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Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: Initial clinical experience
Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: Initial clinical experience Patricia Gramling:Babb, MD, Michael J. Miller, MD, Scott T. Reeves, MD, Raymond C. Roy, MD, and Michael R. Zile, MD Charleston, S.C. Surgical sympathectomy can relieve symptoms of angina in patients with refractory angina. However, in these high-risk patients this thoracic surgery may result in significant morbidity and mortality rates. Similar sympathetic blockade can now be produced with high thoracic epidural analgesia (HTEA). From September 1995 to August 1996, we treated 10 consecutive patients with HTEA. These eight men and two women, aged 58 ± 5 years, with extensive three-vessel coronary disease and ejection fractions of 40% ± 5%, had New York Heart Association (NYHA) class IV angina despite medical therapy, including nitrates, I~-blockade, calcium channel blockade, and narcotics. HTEA was performed at the T1 through T4 levels with a catheter placed either percutaneously or surgically, with radiographic confirmation of catheter placement with an epidurogram or computed tomography scan. Bupivacaine (0.25% to 0.5%), an amide local anesthetic, was given as a bolus through the epidural catheter and then maintained either as a continuous infusion or an intermittent rebolus. The epidural catheter remained in place for 7 days in four patients, 14 days in three patients, and >-90 days in three patients. Before consideration for HTEA, each patient was deemed unsuitable for or refused coronary bypass surgery and percutaneous coronary angioplasty and had NYHA class IV symptoms of angina. Seven of 10 patients required intravenous nitroglycerin and heparin and were unable to be discharged from the intensive care unit because of anginal symptoms. Two of these seven patients also required an intraaortic balloon pump for symptom control. After HTEA, all 10 patients had improved symptoms, with five patients improving to NYHA class II symptoms and five improving to NYHA class II1.All seven patients receiving intravenous nitroglycerin, heparin, or intraaortic balloon pump support had these modalities discontinued. Six of these seven patients were subsequently discharged from the hospital. One patient died from a non-HTEA related cause. There were no HTEA-related deaths. There were three From the Department of Anesthesia and Perioperative Medicine, and the Department of Medicine, Division of Cardiology, the Ralph H. Johnson Department of Veterans Affairs Medical Center, and the Medical University of South Carolina. Received for publication Dec. 20, 1996; accepted March 26, 1997. Reprint requests: Patricia Gramling-Babb, MD, Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425. E-mail: [email protected] Copyright © 1997 by Mosby Year Book, Inc. 0002-8703/97/$5.00 + 0 4/1/82104
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catheter-related complications necessitating catheter removal during 12 months of HTEA use. Local infection developed in one patient, one had catheter occlusion caused by fibrosis, and one patient had chronic back pain exacerbation from a paraspinous muscle spasm. No patient had a myocardial infarction or a significant arrhythmia. In patients with otherwise intractable angina pectoris, HTEA is an effective modality that produces symptomatic relief of angina pectoris and allows increased activity level. (Am Heart J 1997; 134:646-55.)
During the past decade there have been significant improvements in techniques of surgical revascularization, catheter-based revascularization, and medical therapy for patients with coronary artery disease and angina pectoris. 1-3 However, despite these advances, there are an increasing number of patients with angina pectoris who are refractory to medical therapy and are not candidates for coronary artery bypass grafting or interventional catheterization. These patients are often treated with narcotics for pain relief and are forced to severely reduce their level of activity and productivity. This group of patients presents a difficult management problem for physicians and the medical community because their care requires frequent outpatient office visits, emergency room visits, and hospitalizations. Thus, in addition to patients having frequent recurrences of anginal pain, refractory angina consumes significant health care resources. Recently it has become clear that alleviating the pain caused by myocardial ischemia may be possible by altering sympathetic afferent nerve fibers. 4, 5 Indeed, previous studies showed that surgical sympathectomy could relieve symptoms of angina pectoris in patients with refractory angina. 6 However, in this group of patients with refractory angina, the invasive surgery necessary to perform this sympathectomy results in significant morbidity and mortality rates.6, 7 Now, however, sympathetic blockade can be produced with high thoracic epidural analgesia
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Table I.Patient population
Age Sex Extent of CAD Previous CABG Previous PTCA Ejection fraction Coronary risk factors Smoking Hypertension Diabetes Cholesterol Family history Medications Nitrates ~-blocker Calcium channel blockers Intravenous nitrates Intravenous heparin Intraaortic balloon pump ACE inhibitor Previous myocardial infarction NYHA class IV Currently in the ICU Currently an outpatient
58 - 5 yrs 8 men/2 women 3-vessel 6 6 40% _+5%
P i l r c u t l n i l l PIKClIK~t
L__
4 5 4 4 2 10 8* 9t 7 7 2 6 7 10 7 3
CAD, Coronary artery disease; CABG,coronary artery bypass graft; PTCA, percutaneous t r a n s l u m i n a l coronary angioplasty; ACE, angiotensin converting enzyme; ICU, intensive care unit. *One patient could not take ~3-blockers because of a markedly reduced ejection fraction, and one patient had severe chronic obstructive lung disease. tOne patient could not take a calcium channel blocker because of severe hypotension.
(HTEA). 8-1° E p i d u r a l blockade of t h e cardiac a f f e r e n t a n d efferent s y m p a t h e t i c fibers in t h e u p p e r thoracic s y m p a t h e t i c s e g m e n t s w i t h local a n e s t h e t i c s m a y b l u n t the p e r c e p t i o n of cardiac p a i n d u r i n g m y o c a r dial ischemia, which is m e d i a t e d t h r o u g h cardiac s y m p a t h e t i c a f f e r e n t n e r v e fibers a n d provides p a i n relief to p a t i e n t s w i t h r e f r a c t o r y a n g i n a pectoris. I t is also possible t h a t H T E A m a y p r e v e n t m y o c a r d i a l i s c h e m i a b y a l t e r i n g m y o c a r d i a l oxygen d e m a n d or supply. H T E A m a y r e d u c e t h e m a j o r d e t e r m i n a n t s of m y o c a r d i a l oxygen d e m a n d b y d e c r e a s i n g h e a r t r a t e and reducing preload and afterload without altering c o r o n a r y p e r f u s i o n p r e s s u r e . 4,s, 11, 12 I n addition, H T E A m a y a l t e r m y o c a r d i a l oxygen s u p p l y b y inc r e a s i n g t h e d i a m e t e r of stenotic vessels a n d the p r e f e r e n t i a l shifting f r o m epicardial to endocardial blood flow. 9 T h e p u r p o s e of this r e t r o s p e c t i v e s t u d y w a s to t e s t t h e h y p o t h e s i s t h a t H T E A is a n effective m e t h o d of a l l e v i a t i n g s y m p t o m s of a n g i n a l p a i n in p a t i e n t s w i t h m e d i c a l l y a n d surgically r e f r a c t o r y a n g i n a pectoris. METHODS Patients. Table I presents the clinical characteristics of
the 10 patients examined in this study. Patients treated at
Ventral Incision (exit site) Incision
\
.cuff: iw Filter
Dupen Catheter Insertion Fig. 1. Method of HTEA catheter placement and catheters and other components used to perform HTEA.
