Key words: Analgesia: epidural, Anesthesia: epidural; general, Complications: postoperative, Morbidity.

INCREASING insight into mechanisms of perioperative physiologic responses and resultant effects on patient outcome suggests that some responses may be detrimental. Thus, initial belief in the adaptive "wisdom" of the body [1]has been supplanted by the concept that a "stress-free" perioperative period may attenuate detrimental physiologic responses and decrease resultant morbidity. [2].

Perioperative pain is a potent trigger for the stress response, activates the autonomic system, [3]and is thought to be an indirect cause of adverse effects on various organ systems. [4-7]Thus, the theory has arisen that effective analgesia may improve patient outcome. Although it is clear that traditional intramuscular injections of opioids are inferior to both patient-controlled analgesia (PCA) with intravenous opioids [7,8]and epidural administration of opioids, [9]it remains controversial whether epidural administration of opioids alone provides superior analgesia to intravenous infusions or PCA administration of opioids. [10-13]However, the combination of epidural opioids and local anesthetic provides synergistic analgesia [14]and appears to provide superior analgesia with activity. [15]Nonetheless, the exact relation between quality of analgesia and postoperative outcome remains ill defined, and there is growing evidence that relief of pain per se plays a limited role in attenuation of postoperative physiologic responses and morbidity. [16-18].

On the other hand, numerous studies have demonstrated that epidural anesthesia and analgesia reduces perioperative physiologic responses in addition to providing pain relief. However, effects of epidural anesthesia and analgesia on postoperative morbidity remain controversial. Most studies to date do not have sufficient power to detect clinically significant differences. Others are not randomized, do not control intra- and postoperative care, or do not prospectively define outcome criteria. Nevertheless, selected subsets of these studies are often cited as providing consistent proof of either benefit, or lack thereof from epidural analgesia.

To provide an overview of current knowledge, we review and synthesize experimental and clinical evidence from studies examining effects of epidural anesthesia and analgesia on postoperative morbidity in specific physiologic systems. For the purposes of this review, epidural anesthesia is defined as the intraoperative use of local anesthetics, and epidural analgesia is defined as the postoperative use of local anesthetics or opioids. The method of delivery of systemic analgesia from comparative studies also is discussed, because there are differences in analgesic efficacy. Finally, we address the following issues. (1) Is there a difference between effects of epidural analgesia provided with local anesthetic or opioid, as the mechanisms of action are different? [19,20](2) Is it necessary to provide intraoperative epidural anesthesia, postoperative epidural analgesia, or both to affect physiologic responses and possibly reduce postoperative morbidity? (3) Are there advantages in the use of thoracic versus lumbar epidural catheters?.

Experimental and Clinical Effects of Epidural Anesthesia and Analgesia

Cardiovascular System

Approximately one in eight patients who undergo surgery in the United States has risk factors for or has known coronary artery disease. [21]Some patient populations are at especially high risk for coronary artery disease. For example, asymptomatic patients with peripheral vascular disease have a 40-70% incidence of significant coronary stenoses (documented with coronary angiography). [22,23]It is no surprise therefore that cardiac morbidity is the primary cause of death after anesthesia and surgery with reported incidences in high-risk populations ranging from 2% to 15%. [24]Thus, anesthetic and analgesic techniques that reduce postoperative cardiac morbidity should significantly improve patient outcome.

Experimental Effects. Previous studies in nonsurgical populations have demonstrated that activation of the sympathetic nervous system may result in myocardial ischemia and infarction. [25-27]Similarly, interventions that inhibit the sympathetic response can reduce cardiac morbidity. [28-33]Because sympathetic activation occurs during the perioperative period, inhibition of sympathetic activity during the perioperative period may reduce postoperative myocardial morbidity (Figure 1). The mechanisms whereby sympathetic activation causes cardiac morbidity can be mediated both by increases in myocardial oxygen demand or reductions in myocardial oxygen supply. For example, pain from surgical stimuli can activate sympathetic efferent nerves and increase heart rate, inotropy, and blood pressure (Figure 1). Although activation of the sympathetic nervous system can increase indexes of myocardial oxygen demand and result in ischemia, most episodes of myocardial ischemia occur in the absence of major hemodynamic changes. [34-37]In fact, most episodes of "silent ischemia" are not preceded by increases in myocardial oxygen demand with the exception of small increases in heart rate. [38,39]Thus, reductions in myocardial oxygen supply may be the primary cause of silent ischemia.

Figure 1. Neural pathways for sympathetic activation in response to surgery. Painful stimuli transmitted through afferent nociceptive pathways activate sympathetic efferent pathways. Sympathetic stimulation of the myocardium increases heart rate (HR) and inotropy. Stimulation of the peripheral vascular bed produces vasoconstriction with a resulting increase in blood pressure (BP). EPI = epinephrine; NEPI = norepinephrine.

Figure 1. Neural pathways for sympathetic activation in response to surgery. Painful stimuli transmitted through afferent nociceptive pathways activate sympathetic efferent pathways. Sympathetic stimulation of the myocardium increases heart rate (HR) and inotropy. Stimulation of the peripheral vascular bed produces vasoconstriction with a resulting increase in blood pressure (BP). EPI = epinephrine; NEPI = norepinephrine.

Reduction in myocardial oxygen supply may result from coronary vasoconstriction or thrombosis in coronary arteries and may be exacerbated by episodes of perioperative hypoxemia. [40,41]Activation of the sympathetic nervous system may trigger both of these mechanisms. For example, activation of cardiac sympathetic nerves is correlated with coronary vasoconstriction, [42,43]paradoxical coronary vasoconstrictor response to intrinsic vasodilators, [44]and poststenotic coronary vasoconstriction (Figure 2) [45]with resultant signs of myocardial ischemia such as ST-segment changes, angina, dysrhythmias, and increases in myocardial infarct size. [46-50]Sympathetic activation has also been proposed to cause postoperative hypercoagulable states [51]and thus may be a factor in thrombotic causes of myocardial ischemia. Once ischemia develops, secondary increases in heart rate and blood pressure can increase myocardial oxygen demand and further aggravate ischemia (Figure 3). Thus, sympathetically mediated decreases in myocardial oxygen supply may be a major factor in postoperative cardiac morbidity.

