Intracoronary Aminophylline for Management of Bradyarrhythmias during Thrombectomy with the AngioJet® Catheter

ABSTRACT: Thrombectomy with the AngioJet® rheolytic thrombectomy catheter frequently causes bradyarrhythmias. This necessitates temporary pacemaker insertion and limits the device’s use. Novel approaches for treatment of bradyarrhythmias are being tested. This article focuses on the evidence supporting the role of adenosine in bradyarrhythmias during thrombectomy and presents data from a porcine model and the first human experience supporting the use of aminophylline, a competitive inhibitor of the adenosine receptor, via an intracoronary route, for prevention of bradyarrhythmias during thrombectomy. J INVASIVE CARDIOL 2008;20:12A–18A Bradyarrhythmias occur in up to 30% of percutaneous coronary interventions treated with the AngioJet® rheolytic thrombectomy (RT) catheter (Possis Medical, Inc., Minneapolis, Minnesota).1 The incidence is higher during interventions in the right coronary (RCA) or dominant circumflex (LCX) arteries, which supply the atrioventricular (AV) nodal branch. Their severity ranges from sinus bradycardia to varying degrees of heart block, including asystole. Most high-grade conduction blocks are hemodynamically significant and need immediate discontinuation of RT. Upon cessation, the rhythm quickly improves, usually without the need for any treatment, but can potentially have serious adverse outcomes. Therefore, Possis Medical recommends routine insertion of a temporary pacemaker during use of the RT catheter in the event of heart block.2 Since RT is used mostly in the emergent setting of acute myocardial infarction, the additional time required to obtain access in the right femoral vein and to insert a temporary pacemaker and the increased bleeding complications associated with venous access in anticoagulated patients are major deterrents to the use of RT. The RT catheter remains the only approved thrombectomy device that is able to substantially reduce clot burden and risk of distal embolization. The “no-reflow” phenomenon is a serious adverse event that impairs microvascular perfusion and causes myocardial injury, pain and hemodynamic and electrical instability with increased periprocedural morbidity and mortality. However, the absence of benefit in existing clinical data does not support the routine use of thrombectomy. Alternative management options for bradyarrhythmias have emerged with variable success and acceptability. Intravenous atropine and aminophylline, pacing via coronary guidewire and short-run use of the RT catheter to minimize occurrence of heart block are the most common alternatives. This article addresses the role of adenosine as a mediator of heart block during thrombectomy and the potential of intracoronary aminophylline to prevent and treat heart block during thrombectomy. Electrophysiological Effects of Adenosine on the Heart Adenosine has multiple electrophysiological effects on the heart. A regulator of coronary blood flow (A2 receptor subtype),3 it possesses negative dromotropic, inotropic and anti-beta adrenergic activity (A1 receptor subtype) and attenuates the myocardial effects of catecholamines.4 Adenosine is a biochemical mediator of AV conduction disturbances during decreased myocardial oxygen supply.5,6 These effects are mediated by adenosine receptors located on the extracellular surface membranes.7 Belardinelli et al6 have shown in a canine model that injection of adenosine via a catheter placed into the AV nodal branch of the RCA causes heart block (Figure 1 and 2). Adenosine mediates AVN block by prolongation of the A-H interval without any effect on the H-V interval.8 This effect was potentiated by infusion of dipyridamole, a nucleoside transport inhibitor (Figure 3). Methylxanthines, such as theophylline and aminophylline, are extracellular, competitive antagonists of the adenosine receptor, selectively reversing AVN conduction abnormalities mediated by adenosine.6,9 Belardinelli et al8 have shown that injection of aminophylline in the AV nodal artery in dogs reverses adenosine-mediated heart block by reversing the A-H interval prolongation caused by adenosine. In low concentrations, aminophylline does not independently influence cellular conduction, does not increase cyclic AMP level and does not increase the release of catecholamines (Figures 4 and 5). Mediator of Heart Block during Thrombectomy Thrombectomy with the RT catheter causes cellular hemolysis due to the high-pressure saline jet injected in the coronary artery. Red blood cells are rich in adenosine, and its release during