REGIONAL VERSUS GENERAL ANESTHESIA

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REGIONAL VERSUS GENERAL ANESTHESIA

Rose Christopherson, MD, PhD, and Edward J. Norris, MD

Over the last decade medical care has been driven by two dominant forces: pressures to reduce use of medical resources and improvements in quality of patient care. Improvements in patient outcome and reduced use of resources have been suggested to result from using regional techniques as compared with general anesthesia alone for high-risk patients undergoing significant operative procedures. Other proposed advantages of regional anesthesia techniques include decrease in the neuroendocrine "stress" response, improved postoperative pulmonary function, reduced thrombotic complications, and reduced perioperative cardiac morbidity.

Patients with cardiac disease undergoing noncardiac surgery represent a significant management challenge to the anesthesiologist. Unlike patients pres- enting for cardiac surgery, these patients frequently do not have extensive work-ups directed at the cardiovascular system, have not been as aggressively medically managed, and are not expected, based upon their surgical procedure, to need cardiac monitoring or intervention after surgery. Outcome research comparing regional with general anesthesia over the last decade has been focused primarily on the high-risk patient undergoing noncardiac vascular surgery. Vascular surgery patients have been shown to be at higher risk of perioperative cardiac morbidity than patients having other types of surgery; and patients with peripheral vascular disease have a higher rate of mortality overall than those without it? Patients who are at high risk for cardiovascular morbidity can be expected to have an increased rate of morbidity regardless of their anesthetic. Thus, trials performed upon a relatively small number of patients can have a large enough number of adverse outcomes to establish whether one type of anesthetic is more dangerous than another.

Options for regional anesthesia for patients with cardiovascular disease include use of subarachnoid or epidural local anesthetics or narcotics, regional

From the Anesthesiology Service, Portland Veterans Administration Medical Center, Port- land, Oregon (RC); and the Departments of Anesthesiology and Critical Care Medi- cine, Johns Hopkins Hospital, Baltimore, Maryland (EJN)

ANESTHESIOLOGY CLINICS OF NORTH AMERICA

VOLUME 15 * NUMBER 1 * MARCH 1997 37

38 CHRISTOPHERSON & NORRIS

anesthesia for carotid artery endarterectomy, use of interscalene or axillary block for placement of fistulas in the arm for renal dialysis, and intercostal blockade as an adjunct for upper abdominal surgery. Several recent prospective clinical trials have examined the use of epidural or spinal anesthesia either as an adjunct or as the sole anesthetic for procedures, including thoracic surgery, aortic surgery, and lower extremity vascular surgery. Non-neuraxial regional anesthesia has not been studied with the same intensity. It does not involve as great a physiologic trespass because it does not cause sympathectomy, which may be accompanied by hypotension. It is also appropriate for less major surgery, such as eye surgery or arteriovenous fistula formation, for patients with renal failure. Even though patients having these procedures often have cardiac disease, these surgical procedures are not associated with high rates of perioperative cardiovascular complications. Therefore, this article focuses upon neuraxial anesthesia rather than upon other types of regional anesthesia.

RESULTS OF CLINICAL TRIALS

Five prospective randomized clinical trials have assessed the value of epidural anesthesia for patients at high risk for perioperative cardiac morbidity-four focused on vascular surgery patients‘, 2. 4, l7 and the fifth studied a more mixed population of patients who required intensive care unit (ICU) beds for postoperative recovery.’8 One study compared epidural anesthesia with general anesthesia: one compared epidural, spinal, and general anesthesia; and the other three assessed the value of using epidural anesthesia as an adjunct to general anesthesia.’, 17, l8 Two of these studies found improved surgical outcome after vascular surgery4 ”; two studies found a reduction in cardiac morbidity associated with epidural anesthesia17, Is; and the other three did not find reductions in cardiac morbidity, even though the studies were designed to detect differences in this outcome.’, *, Two of these studies did not have adequate power to detect a clinically important difference in cardiac morbidity?, The third, however, had adequate power to detect a difference in cardiac morbidity, and did not find one (Table l).’