the Ralph H. Johnson Department of Veterans Affairs Medical Center in Charleston, S.C., were men and account for the preponderance of male patients in this study. Some patients were treated at the Medical University of South Carolina Hospital. Patients were excluded if they had a history of significant spinal disease or extensive spinal surgery, were receiving anticoagulation therapy that could not be stopped, had a bleeding history, or had an allergy to local anesthetics. Before consideration for HTEA, all patients were "treated with maximally tolerated medical therapy. Treatment included nitrate, calcium channel blocker, and p-blocker administration, except for one patient who became profoundly hypotensive from a calcium channel blocker and two patients in whom p-blockade was contraindicated by heart failure (one patient) and severe chronic obstructive lung disease (one patient). Each of the above medications was titrated to its highest tolerated level under the direction of a cardiologist. All patients had undergone cardiac catheterization demonstrating extensive three-vessel coronary artery disease, and all cineangiograms were reviewed by at least two cardiologists and one cardiothoracic surgeon. All physicians agreed that eight of 10 patients were not candidates for coronary bypass grafting or catheter-based revascularization techniques. Revascularization could not be performed because the coronary anatomy was unsuitable (chronic total occlusion or poor distal targets) or because of significant comorbid factors. The remaining two of the 10 patients refused
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Fig. 2. HTEA catheter and other components used in catheter placement. repeat coronary bypass grafting and were not suitable for percutaneous transluminal coronary angioplasty. One of the patients who was initially believed to be unsuitable for surgery was reconsidered after HTEA when his medical condition had significantly improved. Seven patients were unable to be discharged from the intensive care unit because of continuous unstable angina, despite the use of intravenous nitroglycerine and intravenous heparin. Two of these seven patients were also being treated with intraaortic balloon counter pulsation. All 10 patients had New York Heart Association (NYHA) class IV angina before consideration for HTEA. All patients had objective electrocardiographic evidence of ischemia during chest pain, that is, ST-segment depression of->l mm in two contignous leads. Ejection fractions ranged from 20% to 70% with a mean +- SD of 40% _+ 5%; ages ranged from 37 to 75 years (58 -+ 5 years). Procedures. In general, HTEA treatment was begun with a trial catheter placed percutaneously. The temporary trial catheter was subsequently removed, and a semipermanent catheter was surgically placed. This retrospective case study met the guidelines of the Medical University of South Carolina Institutional Review Board, and all patients signed informed consent before catheter insertion. If a patient was receiving heparin before HTEA, this anticoagulation was stopped 4 hours before catheter placement and was restarted 6 to 8 hours after catheter placement. These patients were monitored by partial thromboplastin time values and international normalized ratio levels that were maintained 1.5 times normal values. Trial catheter placement. During placement of the epi-
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dural catheter electrocardiogram, blood pressure and oxygen saturation levels were continuously monitored. A 19gauge thoracic epidural catheter (Arrow, Flextip Plus) was inserted by an 18-gauge Tuohy needle in the third or fourth thoracic vertebral interspace by the median approach with the loss of resistance technique. The catheter was positioned so that the tip of the catheter was at the level of the upper thoracic vertebrae between T1 and T3. Catheter position was confirmed by computed tomographic scan, fluoroscopy, or T-spine radiograph with contrast. A sufficient amount of bupivacaine (0.25% to 0.5%, 2.5 to 5.0 mg/ml), usually 3 to 6 ml, was given to induce blockade of cardiac sympathetic segments of T1 through T5. Adequacy of blockade was determined by assessing sensory changes in the appropriate dermatome at T2 through T5 and by alleviation of anginal symptoms. The patients had no significant disability or discomfort caused by the dermatomal analgesia, largely because the extent of this analgesia was limited to a small local area. After initia ! placement the patient continued to receive epidural medication by intermittent epidural injections with a patient-controlled analgesia (PCA) pump. Before and after placement of the catheter, the patient was educated about catheter injection and care. These injections were given by patients to themselves at their own discretion with a lockout period to prevent administration more frequently than every 4 hours. The trial catheter remained in place for no longer than 14 days. Long-term catheter placement. Six of the 10 patients were treated with an implantable long-term epidural catheter (Figs. 1 and 2). A Dupen epidural catheter (Bard) was placed under local anesthesia after intravenous sedation. The Dupen catheter is composed of two sections: an epidural and a subcutaneous section. The epidural portion of the Dupen catheter was placed percutaneously through a 14-gauge Hustead needle at an interspace between T9 and T12. The catheter was threaded over a guide wire superiorly to the T1-T2 position under fluoroscopic guidance. The position was then confirmed with fluoroscopy and contrast injection. A 1.5 cm incision was made at the Tuohy needle insertion site at T9-T12. The subcutaneous section of the Dupen catheter was tunneled from the anterior-inferior chest wall to the 1.5 cm insertion incision at T9-T12 with a subcutaneous sheathed tunneling device (Cordis peritoneal introducer with sheath). This subcutaneous section of the Dupen had a breakaway cuff around it positioned 10 cm from the anterior-inferior insertion site. This cuff acted as an anchor to hold the catheter in place and prevent dislodgement. At the 1.5 cm T9-T12 insertion incision site, the epidural and subcutaneous sections of the catheter were joined with a metal adapter, cross-tied with 2-0 nylon sutures and buried subcutaneously by primarily closing the 1.5 cm incision. The subcutaneous section of the catheter was secured to the anterior-inferior chest with an interlacing 2-0 nylon suture for 1 week until the catheter cuff was adequately anchored in the subcutaneous tissue. The catheter was flushed with preservative-free 0.9% saline solution in the operating room to ensure patency and then reinjected with a 3 ml (2.5%, 7.5 mg) dose of
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bupivacaine in the recovery room. Depending on the patient's status, the patient was either returned to a hospital room with a PCA epidural pump (Baxter) or was met by the home health nurse who reviewed the protocol for bolus dosing by the PCA pump with the patient. The bolus protocol was identical to that used with the trial catheter. Method of follow-up. All hospitalized patients were evaluated daily. Ambulatory patients were seen by the home health nurse on the evening of surgery, postoperative day 1, and every 3 days thereafter. Urgent patient or nursing concerns were addressed by the on-call physician. Outpatients were evaluated one to four times per month depending on adequacy of angina control, satisfactory catheter use and care and comorbidities. During weekly follow-up visits, catheter integrity was assessed, the efficacy of catheter use was evaluated and noted, and the PCA pump was refilled with bupivacaine. RESULTS Details of procedure. At the time of catheter place-
ment all 10 patients were treated with an initial 3 to 5 ml bolus ofbupivacaine (0.25%, 7.5 to 12.5 mg). In all patients this initial bolus resulted in either a marked diminution or a total resolution of their anginal symptoms. It was noted that the blood pressure decreased 10% to 15% and the heart rate deceased 10% to 20% after bolus injection. Before initiation of HTEA four patients had severe, unstable, or almost continuous angina at rest. Our early experience with this kind of patient showed t h a t the initial 3 to 5 ml bolus of bupivacaine either did not completely resolve the anginal symptoms or resulted in a very short (<1 hour) pain-free interval. Therefore, for the four patients with this type of severe, unstable, continuous angina, the initial bolus was followed by a continuous infusion of 3 to 4 ml/hr (0.25%, 7.5 to 10 mg/hr) bupivacaine for 4 to 7 days (mean 5 days). After this prolonged infusion, all four of these patients were completely angina free for m a n y hours at a time (5 to 10 hours after injection). Further anginal episodes were treated with intermittent bolus therapy as described below. Before initiation of HTEA six patients had NYHA class IV angina but were not having continuous angina at rest. In these six patients the initial bolus resulted in total resolution of angina and effectively prevented recurrence of angina for many hours after the initial injection. In these patients a continuous infusion was not necessary. Subsequent anginal episodes were treated with intermittent bolus therapy. The dose used for intermittent bolus was determined by titration during an anginal episode. The dose required ranged from 3 to 6 ml of 0.25% bupivacaine (7.5 to 15 mg) to produce complete pain re-
