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(Circulation. 1997;96:2178-2182.)
© 1997 American Heart Association, Inc.

Articles

Anti-Ischemic and Anti-Anginal Effects of Thoracic Epidural Anesthesia Versus Those of Conventional Medical Therapy in the Treatment of Severe Refractory Unstable Angina Pectoris

Karin Olausson, MD; Helga Magnusdottir, MD; Leon Lurje, MD; Bertil Wennerblom, MD, PhD; Håkan Emanuelsson, MD, PhD; ; Sven-Erik Ricksten, MD, PhD

From the Department of Anesthesia and Intensive Care (K.O., H.M., S.-E.R.), and the Department of Cardiology (L.L., B.W., H.E.), Sahlgrenska University Hospital, Göteborg, Sweden.

Correspondence to Sven-Erik Ricksten, MD, PhD, Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

	Abstract

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Background Cardiac sympathetic blockade by thoracic epidural anesthesia (TEA) dilates stenotic coronary arteries and has been used to control pain in patients with unstable angina. The aim of the present study was to evaluate the potential anti-ischemic effects of cardiac sympathetic blockade by TEA in severe, refractory, unstable angina.

Methods and Results Forty patients with unstable angina refractory to standard anti-anginal therapy were randomized to receive either continuous epidural infusion of bupivacaine (TEA, Th1 to Th5) or to standard anti-anginal therapy including ß-blockers, calcium antagonists, aspirin, heparin, and nitroglycerin infusion (control group). The primary end points were number of anginal attacks and severity of myocardial ischemia assessed by 48-hour ambulatory Holter monitoring. The incidence of myocardial ischemia was lower in the TEA group (22% versus 61%; P<.05). The number of ischemic episodes per patient was 1.0±0.6 in the TEA group and 3.6±0.9 in the control group (P<.05). The episode duration per patient was 4.1±2.5 minutes and 19.7±6.2 minutes in the TEA and the control groups, respectively (P<.05). The mean area-under-the-ST-time-curve was 6.8±4.3 and 32.2±14.3 (mm · min) in the TEA and the control groups, respectively (P<.05). Fifteen anginal attacks were recorded in the control group and one attack in the TEA group (0.83±0.21 versus 0.06±0.06/patient, respectively, P<.01).

Conclusions The anti-ischemic and anti-anginal effects of continuous TEA are superior to those of conventional therapy in the treatment of refractory unstable angina.

Key Words: angina • ischemia • anesthesia • nervous system • autonomic • electrocardiography

	Introduction

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Perception of pain arising from myocardial ischemia is mediated by the sympathetic afferent nerves.¹ Epidural blockade of the upper five thoracic sympathetic segments with local anesthetics has been shown to offer good pain relief in patients with severe unstable angina resistant to conventional medical therapy.² Furthermore, treatment of symptomatic ischemia by TEA has beneficial effects on the major determinants of myocardial oxygen demand, as it reduces heart rate, preload, and afterload without affecting coronary perfusion pressure.³ Cardiac sympathetic blockade with TEA also increases the luminal diameter of stenotic epicardial coronary arteries⁴ and improves ischemia-induced left ventricular global and regional wall motion abnormalities at a certain physical stress, associated with less-pronounced ST-segment depression.^{2 5} In the present randomized, controlled study we have evaluated the possible therapeutic advantage of TEA compared with maximal pharmacological treatment on Holter-positive myocardial ischemia and anginal attacks in patients with severe refractory unstable angina pectoris.

	Methods

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Patients and Inclusion Criteria
The study was approved by the Human Ethics Committee of the University of Gothenburg and complies with the Declaration of Helsinki. Forty patients with the diagnosis of unstable angina who satisfied the entry criteria were prospectively enrolled in this investigation after informed consent. The patients were all treated in a Coronary Care Unit, and the responsible investigators were not involved in the clinical management of the patients, which thus reflected the therapeutic practice of our or the referring hospitals, until the inclusion criteria were fulfilled. The following inclusion criteria were used: (1) Typical chest pain occurring at rest, associated with reversible ST-segment depression of at least 0.1 mV, 60 ms after the J-point, no development of new Q waves and no rise of CK-MB more than twice the upper normal limit; (2) treatment with aspirin and/or heparin infusion; (3) treatment with ß-adrenergic blockers; (4) treatment with nitroglycerin IV for more than 24 hours at an optimal infusion rate, according to ischemic symptoms and side effects; and (5) recurrence of chest pain or more severe chest pain during at least one attempt to discontinue the nitroglycerin infusion. The patients included were thus classified as IIIB3 or IIIC3 according to Braunwald.⁶ The clinical history, angiographic findings, and pharmacological treatment before inclusion and randomization are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Two Study Groups Before Inclusion

Study Design and Treatment
The patients were randomized into two groups.