TABLE 1. CLINICAL TRIALS EVALUATING EFFECTS OF NEURAXIAL ANESTHESIA ON CARDIOVASCULAR MORBIDITY

Vascular Number of Cardiac Surgical

Study Patients Population Morbidity Morbidity

Yeager et al 53 Mixed, requiring Reduced with Not reported ICU recovery epidural

Tuman et al 80 Vascular Reduced with Reduced with surgery epidural epidural patients

Baron et al 173 Aortic surgery No difference Not reported Christopherson 100 Lower extremity No difference Reduced with

et al vascular epidural surgery

Bodie et al 423 Lower extremity No difference Not reported vascular surgery

REGIONAL VERSUS GENERAL ANESTHESIA 39

The data these clinical trials provide can help the clinician determine what changes in their practice will yield the best outcomes. For data from any clinical trial or outcome study to be useful the author must provide the following information:

The population of patients being studied The techniques or drug being compared The power of the study The outcome measure

Without such information the clinician has no way to validate his or her current practice or direct a meaningful change in that practice. To this end, several important questions must be asked of all outcome research:

Is the research scientifically sound? Is the outcome measured clinically important? Is the study appropriately powered to support its conclusions? Have the findings been reproduced?

Ultimately, the most important question the clinician must answer is, "How should I change my clinical practice based on the data?"

Yeager et al

In their landmark 1987 report, Yeager et alls found that epidural-supplemented general anesthesia combined with postoperative epidural analgesia re- sulted in a significant beneficial effect on the operative outcome in a group of high-risk patients. Significantly less cardiac morbidity (18% vs 52%), fewer pulmonary complications (6% vs l6%), fewer infectious complications (7% vs 52%), and significantly less mortality (OYO vs 16%) was found in patients randomized to epidural anesthesia and postoperative analgesia as compared with patients randomized to general anesthesia and postoperative parental narcotic analgesia.18 The results of this study were surprising. Few practicing clinicians would expect such dramatic improvements in perioperative morbidity and mortality to be associated simply with the perioperative use of an epidural catheter. This study caused many clinicians to reevaluate their clinical practice, and it stimulated investigators to embark upon further clinical trials.

Outcome data of this radical nature should be viewed as hypothesis-generating. That is to say, if a major change in clinical practice is suggested by the outcome data, it should be independently confirmed before it is accepted. The limitations of the study-generating outcome data must also be addressed. Al- though Yeager et a1 found a reduced rate of both overall mortality and major cardiovascular morbidity, it is not clear that this was due to direct effects of the anesthetics on the cardiovascular system. Patients randomized to unsupplemented general anesthesia in that trial had a significantly elevated rate of morbidity due to infections. The increased cardiac morbidity and death may in some cases have been the common endpoints of morbidities that were initially unrelated to the heart. That study has also been criticized because the rate of perioperative morbidity following unsupplemented general anesthesia was unusually high. Thus, the findings might not be applicable to unsupplemented general anesthesia at other hospitals.

A further problem in applying the findings of that study to specific patients is the fact that a broad variety of patients were studied, and it is not known what morbidities were increased for which patients. It is possible, for example,


that the reduced rate of respiratory morbidity found was due to a beneficial effect upon patients who underwent pulmonary resection, that was not evident among other patients, or that the reduction in cardiac morbidity was mainly due to a reduction among patients with known cardiovascular disease. Because such a varied group of patients was studied, it is difficult to apply the findings to specific patients.

A related problem is the lack of anesthetic protocols reported. It would be impossible to have a single anesthetic protocol for patients undergoing such a wide variety of procedures; however, with little detail on the protocols reported, it is hard to know what kind of epidural anesthesia was effective; was it full neuraxial blockade with the same volume and concentration as would be sufficient for unsupplemented regional anesthesia, or was the use of very dilute local anesthetics or narcotics equally effective?

In summary, the most significant limitations of Yeager et a1 are the follow-

Nonuniform patient population and surgical stress No standardization of perioperative care An unusually high rate of morbidity after general anesthesia

Although the study has these flaws, it was prospective and randomized,

ing:

and the positive findings Yeager et a1 reported have been very important.