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lief. Subsequent intermittent bolus therapy was given at a dose determined during the initial titration. Intermittent bolus therapy was used in all 10 patients as needed to treat anginal episodes but did not exceed five doses per day. Patient outcome. HTEA resulted in a dramatic decrease in the frequency and severity of angina pectoris in all 10 patients. All seven patients in the intensive care unit who had intractable angina despite treatment with intravenous nitroglycerine, intravenous heparin, or intraaortic balloon counter pulsation were able to discontinue these treatment modalities and were discharged from the intensive care unit. Six of these seven patients were subsequently discharged from the hospital. In five patients symptoms decreased from NYHA class IV to NYHA class III symptoms, and in five patients symptoms decreased from class IV to class II. In general, the number of intermittent bolus doses necessary to treat recurrent angina decreased during the course of HTEA treatment. To date, for the patients who have been treated for >14 days, the dosing frequency during the first 0 to 7 days ranged from three to six doses per day, then decreased during days 7 to 14 to two to three doses per day, and thereafter decreased further to one to two doses per day. This decreased dose occurred despite a marked increased in patient physical activity level. None of the patients had significant side effects from bolus dosing a local anesthetic; none had hypotension, respiratory or cardiac abnormalities, or debilitating dermatomal anesthesia. To date three patients have been treated for 7 days, four for 14 to 21 days, and three >90 days. Of the three patients treated for 7 days, one was later treated with coronary artery bypass grafting and two continued to receive treatment. In the four patients treated for 14 days, one continued to receive treatment, one was later treated with coronary artery bypass grafting, one died ofa non-HTEA related cause, and one had HTEA discontinued because of a complication. Of the three patients treated >90 days, one Continued to receive treatment, one was later treated with coronary artery bypass grafting, and one had HTEA discontinued because of a complication. Of the three patients who subsequently underwent revascularization, two initially declined repeat coronary artery bypass grafting and one was not a surgical candidate at the start of HTEA because concurrent comorbidities, including acute renal failure, made the surgical risk excessive. In this patient HTEA controlled his angina until intensive prolonged medical treatment resulted in resolution of the acute renal failure. Bypass grafting was then performed with
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HTEA in place. The two patients who refused revascularization did so because they believed their risk was excessive and because of profound depression. After HTEA their angina and depression improved to the point they accepted revascularization surgery. Five patients in whom HTEA was discontinued and who did not undergo revascularization had a sustained reduction in anginal frequency and severity for 4 to 8 weeks after the discontinuation of HTEA. In addition, these five patients remained NYHA class II or III during this "honeymoon period." Eventually, however, the frequency and severity of symptoms increased, and these five patients redeveloped N Y H class IV symptoms. In two patients a second HTEA treatment was begun. In these two patients the second HTEA treatment had the same success as the first. Thus HTEA resulted in repeated, extended, and sustained decrease in symptoms a ~ r removal of the HTEA catheter. In addition, the second HTEA treatment was just as effective as the first. Complications. One of the 10 patients suddenly died during HTEA treatment, but the death was not related to the presence of HTEA. No patients had a myocardial infarction during treatment as judged by symptoms, electrocardiogram, or surveillance cardiac enzymes. Each patient had at least one electrocardiogram after catheter placement, and those patients in the intensive care unit had cardiac enzymes drawn. No patient had significant arrhythmias during telemetry monitoring. Paraspinous muscle spasms developed in one patient with fibromyalgia approximately 10 days after Dupen catheter placement. These symptoms resolved after the catheter was removed. After 8 months, cellulitis along the tunneled track developed in one patient and resolved after the catheter was removed. In one patient the catheter became occluded, apparently because of epidural adhesions and fibrosis. As with the use of any epidural anesthesia, potential complications occur, such as hematoma and abscess formation, paresthesias, muscle weakness, decreased deep tendon reflexes, hypotension, subarachnoid migration, and drug reactions. Although these complications are rare and did not occur in our patients, a much larger patient experience is necessary to make any statement concerning safety. DISCUSSION Summary. The purpose of this study was to evalu-
ate the efficacy of HTEA at T1-T4 in producing sympathetic blockade and alleviating symptoms of myocardial ischemia in patients with medically and surgically refractory angina pectoris. Data from this study support a number of conclusions. HTEA is an
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effective method of producing symptomatic relief of angina pectoris and in increasing activity level in patients with otherwise intractable angina pectoris. HTEA produces a prolonged effect, even after the epidural catheter has been removed. Tachyphylaxis does not occur during HTEA because the dosing regimen decreases over time and repeat HTEA is equally as effective as the initial HTEA. The current study confirms and extends the seminal studies performed by Blomberg et al. 5, s, 9, 13 and is the first study to apply these techniques outside Europe. Comparison with other clinical trials. Blomberg et al.5, 14 showed that HTEA was an effective short- and long-term treatment in patients with unstable angina. In a long-term study, Blomberg 5 examined 20 patients in whom HTEA was used to treat severe coronary artery disease and refractory unstable angina with self-administered intermittent dosing through an epidural catheter. The mean duration of HTEA was 6 months, and the longest treatment was 3.2 years. In these patients HTEA was effective in treating and preventing angina pectoris. In a shortterm study, Blomberg et al. 14 stabilized 28 patients with refractory unstable angina pectoris before revascularization with intermittent epidural bolus injections of 0.25% to 0.5% (2.5 to 5 mg/m!) bupivacaine. Before HTEA, all these patients were being treated with intravenous nitroglycerine. After HTEA, intravenous nitroglycerine was discontinued within 3 hours in 22 patients and within 18 hours in the remaining six patients. After stabilization these patients underwent revascularization with surgery or angioplasty. Our study is concordant with both the short- and long-term studies ofBlomberg et al. In the current study, HTEA was successfully used to treat patients with refractory angina over the long term and HTEA was successfully used to stabilize patients before revascularization. Thus this study confirmed the studies of Blomberg et al. and is the first to apply these methods and techniques outside Europe. The techniques used in this study differed from Blomber~s technique in at least three ways. In Blomberg~s studies all patients were initially stabilized with intermittent bolus treatment. Some of the patients in our study could not be stabilized with intermittent bolus treatment and required a continuous infusion. Thus our study was the first to use a continuous technique to stabilize patients with severe unstable angina. However, our study was not the first to use continuous-infusion HTEA. Toft and Jorgensen 15 used continuous thoracic epidural infusion of 0.25% bupivacaine to relieve the pain associated with acute myocardial infarction. The second difference was related to the epidural
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catheter used to deliver HTEA. Blomberg used an implantable Portex Port-a-cath system for long-term intermittent injection with a standard needle and sy: ringe. We were not able to duplicate this method because the devices used by Blomberg were not available in the United States. Instead, we used a Dupen system. The Dupen system includes an externalized device that can be attached to a pump for sterile intermittent dosing and is FDA approved for longterm epidural use. Because of the limitations of the Dupen system, it was not possible to extend HTEA with a single catheter for as long as Blomberg~s study. The third difference in this study was that the catheter was confirmed to be in the correct position with radiologic techniques in each patient. No previous study has done this. Although sensory testing is a good indicator of correct position, it has significant limitations. For example, a paravertebral block can create sensory changes similar to epidural analgesia; however, it does not produce the sympathetic blockade necessary to relieve angina. We believe this is an important refinement of Blomberg's technique. Mechanism of action: Human studies. It has been hypothesized that HTEA directly acts through its effects on the sympathetic nervous system and acts indirectly by altering the determinants of coronary blood flow and myocardial oxygen demand. The symptoms of angina are perceived through peripheral receptors of the sympathetic nervous system, the parasympathetic nervous system, and the brain stem. The cardiac neural mechanoreceptors and chemoreceptors are sensitized to chemical substances such as potassium, bradykinin, and adenosine and to changes in ventricular wall motion.16 The ventrocaudal nucleus in the thalamus also appears to play a role in perceiving symptoms of angina. 17 Myocardial ischemic pain is conducted by the cardiac afferent sympathetic fibers that are associated with the thoracic sympathetic nerves T1-T5. is Myocardial ischemia and the pain resulting from ischemia cause an increase in the sympathetic efferent activity, which in turn produces an increase in heart rate, inotropy, and blood pressure. The increase in these determinants of myocardial oxygen consumption produced by sympathetic activation initiates a vicious cycle in which increasing myocardial oxygen demand worsens ischemia, which in turn increases sympathetic stimulation, is In addition to sympathetic efferent activity increasing myocardial oxygen demand, it may also decrease coronary blood flow in the large coronary epicardial vessels. Young and Vatner 19 demonstrated that activation of cardiac sympathetic nerves causes vasoconstriction of these large arteries through the stimulation of the ~-ad-