hemolysis is believed to mediate heart block during thrombectomy. In a porcine model, we have shown that operation of the RT catheter in the RCA and injection of hemolyzed blood, collected both from the exhaust tubing of the RT catheter and by ex-vivo hemolysis using the catheter, successfully caused high-grade heart block.10 Pre-treatment with intravenous theophylline (5 mg/kg) successfully prevented subsequent heart block with RT catheter operation and injection of hemolyzed blood (Figure 6).10 Role of Methylxanthines as Adenosine Antagonists Aminophylline is a synthetic derivative of theophylline and is used for the treatment of status asthmaticus (5 mg/kg infusion). As competitive antagonists of the extracellular adenosine receptors, theophylline and aminophylline have been shown to reverse AV conduction delays with adenosine and are candidates for preventing adenosine-mediated heart block during thrombectomy. Anecdotal experience has shown that aminophylline is effective in improving AV conduction in atropine-resistant, high-grade heart block after myocardial infarction, which is probably an adenosine-mediated event.11,12 However, it is ineffective in reversing out-of-hospital bradycardic arrests.13 Intravenous aminophylline has arrhythmogenic and chronotropic effects with its ability to provoke atrial fibrillation, increases myocardial oxygen demand and raises systemic and intra-cardiac pressures and systemic and coronary vascular resistances.14–16 However, in small concentrations, aminophylline does not cause an increase in myocardial norepinephrine release.8 No animal or human study has ever tested the efficacy or safety of intracoronary (IC) aminophylline for treatment of heart block caused by the RT catheter. Animal Study on IC Aminophylline: Dose-ranging, Safety and Efficacy Study before and during Thrombectomy In a porcine model, we performed dose-ranging studies and evaluated the safety and efficacy of intracoronary aminophylline to prevent heart block during RT catheter operation.17 Twelve female pigs weighing 31–58 kg were tested for heart block caused by RT catheter use. All pigs were administered IC aminophylline for dose-ranging and safety studies. In dose-ranging studies, IC aminophylline was administered directly into the RCA via the guide catheter in doses of 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg and 40 mg. These doses produced an increase in heart rate of 20 beats per minute (bpm) with the 10 mg, 20 mg and 30 mg doses and up to 30 bpm with the 40 mg dose. Cumulative doses of up to 70 mg (1.3 mg/kg) were administered over a 20-minute period. Besides sinus tachycardia with a minor increase in systolic blood pressure of 10 mmHg, no significant hemodynamic change or supraventricular or ventricular dysrhythmia occurred. The RT catheter was not operated during dose-ranging safety studies. Only 5 of the 12 pigs that developed heart block with RT were tested for heart block after IC aminophylline was given. These changes normalized immediately after stopping RT catheter operation. IC aminophylline was then administered in doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg and 20 mg to test prevention of heart block. The 10-mg dose successfully prevented heart block in > 90% of pigs during subsequent RT operation. These findings were consistent and reproducible. During RT, the heart rate did not increase, as was noted when aminophylline was administered without RT catheter operation. Mild sinus bradycardia and milder grades of heart block occurred during some RT catheter operations but did not cause hemodynamic changes. The durability of aminophylline was tested by repeating RT catheter operation at 1-, 2-, 5-, 8- and 10-minute intervals from the first 10-mg dose that successfully prevented heart block. In 80% of repeat RT catheter operations, significant bradyarrhythmias were successfully suppressed for 10 minutes after the first aminophylline dose. In 20% of cases, significant bradyarrhythmias recurred within 5 minutes but were successfully suppressed with a second 10-mg dose. Human Experience with Intravenous Aminophylline Experience with IV aminophylline in humans is limited. A single-center experience starting IV aminophylline infusion 25 minutes prior to RT showed promise (K. Browne, MD, unpublished data, July 2002). Lee et al18 demonstrated in one non-randomized study that IV aminophylline started 5 minutes before RT catheter use was ineffective in preventing bradyarrhythmias. There are no published data on intracoronary use of aminophylline. To our knowledge, this article reports the first-ever human experience with