Tuman et al

Tuman et all7 in 1991 reported the results of a prospective randomized trial comparing epidural supplemented general anesthesia and postoperative epidural analgesia with general anesthesia and postoperative parenteral narcotic analgesia in a high-risk population undergoing vascular surgery. They found significantly less cardiovascular morbidity (28% vs lo%), significantly fewer infectious complications (20% vs 5%), and significantly fewer thrombotic complications (28% vs 2.5%) in patients receiving epidural anesthesia and postoperative ana1ge~ia.I~ Although the reduction in thrombotic complications was new, the reduction in cardiac and infectious complications confirmed the results of Yeager et al.

Although the methodologic limitations were not as significant as with Yeager et al, similar limitations existed. The patient population was more homogeneous than that of Yeager et a1 because all the patients enrolled in the study had vascular disease; however, the surgical stress they were submitted to was inhomogeneous-approximately half of them underwent aortic surgery (35), and half underwent lower extremity arterial grafting (45), which is much less stressful. Additionally, nonequivalent modalities for postoperative pain control were used. Patients who had been randomized to the epidural group received continuous postoperative epidural analgesia with daily visits from the pain service whereas those randomized to the unsupplemented general anesthesia group received intramuscular or oral narcotics as needed from the surgical ward nurses with no special monitoring of the efficacy of this modality. This difference in postoperative analgesia continued for an average of 2.4 postoperative days. It is not clear whether the beneficial findings these researchers reported was due to epidural anesthesia and postoperative analgesia or whether it was due to the fact that patients randomized to unsupplemented general anesthesia received systematically inferior postoperative analgesia. Possibly, if both groups had


received equal attention to their postoperative pain, the two groups might not have differed with respect to cardiovascular outcome.

Baron et al

Baron et all in 1991 reported the results of a prospective randomized trial comparing epidural supplemented general anesthesia to general anesthesia for patients undergoing aortic surgery. Unlike the previous two studies, they found no difference in cardiac morbidity, respiratory morbidity, or operative mortality. In this study, although the patient population, intraoperative management, and surgical stress were homogeneous, postoperative care was not standardized. Postoperative analgesia was not directed by study protocol; therefore, no conclusion can be made as to the role of the various modalities for postoperative pain control. This study was larger than the two previous studies combined. It had adequate power to validate its negative findings with respect to cardiac morbidity.' Its disconfirmation of the findings of Yeager and Tuman is therefore important. Furthermore, the patients enrolled in this study were at high risk for cardiovascular morbidity, and they were subjected to a significant surgical stress. Therefore, it cannot be argued that this was not an appropriate study to discover the benefit of epidural anesthesia because of insufficient risk or low surgical stress.

Christopherson et al

In a 1993 report, Christopherson et a1 (senior author) found that in patients undergoing lower extremity vascular surgery, there was no difference in rates between epidural anesthesia with postoperative analgesia, and general anesthesia with intravenous patient-controlled analgesia (PCA) of myocardial ischemia, major cardiac morbidity, or operative mortality? A significant reduction in the incidence of reoperation for vascular graft failure in the epidural group was found, confirming the findings of Tuman et al. This study addressed several of the limitations noted in the previous studies:

The patient population and surgical stress were homogenous Protocols were used to determine intraoperative hemodynamic monitoring

based upon preoperative cardiac risk Intraoperative and early postoperative management were determined by

protocol, with management of blood pressure and heart rate determined by clinical algorithms

Postoperative pain management was determined by protocol and was com- parable between the two groups, with the epidural group receiving epidural PCA whereas those randomized to general anesthesia received intravenous PCA

A cardiologist who was masked to the type of anesthetic patients received diagnosed all cardiac outcomes',

Unfortunately for the discovery of a difference in cardiac morbidity or even myocardial ischemia, this study was stopped early by the authors' research monitoring committee. An increased rate of reoperation for vascular graft failure was found among the patients randomized to general anesthesia. This left the study with insufficient power to be certain that rates of cardiac morbidity and


myocardial ischemia were the same after regional and general anesthesia. At the same time, the authors had not prospectively gathered all the information necessary to assess risks related to vascular graft failure. This problem was compensated for in part by a subsequent study in which the surgeons involved in the original study examined all important surgical risk factors and excluded all patients who were at low risk for graft failure (eg , patients having femoral aneurysm repairs or femoral-femoral grafts. This study confirmed the results of the initial trial, and indirectly, the findings of Tuman et al.I4 No studies to date have disconfirmed the finding that patients undergoing peripheral vascular surgery have lower rates of graft failure after epidural or epidural-supplemented general anesthesia.