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renergic receptors. In 93 patients undergoing cardiac catheterization for evaluation of angina, Brown 2° showed that even areas of significant coronary stenosis will constrict in response to sympathetic stimuli such as isometric hand grip or ergonovine maleate infusion. In that study the luminal area of both normal and diseased coronary segments were decreased by 20% and 22%, respectively. These data suggest that the sympathetic activation that accompanies ischemia can cause vasoconstriction that might further reduce coronary blood flow and increase the severity of myocardial ischemia. It is possible that HTEA acts to relieve angina by altering or preventing activation of cardiac sympathetic nerves and thereby preventing vasoconstriction and increasing coronary blood flow. Blomberg et al. 9 showed that patients treated with HTEA had an increase in the luminal diameter ofstenotic coronary arteries from 1.3 _+ 0.1 to 1.6 _+ 0.1 mm. This effect appeared to improve blood flow to ischemic areas even though total coronary blood flow was unchanged. This may be one mechanism by which HTEA prevents ischemia. Therefore these clinical studies suggest that HTEA may act in part by preventing the vasoconstrictive effects of sympathetic activation. In addition, HTEA may act by decreasing the determinants of myocardial oxygen demand. Blomberg and Ricksten 13 showed that HTEA decreased blood pressure by 13%, heart rate by 7%, and pulmonary capillary wedge pressure by 42% without significant changes in coronary perfusion pressure or cardiac output. Blomberg and Kock 21 showed that these changes in oxygen supply and demand resulted in improvement in global and regional ventricular function in ischemic patients with HTEA. Neither current nor previous studies have included a control group. In general, studies of pain control have consistently reported a 10% placebo effect. In addition, the natural history of angina, including unstable angina, is such that spontaneous remission and exacerbation are common. Further studies will be necessary to separate the effects of HTEA, placebo effects and the natural history of angina. Mechanisms of action: Animal studies. The mechanisms by which HTEA affect coronary blood flow and the determinants of myocardial oxygen demand have been examined in animals models of ischemia. 22 Vik-Mo et al. 23 showed that HTEA caused a reversal in the ST-segment changes induced by experimental coronary artery stenosis in dogs. Data from this study suggested that this reversal of ischemia was caused by an HTEA-induced reduction in determi-
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nants of myocardial oxygen demand, including mean arterial pressure, maximal rate of rise of left ventricular pressure, and heart rate. This antiischemic effect of HTEA was prevented if the fall in blood pressure was prevented by phenylephrine administration and the drop in heart rate prevented by atrial pacing. 23 Both Klassen et al. 11 and Davis et al. 24 showed that HTEA caused an increase in the endocardial/epicardial blood flow ratio in a canine model of acute coronary artery stenosis. Klassen hypothesized that these changes were caused by a change in vascular tone of transmural resistant vessels produced by HTEA. 11 Davis et al. 24 studied the effects of HTEA in an experimental model of acute myocardial infarction. When the infarct was created in animals treated with HTEA, the extent of the infarct was reduced by 45%. Tsuchida et al.25 demonstrated that HTEA attenuated the decrease in subendocardial pH and the ST-segment elevation in the epicardial electrocardiogram induced by experimental ischemia. This attenuation caused by HTEA persisted even when blood pressure and heart rate were held constant during ischemia. Blomberg et al. la, ~.1 showed that HTEA decreased the incidence of ventricular arrhythmias in animal models of ischemia and infarction. Because HTEA causes coronary vasodilatation, there is a potential for coronary steal in the presence of coronary stenosis. However, Blomberg showed that HTEA dilated only stenotic segments of epicardial coronary arteries and did not dilate normal segments, thereby improving ischemic areas without causing coronary steal. In addition, Heusch et al.26, 27and Blomberg et al. 9 demonstrated that sympathetically mediated coronary constriction distal to a coronary stenosis is inhibited by HTEA, improving regional blood flow distal to stenotic areas. Thus clinical studies have shown that HTEA can cause selective blockade of the cardiac sympathetic fibers (T1-T5) when a local anesthetic such as bupivacaine is placed in the epidural space at that level. In patients with coronary artery disease, HTEA produces reductions in heart rate and blood pressure, and can redistribute coronary blood flow to ischemic regions because of its effect on the luminal diameter and preferential shunting of blood to the endocardiurn. 18 Although there is evidence to implicate sympathetic activation as a pathophysiologic mechanism mediating some of the effects of ischemia, other factors, including vasoactive amines and endothelial relaxing factor, may also be involved. The effects of HTEA on these latter factors awaits further studies. The current study and previous clinical studies suggest the use of HTEA in treating angina and limiting myocardial damage during a myocardial infarct.
Other potential indications for HTEA await further studies. Conclusion. This study demonstrated that in patients with otherwise intractable angina pectoris, HTEA is an effective modality that produces symptomatic relief of angina pectoris and an increased activity level. We t h a n k John Handy, MD, A.J. Crumbley, MD, Brian Cuddy, MD, Sunil Patel, MD, Adrian Van Bakel, MD, and Thomas Duc, MD, for their assistance in patient care. We also thank Frank Overdyk, MD, Mark Pinosky, MD, and Richard Fishman, MD, for their assistance in data collection and Bey Ksenzak for her help in preparing this manuscript. Finally, we thank Sture Blomberg, MD, and John Williams, MD, for their advice and encouragement during this study. REFERENCES
1. Kirklin JW. Technical and scientific advances in cardiac surgery over the past 25 years. Ann Thorac Surg 1990;49:26-31. 2. Marrinan MT, Deverall PB. Advances in cardiac surgery in the last decade [editorial]. Int J Cardiology 1991;31:199-206. 3. Reeves TJ. Advances in cardiologyand escalating costs to the patient. View of the practitioner. Circulation 1985;71:637-41. 4. Rosenbaum SH, Barash PG. Is anesthesia therapeutic? Anesth Analg 1989;69:555-7. 5. Blomberg SG. Long-term home self treatment with high thoracic epidural anesthesia in patients with severe coronary artery disease. Anesth Analg 1994;79:413-21. 6. Drott C, Gothberg G, Claes G. Endoscopicprocedures ofthe upper-thoracic sympathetic chain. Arch Surg 1993;128:237-41. 7. Knight C, Fox KM, Mulcahy D. What more can we offerthe patient with intractable angina'? Primary Cardio 1995;21:13-7. 8. Blomberg S, Emanuelsson H, Ricksten SE. Thoracic epidural anesthesia and central hemodynamics in patients with unstable angina pectoris. Anesth Analg 1989;69:558-62. 9. Blomberg S, Emanuelsson H, Kvist H, Lamm C, Ponten J, Waagstein F, et al. Effects ofthoracic epidural anesthesia on coronary arteries and arterioles in patients with coronary artery disease. Anesthesiology 1990;73:840-7. 10. ReizS, Hagginark S, Rydvall A, Ostman M. Beta-blockers and thoracic epidural analgesia. Cardioprotective and synergistic effects. Acta Anaesthesiol Scand 1992;76(suppl):54-61. 11. Klassen GA, Bramwell RS, Bromage PR, Zborowska-Sluis DT. Effect of acute sympathectomy by epidural anesthesia on the canine coronary circulation. Anesthesiology 1980;52:8-15. 12. Liem TH, Booij LH, Hasenbos MA, Gielen M. Coronary artery bypass grafting using two different anesthetic techniques. Part I: Hemodynamic results. J Cardiothorac Vasc Anesth 1992;6(2):148-55. 13. Blomberg S, Ricksten SE. Thoracic epidural anaesthesia decreases the incidence of ventricular arrhythmias during acute myocardial ischaemia in the anaesthetized rat. Acta Anaesthesiol Scand 1988; 32:173-8. 14. Blomberg S, Curelau I, Emanuelsson H, Herlitz J, Ponten J, Ricksten SE. Thoracic epidural anaesthesia in patients with unstable angina pecteris. Eur Heart J 1989;10:437-44. 15. Toi~ P, Jorgensen A. Continuous thoracic epidural analgesia for the control ofpain in myocardialinfarction. Intens Care Med 1987;13:388-9. 16. Sylven C, Borg G, Brandt R, Beermann B, Jonzon B. Dose-effectrelationship of adenosine provoked angina pectoris-like pain a study of the psychophysical power function. Eur Heart J 1988;9:87-91. 17. Lenz FA, Gracely RH, Hope EJ, Baker FH, Rowland LH, Dougherty PM, et al. The sensation of angina can be evoked by stimulation of the human thalamus. Pain 1994;59:119-25. 18. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology 1995;82:1474-506. 19. Young MA, Vatner SF. Regulation of large coronary arteries. Circ Res 1986;59:579-96.