IC aminophylline in prevention of heart block with RT catheter use. Preparation and Intracoronary Use of Aminophylline In our catheterization laboratory, aminophylline (Hospira, Inc., Lake Forest, Illinois) is stored in the PYXIS system. It is packaged as a 10-mL vial with a concentration of 25 mg/mL. A 2-mL amount of aminophylline is withdrawn with a 10-mL syringe and diluted in a sterile cup of 48-mL normal saline to create an aminophylline solution of 1-mg/mL concentration (Figure 7). A 20-mL syringe is used to draw and inject a 20-mg dose via the guide catheter. The RT catheter is advanced into the coronary artery and activated for a trial run proximal to the thrombus. ECG and hemodynamics are monitored (Figure 8 and 9). The RT catheter use is stopped if heart block occurs. The RT catheter is withdrawn into the guide. A 20-mL amount of aminophylline is injected via the guide catheter as a slow bolus over 10 seconds to avoid spillover into the aorta from a rapid, high-pressure injection. The RT catheter is then activated without delay, and thrombectomy is performed. If heart block or bradycardia with hypotension occurs, the RT catheter use is stopped and an additional 20-mg dose is administered in a similar fashion, followed by resumption of the RT catheter use. Human Experience with Intracoronary Aminophylline Since completion of porcine studies, 25 unselected patients have been treated with IC aminophylline for the treatment of hemodynamically significant, high-grade heart block during RT catheter operation or rotational atherectomy. Complete data are available on 20 patients (Table 1 and 2). The ECG tracings on 5 patients could not be retrieved from the CathCor® monitoring system (Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania) and are not reported. Of the 17 reported patients in whom the RT catheter was used, 14 had acute ST elevation myocardial infarction, while 3 had non-ST elevation myocardial infarction. Sixteen of 17 patients (94%) had culprit infarct-related vessels with obvious “large” to “very large” thrombus burden as determined by the operator. Three patients were undergoing rotational atherectomy of the RCA. All patients undergoing RT use had a test RT catheter operation proximal and prior to crossing the thrombotic lesion. In all patients, the RT catheter use caused high-grade heart block with hemodynamic compromise within 5–10 seconds, requiring discontinuation of the catheter use. Hence, all patients acted as their own controls. In the first 5 patients, after return of normal hemodynamics, a lower dose of IC aminophylline (10 mg) was given to test efficacy, followed by repeat RT catheter operation. In 2 of 5 patients (40%), additional doses of 10 mg–20 mg were needed for additional RT catheter runs within 1 minute of the first 10-mg dose: one patient was morbidly obese weighing 370 lb, while the second patient was overweight with a very large clot burden. Aminophylline in 10 mg–40 mg doses successfully prevented hemodynamically significant bradyarrhythmias in all 5 patients without the need for a temporary pacemaker. In one patient, a temporary pacemaker was prophylactically inserted as recommended after he had asystole during baseline RT catheter operation. However, a 25-mg dose of IC aminophylline prevented any recurrence for 5 subsequent RT catheter operations over the next 8 minutes, and the temporary pacemaker was never activated. Following this initial experience, it was apparent that a 10-mg dose had a variable and/or non-durable response in most patients. A 20-mg IC aminophylline dose was given to the next 15 patients. Of these, 12 patients had RT, while 3 patients underwent rotational atherectomy and developed asystole immediately after activation of a 1.5-mm Rotablator burr (Boston Scientific, Natick, Massachusetts) in the RCA. All patients had high-grade, significant AV block or asystole at baseline. Fourteen patients (93%) had a successful response to aminophylline. Three patients (20%) needed a second 20-mg IC dose for persistent heart block after a 20-mg dose. Two patients (13%) were resistant to a 40-mg aminophylline dose. One patient had severe sinus bradycardia with moderate hypotension, during which several short RT catheter runs could be continued. Since high-grade heart block was avoided, a temporary pacemaker was not needed. The second patient had recurrent, transient asystole, and a temporary pacemaker was placed and activated for RT catheter use. This patient was obese, had an exceptionally large clot burden in the RCA and represents the only true failure of aminophylline. None of the patients experienced