This trial did not, unfortunately, enroll enough patients to determine whether the rates of cardiac outcome were truly similar or only appeared similar due to small sample size. It has also been suggested that patients having lower extremity vascular grafting are a lower-risk population for cardiac morbidity than those having aortic surgery, and therefore that a difference between types of anesthesia might not be evident due to lack of surgical stress? In summary, the study had several important limitations:

Inability to separate differences due to intraoperative techniques and postoperative techniques because all patients who received epidural anesthesia received epidural analgesia, and all who received general anesthesia received intravenous PCA

Discontinuation of intensive postoperative pain protocol after only 24 hours The surgical procedure studied may not be stressful enough to demonstrate

Inadequate size to give validity to its negative findings with respect to differences in morbidity and mortality

cardiac morbidity and myocardial ischemia

Bodie et al

The study of Bodie et alz is the largest to date, consisting of 423 patients undergoing lower extremity vascular grafting randomly assigned to general, epidural, or spinal anesthesia. Power calculations based upon their low overall mortality rates of 3.1% indicated that it would be necessary to enroll over 24,000 patients to have adequate statistical power to show that there was no difference related to type of anesthetic for this outcome. Their study was terminated at that point, leaving them, like Christopherson et al, with a study that was too small to show decisively that there is no difference between epidural and general anesthesia with respect to either death or major cardiac morbidity. They did not use protocols to determine perioperative fluid management or postoperative pain control; however, administration of anesthesia was governed by protocol.2

All patients were monitored with pulmonary artery catheters, and all patients remained in monitored beds for 48 hours after surgery. Many patients received intravenous nitroglycerin after surgery to either prophylax against myocardial ischemia, control blood pressure, or lower pulmonary artery pressure. There was no protocol to determine which patients received intravenous nitroglycerin. Interestingly, in this study, patients who were randomized to general anesthesia had lower rates of cardiac morbidity than those randomized to either form of regional anesthesia, and patients who had failed regional anesthetics had the highest rates of postoperative cardiac morbidity.* This result remains unexplained.


It is also interesting that Bodie et a1,2 with very little in the way of management protocols, and Christopherson et a1,4 with highly protocolized management, both found no difference related to type of anesthesia in patients undergoing the same surgical procedure. Unfortunately, both studies are underpowered, and therefore possibly the only lesson to be drawn from the two studies is that infrainguinal bypass grafting may be associated with too little surgical stress to be appropriate for study of the effect of regional versus general anesthesia on cardiac morbidity. In summary, weaknesses of. the trial by Bodie et a1 include the following:

Lack of sufficient size (i.e., sufficient numbers of morbid events) to validate

Lack of protocols so that it is difficult to compare their management to that

Surgical stress that may not be sufficient to produce enough adverse out-

their negative results

of other clinicians

comes to differentiate the effects of regional from general anesthesia

POSSIBLE MECHANISMS FOR REDUCTION IN CARDIAC MORBIDITY

One mechanism common to both reduction in cardiac morbidity and to reduction in vascular graft failure is prevention of thrombosis. Major perioperative myocardial morbidity, including unstable angina, myocardial infarction, and cardiac death, is at least partly due to coronary thrombosis. Obviously, thrombosis of vascular grafts also leads to their failure. Clot formation as measured by thromboelastography was reported by Tuman et a1 to be reduced in patients randomized to epidural-supplemented general ane~thesia.’~ In a large subset of the patients studied by Christopherson et al, plasminogen activator inhibitor levels, which indicate the degree to which clot lysis is inhibited, were measured? They were found to be elevated after general anesthesia but not after epidural anesthesia, and to be predictive of perioperative cardiac morbidity and vascular graft failure.16 In a number of studies, venous thrombosis has also been shown to be reduced following hip surgery under epidural anesthesia.” * Q l3