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20. Brown BG. Response of normal and diseased epicardial coronary arteries to vasoactive drugs: quantitative arteriographic studies. Am J Cardiol 1985;56:23-9. 21. Kock M. Blomberg S, Emanuelsson H, Lomsky M, Stromblad S-O, Ricksten SE. Thoracic epidural anesthesia improves global and regional left ventricular function during stress-induced myocardial ischemia in patients with coronary artery disease. Anesth Analg 1990;71:625-30. 22. Sivarajan M, Amory DW, Lindbloom LE. Systemic and regional blood flow during epidural anesthesia without epinephrine in the Rhesus monkey. Anesthesiology 1976;45:300-10. 23. Vik-Mo H, Ottesen S, Remek H. Cardiac effects of thoracic epidural analysis before and during acute coronary artery occlusion in open chest dogs. Scand J Clin Lab Invest 1978;38;738-46.
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24. Davis RF, DeBoer LWV, Maroko PR. Thoracic epidural anesthesia reduces myocardial infarct size after coronary artery occlusion in dogs. Anesth Analg 1986;65:711-7. 25. Tsuchida H, Omote T, Miyamoto M, Namiki A, Ichihara K, Abiko Y. Effects of thoracic epidural anesthesia on myocardial pH and metabolism during ischemia. Acta Anaesthesiol Scand 1991;35:508-12. 26. Heusch G, Doussen A, Thames V. Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feedback aggravation of myocardial ischemia. J Auto Nerv Syst 1985;13:31126. 27. Heusch G, Schipke J, Thames V. Sympathetic mechanism in poststenotic myocardial ischemia. J Cardiovasc Pharmacol 1986;8 Suppl 3:533-40.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the AMERICAN HEART JOURNAL for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted at a cost of $12.00 per issue. The following quantity discounts are available: 25% offon quantities of 12 to 23, and 0ne-third off on quantities of 24 or more. Please write to Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
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catheter-related complications necessitating catheter removal during 12 months of HTEA use. Local infection developed in one patient, one had catheter occlusion caused by fibrosis, and one patient had chronic back pain exacerbation from a paraspinous muscle spasm. No patient had a myocardial infarction or a significant arrhythmia. In patients with otherwise intractable angina pectoris, HTEA is an effective modality that produces symptomatic relief of angina pectoris and allows increased activity level. (Am Heart J 1997; 134:646-55.)
During the past decade there have been significant improvements in techniques of surgical revascularization, catheter-based revascularization, and medical therapy for patients with coronary artery disease and angina pectoris. 1-3 However, despite these advances, there are an increasing number of patients with angina pectoris who are refractory to medical therapy and are not candidates for coronary artery bypass grafting or interventional catheterization. These patients are often treated with narcotics for pain relief and are forced to severely reduce their level of activity and productivity. This group of patients presents a difficult management problem for physicians and the medical community because their care requires frequent outpatient office visits, emergency room visits, and hospitalizations. Thus, in addition to patients having frequent recurrences of anginal pain, refractory angina consumes significant health care resources. Recently it has become clear that alleviating the pain caused by myocardial ischemia may be possible by altering sympathetic afferent nerve fibers. 4, 5 Indeed, previous studies showed that surgical sympathectomy could relieve symptoms of angina pectoris in patients with refractory angina. 6 However, in this group of patients with refractory angina, the invasive surgery necessary to perform this sympathectomy results in significant morbidity and mortality rates.6, 7 Now, however, sympathetic blockade can be produced with high thoracic epidural analgesia
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Table I.Patient population
Age Sex Extent of CAD Previous CABG Previous PTCA Ejection fraction Coronary risk factors Smoking Hypertension Diabetes Cholesterol Family history Medications Nitrates ~-blocker Calcium channel blockers Intravenous nitrates Intravenous heparin Intraaortic balloon pump ACE inhibitor Previous myocardial infarction NYHA class IV Currently in the ICU Currently an outpatient
58 - 5 yrs 8 men/2 women 3-vessel 6 6 40% _+5%
P i l r c u t l n i l l PIKClIK~t
L__
4 5 4 4 2 10 8* 9t 7 7 2 6 7 10 7 3
CAD, Coronary artery disease; CABG,coronary artery bypass graft; PTCA, percutaneous t r a n s l u m i n a l coronary angioplasty; ACE, angiotensin converting enzyme; ICU, intensive care unit. *One patient could not take ~3-blockers because of a markedly reduced ejection fraction, and one patient had severe chronic obstructive lung disease. tOne patient could not take a calcium channel blocker because of severe hypotension.
(HTEA). 8-1° E p i d u r a l blockade of t h e cardiac a f f e r e n t a n d efferent s y m p a t h e t i c fibers in t h e u p p e r thoracic s y m p a t h e t i c s e g m e n t s w i t h local a n e s t h e t i c s m a y b l u n t the p e r c e p t i o n of cardiac p a i n d u r i n g m y o c a r dial ischemia, which is m e d i a t e d t h r o u g h cardiac s y m p a t h e t i c a f f e r e n t n e r v e fibers a n d provides p a i n relief to p a t i e n t s w i t h r e f r a c t o r y a n g i n a pectoris. I t is also possible t h a t H T E A m a y p r e v e n t m y o c a r d i a l i s c h e m i a b y a l t e r i n g m y o c a r d i a l oxygen d e m a n d or supply. H T E A m a y r e d u c e t h e m a j o r d e t e r m i n a n t s of m y o c a r d i a l oxygen d e m a n d b y d e c r e a s i n g h e a r t r a t e and reducing preload and afterload without altering c o r o n a r y p e r f u s i o n p r e s s u r e . 4,s, 11, 12 I n addition, H T E A m a y a l t e r m y o c a r d i a l oxygen s u p p l y b y inc r e a s i n g t h e d i a m e t e r of stenotic vessels a n d the p r e f e r e n t i a l shifting f r o m epicardial to endocardial blood flow. 9 T h e p u r p o s e of this r e t r o s p e c t i v e s t u d y w a s to t e s t t h e h y p o t h e s i s t h a t H T E A is a n effective m e t h o d of a l l e v i a t i n g s y m p t o m s of a n g i n a l p a i n in p a t i e n t s w i t h m e d i c a l l y a n d surgically r e f r a c t o r y a n g i n a pectoris. METHODS Patients. Table I presents the clinical characteristics of
the 10 patients examined in this study. Patients treated at
Ventral Incision (exit site) Incision
\
.cuff: iw Filter
Dupen Catheter Insertion Fig. 1. Method of HTEA catheter placement and catheters and other components used to perform HTEA.