Conventional Treatment Group
Maximal medical treatment was continued in this control group according to Table 1 and inclusion criteria.

TEA Group
Four to 5 hours after discontinuation of the heparin infusion, an epidural catheter was inserted through one of the second to fifth thoracic vertebral interspaces, using the median approach and the loss-of-resistance technique. An epidural bolus dose of 20 to 30 mg of bupivacaine (5 mg/mL) induced a blockade of the cardiac sympathetic segments (Th1 to Th5), which was assessed by cold discrimination with ice. A continuous epidural infusion of bupivacaine was then started for at least 48 hours. The extent of the blockade as well as side effects was evaluated twice daily by measuring the extent of loss of temperature discrimination ability. An amount of 7.5 to 16 mg/h bupivacaine was administered continuously to maintain a blockade corresponding to at least Th1 to Th5. Within 5 hours after the start of epidural infusion of bupivacaine, the nitroglycerin infusion was discontinued. During this time period, the ST segment of the ischemic leads was carefully monitored for signs of rebound ischemia by means of continuous vector cardiography (MIDA CoroNet, Ortivus Medical). Prerandomization treatment was continued also in this group (except for the heparin and the nitroglycerin infusion). During the study period, the number of patients in each group moving freely on the ward was recorded.

Measurements
Patients were monitored continuously using a three-channel Amplitude Modulated Holter ECG recorder (Marquette Electronic Series 8500) for at least 48 hours. Holter tapes were analyzed for ST-segment deviation after all abnormal QRS complexes had been excluded. The ST segment was trended continuously and the two leads that had shown the most pronounced changes on the standard ECG during a painful episode were used. The baseline ST-segment level was defined as the average ST segment over stable period (60 minutes) preceding each episode. The frequency responses of the recorders were 0.05 to 80 Hz. All possible ischemic episodes were reviewed independently by two investigators. ECG ischemic episodes were defined as reversible ST-segment changes lasting at least 1 minute and involving a shift from baseline of 1.0 mm (0.1 mV) of ST-segment depression, 60 ms after the J-point. For each episode, the following were measured: the maximum ST-segment change from baseline, episode duration, and the AUC. The total accumulated AUC for the 48-hour recording period was calculated for each patient as a measure of total ischemic burden. In the TEA group, the Holter monitoring started after discontinuation of the nitroglycerin infusion.

Coronary angiography was performed in all but 1 patient either before or after the study period. Auscultatory arterial blood pressure was measured four times daily and serum concentrations of CK-MB isoforms were taken twice daily. All patients graded the intensity of chest pain every second hour, or at chest pain, according to the Numerical Rating Scale.⁷ Zero was equivalent to no pain at all and 10 to the most intensive pain imaginable. An attack of chest pain graded >5 was defined as an anginal attack. For each patient the number of anginal attacks were recorded. The end points of the study were thus the presence and severity of myocardial ischemia on ambulatory ECG and the number of anginal attacks.

Statistics
Results are expressed as mean (SD). Continuous variables were evaluated by means of Student's t test or Mann-Whitney U test where appropriate. Categorical data were analyzed by ² test. A value of P<.05 was considered statistically significant.

	Results

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Two patients in each group were excluded because of suboptimal ECG recordings. There were no differences between the two groups concerning age, sex, prior coronary intervention (although there was a tendency for higher incidence of prior PTCA in the TEA group), incidence of myocardial infarction, incidence of post–myocardial infarction unstable angina, coronary anatomy, and prestudy cardiac medication (see Table 1).

None of the patients in the TEA group experienced angina or developed myocardial ischemia during or immediately after the 5-hour discontinuation of nitroglycerin. The incidence of myocardial ischemia and the number of ischemic episodes per patient was significantly lower in the TEA group (see Table 2). The mean duration of ischemic episodes per patient as well as a mean episode duration per patient with ischemia were significantly lower in the TEA group. Total ischemic burden (AUC) was significantly lower in the TEA group. One patient in the TEA group experienced 1 episode of anginal pain. Ten patients in the conventional treatment group experienced 15 episodes of anginal pain (P<.01). One patient in the TEA group had a slight elevation of CK during the study period.

View this table: [in this window] [in a new window]   Table 2. Effects of TEA Compared with Conventional Treatment on Holter Positive Myocardial Ischemia and Anginal Pain During 48 Hours

During the study period, the mean systolic and diastolic blood pressures were 126.8±4.0 mm Hg and 71.9±1.6 mm Hg in the control group. The corresponding values for the TEA group were 127.1±3.0 mm Hg and 73.1±1.6 mm Hg (P=NS). Mean heart rate was significantly lower in the TEA group, 58.7±2.0 versus 65.4±2.0 beats/min (P<.05). Thirteen patients in the TEA group and 6 patients in the control group moved freely on the ward during the study period (P<.01).