Another mechanism that could lead to perioperative cardiac morbidity is elevation of catecholamines. Epinephrine and norepinephrine cause an increase in heart rate; norepinephrine also causes an increase in peripheral vascular resistance. Thus, elevated catecholamines may cause an increase in myocardial oxygen consumption along with reduced oxygen delivery due to reduced time in diastole. Both norepinephrine and epinephrine levels were shown to be elevated after general anesthesia compared with epidural anesthesia in a subset of the patients studied by Christopherson et al.3 Reductions in levels of plasma epinephrine and norepinephrine after spinal or epidural anesthesia have been shown in numerous other studies?,

A number of other mechanisms could explain differences in cardiac morbidity or in vascular thrombosis. Some degree of cardiac depression occurs with general anesthesia, which includes potent inhalational agents. This is obviated or at least reduced by using regional anesthesia either as the sole technique or as a supplement to general anesthesia. Cardiac depression may be associated with increased filling pressures in some patients, and this may in turn give rise to subendocardial ischemia. Regional anesthesia that includes sympathetic blockade, on the other hand, may Peduce afterload, and therefore reduce myocardial oxygen consumption.


WHY THE RANDOMIZED CLINICAL TRIALS DO NOT SHOW A BENEFIT

Although there are mechanisms that suggest that major neuraxial blockade may be protective to the heart, the bulk of the evidence from clinical trials does not support this conclusion. The two studies that showed reduced cardiac morbidity were small early studies whereas the three studies that showed no reduction in cardiac morbidity were much larger. Furthermore, the largest and most recent trial showed a nonsigruhcant tendency for regional anesthesia to be associated with an increased incidence of major cardiac morbidity.z

The findings of all of the studies are compiled in Table 2. It is probably not appropriate to do statistics on the summary numbers from these five studies because they involve different anesthetic regimens, different definitions of cardiovascular morbidity, and different patient populations; however, most would agree that the overall difference of 22% morbidity associated with general anesthesia compared with 17% associated with regional or regional-supplemented general anesthesia is not clinically sigruficant.

Some mechanisms suggesting that spinal or epidural anesthesia should benefit patients with coronary artery disease were discussed previously; however, there are other mechanisms that may actually put patients with coronary artery disease at increased risk. The same sympathectomy that reduces afterload and therefore reduces myocardial oxygen demand may also be associated with a substantial reduction in diastolic blood pressure. Anesthesiologists generally try to maintain patients’ diastolic blood pressures above 60 rnm Hg if they are at risk for cardiac morbidity. Lf patients with coronary artery disease are allowed to have low diastolic blood pressures, they may not have adequate myocardial perfusion during diastole.

The balance between reduced afterload, which should help the ischemic myocardium, and reduced diastolic blood pressure, which may hurt it, will be different in each patient because each will vary in the thickness of the myocardium, the degree of coronary stenosis, and the amount by which subendocardial blood flow is improved by reduced ventricular filling pressures. Thus, although there are mechanisms by which major regional anesthesia should protect all patients with coronary artery disease, there are also mechanisms by which some patients may be harmed. It is probable that, in the trials discussed previously, some patients were protected from adverse outcomes by regional anesthesia whereas some others may have been compromised. The net outcome is that,

TABLE 2. TOTAL NUMBER OF PATIENTS WITH CARDIOVASCULAR MORBIDITY IN MAJOR CLINICAL TRIALS ASSESSING THE EFFECT OF REGIONAL ANESTHESIA

Morbidity Morbidity Morbidity Assoclated wlth Associated wlth Assoclated wlth

Study General Anesthesia Epldural Anesthesia Splnal Anesthesla

Yeager et al 13/25 4/28 Not studied Turnan et al 11/40 4140 Not studied Baron et al 22/86 19181 Not studied Christopherson et al 515 1 3/49 Not studied

Bodie et al 231 38 231 49 2911 36 Totals 741340 (22%) 53/347 (15%) 291136 (21%)

Combining epidural BY483 (1 7%) and spinal


based upon the trials reported to date, there is no substantial, consistent evidence of a protective effect of regional anesthesia on the heart.

