventricular fibrillation in 2 patients.Mortality11: 48 31651: 7021Cardiac rupture11: 48 31651: 7021Asystole11: 48 31621: 17 552Cerebrovascular accident31: 16 10531: 11 701Myocardial infarction111: 5006111: 3191Ventricular fibrillation191: 2898111: 3191Sustained ventricular tachycardia811: 680271: 1300Total major complications116*1: 47559†1: 595It is important to note that for exercise stress testing, dipyridamole stress echocardiography, and dipyridamole stress scintigraphy, lower complication rates were reported of 1 complication in approximately each 1100,123 1400,124 and 1600125 tests, respectively. Several reasons may account for this difference. Patients referred for