the Ralph H. Johnson Department of Veterans Affairs Medical Center in Charleston, S.C., were men and account for the preponderance of male patients in this study. Some patients were treated at the Medical University of South Carolina Hospital. Patients were excluded if they had a history of significant spinal disease or extensive spinal surgery, were receiving anticoagulation therapy that could not be stopped, had a bleeding history, or had an allergy to local anesthetics. Before consideration for HTEA, all patients were "treated with maximally tolerated medical therapy. Treatment included nitrate, calcium channel blocker, and p-blocker administration, except for one patient who became profoundly hypotensive from a calcium channel blocker and two patients in whom p-blockade was contraindicated by heart failure (one patient) and severe chronic obstructive lung disease (one patient). Each of the above medications was titrated to its highest tolerated level under the direction of a cardiologist. All patients had undergone cardiac catheterization demonstrating extensive three-vessel coronary artery disease, and all cineangiograms were reviewed by at least two cardiologists and one cardiothoracic surgeon. All physicians agreed that eight of 10 patients were not candidates for coronary bypass grafting or catheter-based revascularization techniques. Revascularization could not be performed because the coronary anatomy was unsuitable (chronic total occlusion or poor distal targets) or because of significant comorbid factors. The remaining two of the 10 patients refused
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Fig. 2. HTEA catheter and other components used in catheter placement. repeat coronary bypass grafting and were not suitable for percutaneous transluminal coronary angioplasty. One of the patients who was initially believed to be unsuitable for surgery was reconsidered after HTEA when his medical condition had significantly improved. Seven patients were unable to be discharged from the intensive care unit because of continuous unstable angina, despite the use of intravenous nitroglycerine and intravenous heparin. Two of these seven patients were also being treated with intraaortic balloon counter pulsation. All 10 patients had New York Heart Association (NYHA) class IV angina before consideration for HTEA. All patients had objective electrocardiographic evidence of ischemia during chest pain, that is, ST-segment depression of->l mm in two contignous leads. Ejection fractions ranged from 20% to 70% with a mean +- SD of 40% _+ 5%; ages ranged from 37 to 75 years (58 -+ 5 years). Procedures. In general, HTEA treatment was begun with a trial catheter placed percutaneously. The temporary trial catheter was subsequently removed, and a semipermanent catheter was surgically placed. This retrospective case study met the guidelines of the Medical University of South Carolina Institutional Review Board, and all patients signed informed consent before catheter insertion. If a patient was receiving heparin before HTEA, this anticoagulation was stopped 4 hours before catheter placement and was restarted 6 to 8 hours after catheter placement. These patients were monitored by partial thromboplastin time values and international normalized ratio levels that were maintained 1.5 times normal values. Trial catheter placement. During placement of the epi-
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dural catheter electrocardiogram, blood pressure and oxygen saturation levels were continuously monitored. A 19gauge thoracic epidural catheter (Arrow, Flextip Plus) was inserted by an 18-gauge Tuohy needle in the third or fourth thoracic vertebral interspace by the median approach with the loss of resistance technique. The catheter was positioned so that the tip of the catheter was at the level of the upper thoracic vertebrae between T1 and T3. Catheter position was confirmed by computed tomographic scan, fluoroscopy, or T-spine radiograph with contrast. A sufficient amount of bupivacaine (0.25% to 0.5%, 2.5 to 5.0 mg/ml), usually 3 to 6 ml, was given to induce blockade of cardiac sympathetic segments of T1 through T5. Adequacy of blockade was determined by assessing sensory changes in the appropriate dermatome at T2 through T5 and by alleviation of anginal symptoms. The patients had no significant disability or discomfort caused by the dermatomal analgesia, largely because the extent of this analgesia was limited to a small local area. After initia ! placement the patient continued to receive epidural medication by intermittent epidural injections with a patient-controlled analgesia (PCA) pump. Before and after placement of the catheter, the patient was educated about catheter injection and care. These injections were given by patients to themselves at their own discretion with a lockout period to prevent administration more frequently than every 4 hours. The trial catheter remained in place for no longer than 14 days. Long-term catheter placement. Six of the 10 patients were treated with an implantable long-term epidural catheter (Figs. 1 and 2). A Dupen epidural catheter (Bard) was placed under local anesthesia after intravenous sedation. The Dupen catheter is composed of two sections: an epidural and a subcutaneous section. The epidural portion of the Dupen catheter was placed percutaneously through a 14-gauge Hustead needle at an interspace between T9 and T12. The catheter was threaded over a guide wire superiorly to the T1-T2 position under fluoroscopic guidance. The position was then confirmed with fluoroscopy and contrast injection. A 1.5 cm incision was made at the Tuohy needle insertion site at T9-T12. The subcutaneous section of the Dupen catheter was tunneled from the anterior-inferior chest wall to the 1.5 cm insertion incision at T9-T12 with a subcutaneous sheathed tunneling device (Cordis peritoneal introducer with sheath). This subcutaneous section of the Dupen had a breakaway cuff around it positioned 10 cm from the anterior-inferior insertion site. This cuff acted as an anchor to hold the catheter in place and prevent dislodgement. At the 1.5 cm T9-T12 insertion incision site, the epidural and subcutaneous sections of the catheter were joined with a metal adapter, cross-tied with 2-0 nylon sutures and buried subcutaneously by primarily closing the 1.5 cm incision. The subcutaneous section of the catheter was secured to the anterior-inferior chest with an interlacing 2-0 nylon suture for 1 week until the catheter cuff was adequately anchored in the subcutaneous tissue. The catheter was flushed with preservative-free 0.9% saline solution in the operating room to ensure patency and then reinjected with a 3 ml (2.5%, 7.5 mg) dose of
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bupivacaine in the recovery room. Depending on the patient's status, the patient was either returned to a hospital room with a PCA epidural pump (Baxter) or was met by the home health nurse who reviewed the protocol for bolus dosing by the PCA pump with the patient. The bolus protocol was identical to that used with the trial catheter. Method of follow-up. All hospitalized patients were evaluated daily. Ambulatory patients were seen by the home health nurse on the evening of surgery, postoperative day 1, and every 3 days thereafter. Urgent patient or nursing concerns were addressed by the on-call physician. Outpatients were evaluated one to four times per month depending on adequacy of angina control, satisfactory catheter use and care and comorbidities. During weekly follow-up visits, catheter integrity was assessed, the efficacy of catheter use was evaluated and noted, and the PCA pump was refilled with bupivacaine. RESULTS Details of procedure. At the time of catheter place-
ment all 10 patients were treated with an initial 3 to 5 ml bolus ofbupivacaine (0.25%, 7.5 to 12.5 mg). In all patients this initial bolus resulted in either a marked diminution or a total resolution of their anginal symptoms. It was noted that the blood pressure decreased 10% to 15% and the heart rate deceased 10% to 20% after bolus injection. Before initiation of HTEA four patients had severe, unstable, or almost continuous angina at rest. Our early experience with this kind of patient showed t h a t the initial 3 to 5 ml bolus of bupivacaine either did not completely resolve the anginal symptoms or resulted in a very short (<1 hour) pain-free interval. Therefore, for the four patients with this type of severe, unstable, continuous angina, the initial bolus was followed by a continuous infusion of 3 to 4 ml/hr (0.25%, 7.5 to 10 mg/hr) bupivacaine for 4 to 7 days (mean 5 days). After this prolonged infusion, all four of these patients were completely angina free for m a n y hours at a time (5 to 10 hours after injection). Further anginal episodes were treated with intermittent bolus therapy as described below. Before initiation of HTEA six patients had NYHA class IV angina but were not having continuous angina at rest. In these six patients the initial bolus resulted in total resolution of angina and effectively prevented recurrence of angina for many hours after the initial injection. In these patients a continuous infusion was not necessary. Subsequent anginal episodes were treated with intermittent bolus therapy. The dose used for intermittent bolus was determined by titration during an anginal episode. The dose required ranged from 3 to 6 ml of 0.25% bupivacaine (7.5 to 15 mg) to produce complete pain re-