Furthermore, not all patients studied in the trials discussed previously or appearing in operating rooms have coronary artery disease by itself. Many also have fixed valvular heart disease, idiopathic hypertrophic subaortic stenosis (IHSS), or left ventricular hypertrophy. All of these lesions affect a patient’s response to major regional blockade with associated sympathectomy.

PATIENTS WITH VALVULAR HEART DISEASE AND VENTRICULAR HYPERTROPHY

Patients with valvular heart disease may be divided into those with regurgitant lesions and those with stenotic lesions. Major regional anesthesia with associated sympathetic blockade reduces both preload and afterload. Patients with fixed stenotic lesions are not benefited by reductions in afterload because vasodilation in the face of a low cardiac output results in hypotension. These patients may also be hurt by a reduction in preload because a high preload is needed to maintain cardiac output. The relative harm or benefit that a patient with a fixed stenotic valvular lesion may experience due to a regional anesthetic will, therefore, depend upon the degree of venodilation (reducing preload) and the degree of arterial dilation (reducing afterload) associated with the anesthetic.

Patients with regurgitant lesions benefit from afterload reduction because this improves forward flow; however, stroke volume may be reduced with reduced preload. Thus, the relative degree of benefit or harm they will experience after a neuraxial blockade depends upon the balance between venodilation and arterial dilation caused by the anesthetic as well as the volume loading that they receive prior to or during the onset of the anesthesia. Volume loading will obviously protect the patient from preload reduction due to venodilation, but may be deleterious upon termination of the sympathetic blockade.

Patients with chronic hypertension often develop left ventricular hypertrophy. It is not uncommon in patients with peripheral vascular disease. As defined by voltage criteria, it occurred in 17% of patients enrolled in the study of Christopherson et a1 and in a similar population of 305 patients having vascular surgery at Hadassah Hospital in Israel (Giora Landesberg, MD, personal commu- nication, 1995). In both groups of patients preoperative ventricular hypertrophy was predictive of postoperative major cardiac morbidity, including cardiac death, myocardial infarction, and unstable angina. Patients with ventricular hypertrophy are exquisitely sensitive to determinants of subendocardial blood flow. The reduced diastolic blood pressure associated with regional anesthesia could cause myocardial ischemia in these patients. On the other hand, they might benefit by the reduction in filling pressure that might be associated with major regional anesthesia.

How changes in preload and afterload associated with regional anesthesia affect the performance of any individual patient’s heart cannot be predicted from a clinical trial upon a large number of other patients. The characteristics of the individual patient’s heart and of the individual anesthetic, including degree of sympathetic blockade, combination with a general anesthetic, and fluid loading, will determine how well the anesthetic is tolerated. Thus, the wise clinician should use invasive hemodynamic monitoring appropriate to the patient’s cardiac lesions and to the expected-surgical stress. In many cases it will be appropriate to measure preload, afterload, cardiac output, and stroke volume using a pulmonary artery catheter. The fact that regional anesthesia is to be performed


should never be used as a reason to reduce the degree of invasive hemodynamic monitoring used for a patient with valvular or coronary artery disease.

SUMMARY

In summary, this article has focused upon recent randomized clinical trials to evaluate the relative protective effect of major neuraxial blockade either alone or in conjunction with general anesthesia for patients at risk for major cardiovascular perioperative morbidity. Some mechanisms that have been shown to be associated with regional anesthesia, which should be protective to the heart, have also been briefly discussed. Although the earlier, smaller trials showed a reduction in cardiac morbidity associated with regional anesthesia, this was not confirmed by larger, more recent trials. When the findings of all the trials are summed, there does not seem to be a substantial benefit associated with regional anesthesia. Some of the hemodynamic effects of regional anesthesia, and how these might compromise some patients with cardiac disease, especially those with valvular lesions or left ventricular hypertrophy, have been addressed. These effects must be taken into account when designing any patient’s anesthetic.