Side Effects
Eight patients in the TEA group developed urinary retention requiring catheterization of the urinary bladder and 2 patients in the TEA group developed one-sided Horner's syndrome as a side effect to the continuous epidural infusion of bupivacaine. Both these side effects were completely reversible.

	Discussion

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Continuous blockade of cardiac sympathetic afferents and efferents by epidural infusion of bupivacaine reduced the incidence of myocardial ischemia, decreased the number and duration of ischemic episodes, and also reduced the number of anginal attacks compared with maximal conventional medical treatment in patients with unstable refractory angina. In addition, TEA, in these patients with ß-adrenergic receptor blockade, further decreased heart rate, while no effect on arterial blood pressure was seen. The efficacy of continuous TEA was supported by the large number of events, even if the number of randomized patients was limited. We have previously shown, in an uncontrolled study, that TEA effectively controls pain and stabilizes the patients² and that TEA exerts beneficial central hemodynamic effects including a decrease in heart rate and pulmonary capillary wedge pressure during a symptomatic ischemic attack in patients with unstable angina.³ In the present study we have shown that TEA also induces a direct anti-ischemic effect in patients with refractory unstable angina pectoris, which is superior to that of maximal pharmacological treatment.

This study highlights the pathophysiological and clinical role of the cardiac sympathetic nerves for the development of myocardial ischemia in unstable angina. The cardiac sympathetic nerves innervate vasoconstrictor -receptors of both coronary arteries and coronary resistance vessels, and there is considerable evidence for -adrenergic regulation of large coronary arteries and coronary resistance vessels.⁸ It is well known that cardiac sympathetic stimulation by, for example, the cold pressor test,⁹ isometric handgrip,¹⁰ or dynamic exercise¹¹ reduces the diameter of epicardial stenotic coronary arteries. Furthermore, it has been shown that ischemic episodes in patients with unstable angina are caused by a transient impairment of regional coronary blood flow, which in turn is caused by dynamic stenosis of epicardial coronary arteries at the site of the atherosclerotic plaques.¹² It has also been speculated that transient dynamic stenosis of epicardial arteries is caused by sympathetic nerves, stimulating postsynaptic -adrenoreceptors, and that the sympathetic nerves exert continuous restraint on the coronary smooth muscle.¹³ Neri Serneri et al¹⁴ and McCance and Forfar¹⁵ have shown that patients in the acute phase of unstable angina or patients with recent symptoms of unstable angina have a pronounced and sustained, selective cardiac sympathetic overactivity compared with patients with stable effort angina. A significant positive correlation was found between the number of ischemic episodes and the cardiac sympathetic activity measured as norepinephrine spillover.¹⁴

We have previously shown that TEA in patients with CAD completely blocks the cardiac sympathetic efferent activity, measured as norepinephrine spillover,¹⁶ and that a blockade of this efferent impulse traffic dilates stenotic coronary arteries,⁴ suggesting that cardiac sympathetic nerves exert a tonic -mediated constriction of stenotic epicardial coronary arteries in patients with CAD. Myocardial ischemia induced by experimental coronary occlusion activates cardiac sympathetic afferents and may elicit a cardio-cardiac spinal reflex with a consequent increase in sympathetic efferent activity, which in turn largely will override and limit the local ischemia-induced metabolic vasodilation and may thus further aggravate ischemia.^{17 18} In animal studies it has been shown that epidural blockade of this reflex with a local anesthetic may inhibit this poststenotic sympathetically mediated vasoconstriction.¹⁸ In the present study, TEA almost completely abolished the anginal attacks due to the blockade of the sympathetic afferents. The anti-ischemic and anti-anginal effects of TEA as demonstrated in the present study could therefore tentatively be explained by a complete blockade of the sympathetically mediated spinal reflex with a consequent inhibition of the intense sympathetic stimulation of coronary -adrenergic and myocardial ß-adrenergic receptors. This is followed by a dilation of dynamic stenoses of epicardial arteries, a possible poststenotic coronary vasodilation, and a heart rate decrease.

In the TEA group, the nitroglycerin infusion was discontinued when treatment with epidural bupivacaine was started. It has previously been shown that abrupt interruption of intravenous nitroglycerin induces rebound myocardial ischemia in approximately 50% of patients with unstable angina.²⁰ This was not seen in the present study, probably because nitroglycerin was gradually, not abruptly, discontinued and because cardiac efferent sympathetic blockade by TEA itself dilates stenotic coronary arteries.⁴ Another obvious reason for the anti-ischemic effect of TEA is the decrease in myocardial oxygen demand caused by the heart rate decrease. However, during exercise-induced myocardial ischemia for example, the anti-ischemic effect of TEA is not related to changes in myocardial oxygen demand.⁵ It has also been shown that a 10% heart rate reduction by the use of esmolol has no effect on cardiac events or silent ischemia in patients with unstable angina,²¹ suggesting that the heart rate reduction by TEA is not the major cause of its anti-ischemic effect.