any adverse arrhythmogenic or hemodynamic effects due to IC aminophylline. All patients had successful PCIs with normal TIMI III flow and were pain free with complete ST-segment resolution. There were no arrhythmias or deaths in this group at the 6-month follow-up. In this unselected cohort of 20 patients, aminophylline successfully prevented the need for temporary pacemaker insertion in 19 patients (95%), allowing uninterrupted thrombectomy with the RT catheter. During this time period, 12 patients with inferior myocardial infarction were treated with RT but did not require aminophylline in the absence of any significant heart block during a test run. Six patients had significant arrhythmias toward the end of RT catheter use: 1 had severe bradycardia with hypotension requiring atropine, 2 developed third-degree heart block (one of whom needed a temporary pacemaker insertion), 1 patient needed cardioversion for complete heart block followed by ventricular tachycardia and 2 patients had severe bradycardia or idioventricular rhythm with hypotension that resolved spontaneously. All patients had an uneventful clinical course as well. Discussion Thrombectomy is an effective strategy for clot removal from an infarct-related vessel. Despite the absence of data from randomized, clinical trials showing effectiveness of thrombectomy in improving clinical outcomes, use of thrombectomy continues to remain a valuable tool in selected patients with acute myocardial infarction who have large clot burdens. The frequent occurrence of bradyarrhythmias and recommendation for a temporary pacemaker, along with its inherent delays and bleeding risks, continues to be a major deterrent for its use for many operators despite its niche use as an effective thrombectomy device. The role of adenosine in mediating heart block is unequivocally proven from sophisticated animal studies. Theophylline and aminophylline are competitive antagonists of the adenosine receptor and prevent and effectively treat adenosine-mediated heart block by reversing the A-H interval delay caused by adenosine. This article summarizes the first published data from a porcine model demonstrating the safety and efficacy of intracoronary aminophylline with RT catheter use. More importantly, it is the first published experience of IC aminophylline in humans. Our anecdotal, single-center, observational experience in 20 patients has shown that intracoronary aminophylline is safe in 20 mg–40 mg doses and highly effective in preventing heart block induced by thrombectomy and rotational atherectomy in 95% of patients. Each of these patients acted as his or her own control: aminophylline was given only after each had demonstrated hemodynamically significant bradyarrhythmias during a test RT catheter run. The success in preventing heart block with subsequent RT catheter runs can be attributed solely to IC aminophylline use, since no other positive chronotropic drug was used. The dose range used (0.14 mg/kg–0.3 mg/kg) is significantly lower than the 1.3 mg/kg dose tested in pigs and less than 5% of the intravenous dose approved for use of aminophylline (5 mg/kg). With its brief transit time in the coronary circulation with subsequent distribution and dilution in the larger systemic circulation, these low doses of IC aminophylline have not caused any adverse effects. Additional doses may be necessary in some patients who are morbidly obese or have a particularly large thrombus burden requiring long and/or repeat RT catheter runs. Even with aminophylline’s effectiveness in preventing high-grade heart block, most patients will have either sinus bradycardia or even low-grade heart block, but the hemodynamic impact of these is minimal, and RT is easily tolerated, such that the procedure can be uninterrupted and temporary pacemaker insertion is easily avoidable. That tolerability and threshold for comfort, however, will depend on the operator. Conclusion Intracoronary bolus administration of aminophylline provides an easy, quick and effective alternative to temporary pacemaker insertion in patients who have hemodynamically significant high-grade heart block. For patients with a large thrombus burden who could benefit from thrombectomy using the RT catheter, bradyarrhythmias and need for temporary pacemaker insertion should not be an impediment to the use of RT, given the potential of IC aminophylline in preventing hemodynamically significant bradyarrhythmias. The limitations of an anecdotal experience are recognized. More rigorous evaluation may be needed with future studies.

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