This article has not dealt with regional anesthesia for more minor procedures, such as interscalene or axillary blockade for creation of arteriovenous fistulas for renal dialysis. The surgical trespasses that can be performed under these less physiologically stressful regional anesthetics are smaller than those that require major neuraxis blockade (e.g., aortic aneurysm resection, abdominal surgery). Therefore, these types of surgery are associated with low rates of major cardiovascular morbidity, no matter what type of anesthesia is used. This does not mean that choice of anesthetic is unimportant for these types of surgery. It is very important, and might have a major impact upon the perioperative morbidity of any given patient who has cardiovascular disease. It means, rather, that it is difficult to perform prospective, randomized clinical trials of a size large enough to determine whether there is a difference in perioperative morbidity related to choice of anesthetic.

References

1. Baron JF, Bertrand M, Barre E, et al: Combined epidural and general anesthesia versus general anesthesia for abdominal aortic surgery. Anesthesiology 75:611, 1991

2. Bodie RH Jr, Lewis KP, Zarich SW, et al: Cardiac outcome after peripheral vascular surgery: Comparison of general and regional anesthesia. Anesthesiology 84:3, 1996

3. Breslow MJ, Parker SD, Frank SM, et a1 Determinants of catecholamine and cortisol responses to lower extremity revascularization: The PIRAT Study Group. Anesthesiol- ogy 79:1202, 1993

4. Christopherson R, Beattie C, Frank SM, et a1 Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery: Perioperative Ischemia Randomized Anesthesia Trial Study Group [see comments]. Anesthesiology 79422, 1993

5. Eagle KA, Rihal CS, Foster ED, et a1 Long-term survival in patients with coronary artery disease: Importance of peripheral vascular disease: The Coronary Artery Surgery Study (CASS) Investigators. J Am Coll Cardiol23:1091, 1994

6. Hakanson E, Rutberg H, Jorfeldt L, et a1 Effects of the extradural administration of morphine or bupivacaine, on the metabolie response to upper abdominal surgery. Br J Anaesth 57:394, 1985


7. Jorgensen LN, Rasmussen LS, Nielsen PT, et al: Antithrombotic efficacy of continuous extradural analgesia after knee replacement [see comments]. Br J Anaesth 66:8, 1991

8. Liu S, Carpenter RL, Neal JM: Epidural anesthesia and analgesia: Their role in postoperative outcome. Anesthesiology 82:1474, 1995

9. Mangano DT, Browner WS, Hollenberg M, et al: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 323:1781, 1990

10. Mitchell D, Friedman RJ, Baker JD 3d, et a1 Prevention of thromboembolic disease following total knee arthroplasty. Epidural versus general anesthesia. Clin Orthop (269):109, 1991

11. Modig J: The role of lumbar epidural anaesthesia as antithrombotic prophylaxis in total hip replacement. Acta Chir Scand 151:589, 1985

12. Modig J, Borg T, Karlstrom G, et a1 Thromboembolism after total hip replacement Role of epidural and general anesthesia. Anesth Analg 62174, 1983

13. Nielsen PT, Jorgensen LN, Albrecht-Beste E, et al: Lower thrombosis risk with epidural blockade in knee arthroplasty. Acta Orthop Scand 61:29, 1990

14. Perler BA, Christopherson R, Rosenfeld BA, et al: The influence of anesthetic method on infrainguinal bypass graft patency: A closer look. Am Surg 61:784, 1995

15. Pflug AE, Halter JB: Effect of spinal anesthesia on adrenergic tone and the neuroendocrine responses to surgical stress in humans. Anesthesiology 55:120, 1981

16. Rosenfeld BA, Beattie C, Christopherson R, et a1 The effects of different anesthetic regimens on fibrinolysis and the development of postoperative arterial thrombosis: Perioperative Ischemia Randomized Anesthesia Trial Study Group [see comments]. Anesthesiology 79:435, 1993

17. Tuman KJ, McCarthy RJ, March RJ, et al: Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 73:696, 1991

18. Yeager MP, Glass DD, Neff RK, et a1 Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 66:729, 1987

Address reprint requests to Rose Christopherson, MD, PhD

Anesthesiology Service (199) Portland Veterans Administration Medical Center

Post Office Box 1034 Portland, OR 97207

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