Platelet aggregation on the ruptured atherosclerotic plaques and the ensuing thrombus formation play an important role in the cause of unstable angina.^{22 23} Anti-thrombotic therapy with heparin infusion reduces episodes of symptomatic and nonsymptomatic ischemia by 70% to 90% in refractory unstable angina.^{24 25} In the TEA group, heparin infusion was discontinued to avoid an epidural bleeding complication. It has been shown that discontinuation of heparin may reactivate unstable angina.²⁶ The lack of such withdrawal phenomenon in the TEA group was probably caused by the fact that almost all patients were treated with aspirin, which may prevent this reactivation.²⁶ It is tempting to speculate that TEA itself may have a favorable interaction with the hemostatic system. Emotional stress activates platelets and increases the aggregability in patients with CAD and unstable angina.^{27 28} TEA decreases norepinephrine release¹⁶ and has been shown to exert an inhibitory effect of platelet aggregation and an anti-thrombotic effect in connection with surgery.²⁹

Treatment of the patients in the control group was based on the combination of ß-adrenergic blockers, calcium antagonists, intravenous nitroglycerin, and heparin infusion, all of which have a clear-cut documented anti-ischemic effect in unstable angina.³⁰ Three previous studies on patients with unstable angina refractory to conventional treatment, using the same methodology for diagnosing myocardial ischemia, and with approximately the same inclusion criteria and sample sizes of study groups as the present study, have recently been published (see Table 3). In those studies it was shown that the number of ischemic episodes per patient over a 48-hour period varied between 2.0 and 8.8 with heparin IV, heparin SC or heparin IV plus recombinant tissue plasminogen activator (rTPA).^{24 25 31} The corresponding data of the present study in the conventional treatment group and the TEA group are 3.6 and 1.0, respectively. The ischemic duration per patient varied from 14.0 to 29.6 minutes in those studies, which should be compared to 19.7 minutes and 4.1 minutes, respectively, for the conventional treatment group and the TEA group of the present study. Finally, the incidence of myocardial ischemia varied from 60% to 90% in the study by Romeo et al³¹ compared with 61% of the control group and 22% of the TEA group of the present study. From these comparisons we believe that the anti-ischemic treatment of the patients in the control group was as effective as previously documented therapeutic regimens and that the anti-ischemic and anti-anginal effects of continuous cardiac sympathetic blockade with TEA may be an even more effective tool for treatment of severe refractory unstable angina. In patients with anginal attacks and myocardial ischemia in spite of maximal medical treatment, there is a need for emergent invasive revascularization. However, the complication rate increases with the instability of the patients, and the very patients who are indicated for emergency revascularization are those who are also at increased risk of procedural complications.³² We therefore suggest that TEA could be an interesting alternative to use as an adjunct or alternative to medical therapy before invasive management, to decrease the ischemic burden and to stabilize those patients with the most severe refractory angina and myocardial ischemia.

View this table: [in this window] [in a new window]   Table 3. Previously Reported Effects of Various Treatments on 48-Hour Holter Positive Myocardial Ischemia in Severe Refractory Unstable Angina Compared With the Outcome of the Present Study

There was an unexpectedly high incidence of urinary retention requiring intermittent or continuous bladder catheterization in the TEA group (50%, and only in males). It is well known that epidural administration of local anesthetics in the lumbar region, especially when administered continuously, may cause urinary retention due to a blockade of sacral segments and that there is a correlation between the total amount of local anesthetic given epidurally and the incidence of urinary retention.³³ To our knowledge, there is no previous study on the effects of continuous thoracic epidural administration of local anesthetics on the bladder function in nonsurgical patients. It is likely that continuous TEA may, in some patients, reversibly block efferent and afferent nerve fibers contributing to spinal and supraspinal mechanisms involved in micturition reflex.

	Selected Abbreviations and Acronyms

 

AUC = area-under-the-ST-time curve CAD = coronary artery disease CK-MB = creatine kinase myocardial band isoenzyme PTCA = percutaneous transluminal coronary angioplasty TEA = thoracic epidural anesthesia

	Acknowledgments

 
This study was supported by grants from the Swedish Medical Research Council (No. 8682), the Gothenburg Medical Association, Sahlgrenska Hospital Foundations, and the Medical Faculty.

Received January 16, 1997; revision received April 28, 1997; accepted May 5, 1997.

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