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lief. Subsequent intermittent bolus therapy was given at a dose determined during the initial titration. Intermittent bolus therapy was used in all 10 patients as needed to treat anginal episodes but did not exceed five doses per day. Patient outcome. HTEA resulted in a dramatic decrease in the frequency and severity of angina pectoris in all 10 patients. All seven patients in the intensive care unit who had intractable angina despite treatment with intravenous nitroglycerine, intravenous heparin, or intraaortic balloon counter pulsation were able to discontinue these treatment modalities and were discharged from the intensive care unit. Six of these seven patients were subsequently discharged from the hospital. In five patients symptoms decreased from NYHA class IV to NYHA class III symptoms, and in five patients symptoms decreased from class IV to class II. In general, the number of intermittent bolus doses necessary to treat recurrent angina decreased during the course of HTEA treatment. To date, for the patients who have been treated for >14 days, the dosing frequency during the first 0 to 7 days ranged from three to six doses per day, then decreased during days 7 to 14 to two to three doses per day, and thereafter decreased further to one to two doses per day. This decreased dose occurred despite a marked increased in patient physical activity level. None of the patients had significant side effects from bolus dosing a local anesthetic; none had hypotension, respiratory or cardiac abnormalities, or debilitating dermatomal anesthesia. To date three patients have been treated for 7 days, four for 14 to 21 days, and three >90 days. Of the three patients treated for 7 days, one was later treated with coronary artery bypass grafting and two continued to receive treatment. In the four patients treated for 14 days, one continued to receive treatment, one was later treated with coronary artery bypass grafting, one died ofa non-HTEA related cause, and one had HTEA discontinued because of a complication. Of the three patients treated >90 days, one Continued to receive treatment, one was later treated with coronary artery bypass grafting, and one had HTEA discontinued because of a complication. Of the three patients who subsequently underwent revascularization, two initially declined repeat coronary artery bypass grafting and one was not a surgical candidate at the start of HTEA because concurrent comorbidities, including acute renal failure, made the surgical risk excessive. In this patient HTEA controlled his angina until intensive prolonged medical treatment resulted in resolution of the acute renal failure. Bypass grafting was then performed with
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HTEA in place. The two patients who refused revascularization did so because they believed their risk was excessive and because of profound depression. After HTEA their angina and depression improved to the point they accepted revascularization surgery. Five patients in whom HTEA was discontinued and who did not undergo revascularization had a sustained reduction in anginal frequency and severity for 4 to 8 weeks after the discontinuation of HTEA. In addition, these five patients remained NYHA class II or III during this "honeymoon period." Eventually, however, the frequency and severity of symptoms increased, and these five patients redeveloped N Y H class IV symptoms. In two patients a second HTEA treatment was begun. In these two patients the second HTEA treatment had the same success as the first. Thus HTEA resulted in repeated, extended, and sustained decrease in symptoms a ~ r removal of the HTEA catheter. In addition, the second HTEA treatment was just as effective as the first. Complications. One of the 10 patients suddenly died during HTEA treatment, but the death was not related to the presence of HTEA. No patients had a myocardial infarction during treatment as judged by symptoms, electrocardiogram, or surveillance cardiac enzymes. Each patient had at least one electrocardiogram after catheter placement, and those patients in the intensive care unit had cardiac enzymes drawn. No patient had significant arrhythmias during telemetry monitoring. Paraspinous muscle spasms developed in one patient with fibromyalgia approximately 10 days after Dupen catheter placement. These symptoms resolved after the catheter was removed. After 8 months, cellulitis along the tunneled track developed in one patient and resolved after the catheter was removed. In one patient the catheter became occluded, apparently because of epidural adhesions and fibrosis. As with the use of any epidural anesthesia, potential complications occur, such as hematoma and abscess formation, paresthesias, muscle weakness, decreased deep tendon reflexes, hypotension, subarachnoid migration, and drug reactions. Although these complications are rare and did not occur in our patients, a much larger patient experience is necessary to make any statement concerning safety. DISCUSSION Summary. The purpose of this study was to evalu-
ate the efficacy of HTEA at T1-T4 in producing sympathetic blockade and alleviating symptoms of myocardial ischemia in patients with medically and surgically refractory angina pectoris. Data from this study support a number of conclusions. HTEA is an
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effective method of producing symptomatic relief of angina pectoris and in increasing activity level in patients with otherwise intractable angina pectoris. HTEA produces a prolonged effect, even after the epidural catheter has been removed. Tachyphylaxis does not occur during HTEA because the dosing regimen decreases over time and repeat HTEA is equally as effective as the initial HTEA. The current study confirms and extends the seminal studies performed by Blomberg et al. 5, s, 9, 13 and is the first study to apply these techniques outside Europe. Comparison with other clinical trials. Blomberg et al.5, 14 showed that HTEA was an effective short- and long-term treatment in patients with unstable angina. In a long-term study, Blomberg 5 examined 20 patients in whom HTEA was used to treat severe coronary artery disease and refractory unstable angina with self-administered intermittent dosing through an epidural catheter. The mean duration of HTEA was 6 months, and the longest treatment was 3.2 years. In these patients HTEA was effective in treating and preventing angina pectoris. In a shortterm study, Blomberg et al. 14 stabilized 28 patients with refractory unstable angina pectoris before revascularization with intermittent epidural bolus injections of 0.25% to 0.5% (2.5 to 5 mg/m!) bupivacaine. Before HTEA, all these patients were being treated with intravenous nitroglycerine. After HTEA, intravenous nitroglycerine was discontinued within 3 hours in 22 patients and within 18 hours in the remaining six patients. After stabilization these patients underwent revascularization with surgery or angioplasty. Our study is concordant with both the short- and long-term studies ofBlomberg et al. In the current study, HTEA was successfully used to treat patients with refractory angina over the long term and HTEA was successfully used to stabilize patients before revascularization. Thus this study confirmed the studies of Blomberg et al. and is the first to apply these methods and techniques outside Europe. The techniques used in this study differed from Blomber~s technique in at least three ways. In Blomberg~s studies all patients were initially stabilized with intermittent bolus treatment. Some of the patients in our study could not be stabilized with intermittent bolus treatment and required a continuous infusion. Thus our study was the first to use a continuous technique to stabilize patients with severe unstable angina. However, our study was not the first to use continuous-infusion HTEA. Toft and Jorgensen 15 used continuous thoracic epidural infusion of 0.25% bupivacaine to relieve the pain associated with acute myocardial infarction. The second difference was related to the epidural
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catheter used to deliver HTEA. Blomberg used an implantable Portex Port-a-cath system for long-term intermittent injection with a standard needle and sy: ringe. We were not able to duplicate this method because the devices used by Blomberg were not available in the United States. Instead, we used a Dupen system. The Dupen system includes an externalized device that can be attached to a pump for sterile intermittent dosing and is FDA approved for longterm epidural use. Because of the limitations of the Dupen system, it was not possible to extend HTEA with a single catheter for as long as Blomberg~s study. The third difference in this study was that the catheter was confirmed to be in the correct position with radiologic techniques in each patient. No previous study has done this. Although sensory testing is a good indicator of correct position, it has significant limitations. For example, a paravertebral block can create sensory changes similar to epidural analgesia; however, it does not produce the sympathetic blockade necessary to relieve angina. We believe this is an important refinement of Blomberg's technique. Mechanism of action: Human studies. It has been hypothesized that HTEA directly acts through its effects on the sympathetic nervous system and acts indirectly by altering the determinants of coronary blood flow and myocardial oxygen demand. The symptoms of angina are perceived through peripheral receptors of the sympathetic nervous system, the parasympathetic nervous system, and the brain stem. The cardiac neural mechanoreceptors and chemoreceptors are sensitized to chemical substances such as potassium, bradykinin, and adenosine and to changes in ventricular wall motion.16 The ventrocaudal nucleus in the thalamus also appears to play a role in perceiving symptoms of angina. 17 Myocardial ischemic pain is conducted by the cardiac afferent sympathetic fibers that are associated with the thoracic sympathetic nerves T1-T5. is Myocardial ischemia and the pain resulting from ischemia cause an increase in the sympathetic efferent activity, which in turn produces an increase in heart rate, inotropy, and blood pressure. The increase in these determinants of myocardial oxygen consumption produced by sympathetic activation initiates a vicious cycle in which increasing myocardial oxygen demand worsens ischemia, which in turn increases sympathetic stimulation, is In addition to sympathetic efferent activity increasing myocardial oxygen demand, it may also decrease coronary blood flow in the large coronary epicardial vessels. Young and Vatner 19 demonstrated that activation of cardiac sympathetic nerves causes vasoconstriction of these large arteries through the stimulation of the ~-ad-
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renergic receptors. In 93 patients undergoing cardiac catheterization for evaluation of angina, Brown 2° showed that even areas of significant coronary stenosis will constrict in response to sympathetic stimuli such as isometric hand grip or ergonovine maleate infusion. In that study the luminal area of both normal and diseased coronary segments were decreased by 20% and 22%, respectively. These data suggest that the sympathetic activation that accompanies ischemia can cause vasoconstriction that might further reduce coronary blood flow and increase the severity of myocardial ischemia. It is possible that HTEA acts to relieve angina by altering or preventing activation of cardiac sympathetic nerves and thereby preventing vasoconstriction and increasing coronary blood flow. Blomberg et al. 9 showed that patients treated with HTEA had an increase in the luminal diameter ofstenotic coronary arteries from 1.3 _+ 0.1 to 1.6 _+ 0.1 mm. This effect appeared to improve blood flow to ischemic areas even though total coronary blood flow was unchanged. This may be one mechanism by which HTEA prevents ischemia. Therefore these clinical studies suggest that HTEA may act in part by preventing the vasoconstrictive effects of sympathetic activation. In addition, HTEA may act by decreasing the determinants of myocardial oxygen demand. Blomberg and Ricksten 13 showed that HTEA decreased blood pressure by 13%, heart rate by 7%, and pulmonary capillary wedge pressure by 42% without significant changes in coronary perfusion pressure or cardiac output. Blomberg and Kock 21 showed that these changes in oxygen supply and demand resulted in improvement in global and regional ventricular function in ischemic patients with HTEA. Neither current nor previous studies have included a control group. In general, studies of pain control have consistently reported a 10% placebo effect. In addition, the natural history of angina, including unstable angina, is such that spontaneous remission and exacerbation are common. Further studies will be necessary to separate the effects of HTEA, placebo effects and the natural history of angina. Mechanisms of action: Animal studies. The mechanisms by which HTEA affect coronary blood flow and the determinants of myocardial oxygen demand have been examined in animals models of ischemia. 22 Vik-Mo et al. 23 showed that HTEA caused a reversal in the ST-segment changes induced by experimental coronary artery stenosis in dogs. Data from this study suggested that this reversal of ischemia was caused by an HTEA-induced reduction in determi-
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nants of myocardial oxygen demand, including mean arterial pressure, maximal rate of rise of left ventricular pressure, and heart rate. This antiischemic effect of HTEA was prevented if the fall in blood pressure was prevented by phenylephrine administration and the drop in heart rate prevented by atrial pacing. 23 Both Klassen et al. 11 and Davis et al. 24 showed that HTEA caused an increase in the endocardial/epicardial blood flow ratio in a canine model of acute coronary artery stenosis. Klassen hypothesized that these changes were caused by a change in vascular tone of transmural resistant vessels produced by HTEA. 11 Davis et al. 24 studied the effects of HTEA in an experimental model of acute myocardial infarction. When the infarct was created in animals treated with HTEA, the extent of the infarct was reduced by 45%. Tsuchida et al.25 demonstrated that HTEA attenuated the decrease in subendocardial pH and the ST-segment elevation in the epicardial electrocardiogram induced by experimental ischemia. This attenuation caused by HTEA persisted even when blood pressure and heart rate were held constant during ischemia. Blomberg et al. la, ~.1 showed that HTEA decreased the incidence of ventricular arrhythmias in animal models of ischemia and infarction. Because HTEA causes coronary vasodilatation, there is a potential for coronary steal in the presence of coronary stenosis. However, Blomberg showed that HTEA dilated only stenotic segments of epicardial coronary arteries and did not dilate normal segments, thereby improving ischemic areas without causing coronary steal. In addition, Heusch et al.26, 27and Blomberg et al. 9 demonstrated that sympathetically mediated coronary constriction distal to a coronary stenosis is inhibited by HTEA, improving regional blood flow distal to stenotic areas. Thus clinical studies have shown that HTEA can cause selective blockade of the cardiac sympathetic fibers (T1-T5) when a local anesthetic such as bupivacaine is placed in the epidural space at that level. In patients with coronary artery disease, HTEA produces reductions in heart rate and blood pressure, and can redistribute coronary blood flow to ischemic regions because of its effect on the luminal diameter and preferential shunting of blood to the endocardiurn. 18 Although there is evidence to implicate sympathetic activation as a pathophysiologic mechanism mediating some of the effects of ischemia, other factors, including vasoactive amines and endothelial relaxing factor, may also be involved. The effects of HTEA on these latter factors awaits further studies. The current study and previous clinical studies suggest the use of HTEA in treating angina and limiting myocardial damage during a myocardial infarct.
Other potential indications for HTEA await further studies. Conclusion. This study demonstrated that in patients with otherwise intractable angina pectoris, HTEA is an effective modality that produces symptomatic relief of angina pectoris and an increased activity level. We t h a n k John Handy, MD, A.J. Crumbley, MD, Brian Cuddy, MD, Sunil Patel, MD, Adrian Van Bakel, MD, and Thomas Duc, MD, for their assistance in patient care. We also thank Frank Overdyk, MD, Mark Pinosky, MD, and Richard Fishman, MD, for their assistance in data collection and Bey Ksenzak for her help in preparing this manuscript. Finally, we thank Sture Blomberg, MD, and John Williams, MD, for their advice and encouragement during this study. REFERENCES
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20. Brown BG. Response of normal and diseased epicardial coronary arteries to vasoactive drugs: quantitative arteriographic studies. Am J Cardiol 1985;56:23-9. 21. Kock M. Blomberg S, Emanuelsson H, Lomsky M, Stromblad S-O, Ricksten SE. Thoracic epidural anesthesia improves global and regional left ventricular function during stress-induced myocardial ischemia in patients with coronary artery disease. Anesth Analg 1990;71:625-30. 22. Sivarajan M, Amory DW, Lindbloom LE. Systemic and regional blood flow during epidural anesthesia without epinephrine in the Rhesus monkey. Anesthesiology 1976;45:300-10. 23. Vik-Mo H, Ottesen S, Remek H. Cardiac effects of thoracic epidural analysis before and during acute coronary artery occlusion in open chest dogs. Scand J Clin Lab Invest 1978;38;738-46.
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