Figure 2. Cardiac sympathetic stimulation can reduce myocardial oxygen supply through constriction of coronary stenosis. Poststenotic vasoconstriction can shunt blood flow toward or steal blood flow away from ischemic myocardium.

Figure 2. Cardiac sympathetic stimulation can reduce myocardial oxygen supply through constriction of coronary stenosis. Poststenotic vasoconstriction can shunt blood flow toward or steal blood flow away from ischemic myocardium.

Figure 3. Myocardial ischemic pain is conducted by afferent fibers associated with thoracic sympathetic nerves. Ischemia can lead to increased sympathetic efferent activity, producing increases in heart rate, inotropy, and blood pressure. The resulting increase in myocardial oxygen demand may lead to worsening ischemia and a progressive cycle of increasing ischemia and increasing sympathetic stimulation. EPI = epinephrine; NEPI = norepinephrine.

Figure 3. Myocardial ischemic pain is conducted by afferent fibers associated with thoracic sympathetic nerves. Ischemia can lead to increased sympathetic efferent activity, producing increases in heart rate, inotropy, and blood pressure. The resulting increase in myocardial oxygen demand may lead to worsening ischemia and a progressive cycle of increasing ischemia and increasing sympathetic stimulation. EPI = epinephrine; NEPI = norepinephrine.

Selective blockade of cardiac sympathetic innervation (T1-T5) can most easily be achieved by administrating local anesthetics through an epidural catheter placed at an upper thoracic level, a technique commonly known as thoracic epidural anesthesia (TEA). In patients with coronary artery disease, TEA produces small reductions in cardiac output, heart rate, and blood pressure and may thus decrease myocardial oxygen demand. [46,52]Perhaps more important, determinants of oxygen supply may also improve after TEA. Although total coronary blood flow remains unchanged, [42,53]blood flow to ischemic regions of myocardium increases, [42,53,54]regional distribution of myocardial blood flow improves by increasing the endocardial to epicardial blood flow ratio, [42,47,54]and sympathetically mediated coronary constriction distal to the coronary stenosis is inhibited. [45,53]Thus, use of TEA in patients with ischemic myocardium may improve myocardial oxygen supply, as long as blood pressure is maintained in a relatively normotensive range.

These potential improvements in myocardial oxygen supply after TEA with local anesthetics may be attributable to blockade of both alpha- and beta-adrenergic sympathetic stimulatory effects. Activation of cardiac sympathetic nerves can cause vasoconstriction of large coronary epicardial arteries through stimulation of alpha-adrenergic receptors. [55,56]Because approximately 75% of atherosclerotic coronary stenosis are dynamic and not fixed, [57]the majority of stenosis are still able to constrict in response to sympathetic stimulation. [58]This vasoconstriction could further reduce coronary blood flow and increase the severity of myocardial ischemia (Figure 2). Indeed, high TEA (T1-T6) with bupivacaine during coronary angiography in patients with severe coronary artery disease, increased the luminal diameter of 16 (62%) of 26 stenotic epicardial coronary arteries without changing the diameter of non stenotic segments. [53]Thus, alpha-adrenergic blockade may increase blood flow through stenotic coronary arteries.

Sympathetic stimulation of alpha-adrenergic receptors in coronary arterioles also plays an important role in distribution of blood flow within the myocardium. Several studies suggest that vasoconstriction of coronary arterioles in an area distal to a critical coronary stenosis (within the area of ischemic myocardium) may actually shunt blood flow to the area of myocardium at greatest risk of infarction (typically from epicardium to endocardium) (Figure 2). [59,60]Local anesthetic blockade of cardiac sympathetic innervation can decrease the magnitude of poststenotic coronary vasoconstriction and actually decrease myocardial ischemia. [60]Although effects of adrenergic coronary vasoconstriction in the ischemic myocardium remain controversial, [55,59]studies assessing regional myocardial blood flow distribution in intact animals indicate that TEA with local anesthetics results in a beneficial effect by increasing endocardial-to-epicardial blood flow ratios. [47,54,61]Thus, TEA may increase myocardial blood flow both by dilating coronary arteries, improving blood flow distribution through coronary arterioles, and by reducing the stimulus (pain) for activation of cardiac sympathetic nerves. These effects on myocardial oxygen supply in combination with reduction in indexes of myocardial oxygen demand suggests that TEA with local anesthetics provides a beneficial effect on the oxygen supply-demand ratio in ischemic myocardium.

Studies in intact animals have demonstrated that use of TEA after acute coronary artery occlusion decreases the magnitude of ST-segment changes, [62,63]reduces myocardial infarct size (Figure 4), reduces the incidence of ventricular dysrhythmias, [54,64]and lessens ischemia-induced decreases in myocardial pH. [62]Of note, beneficial effects of TEA do not appear to be the result of systemic absorption of the local anesthetic, [54]and effects of epidural opioids on ischemic myocardium are unknown. These studies in animals suggest that TEA with local anesthetics may be effective in the treatment, and perhaps prevention, of myocardial ischemia.

Figure 4. Thoracic epidural anesthesia with lidocaine reduces myocardial infarct size in the epicardium and the endocardium after coronary artery ligation in the dog. *Different from control; P < 0.05. (Modified from Davis et al. [54])

Figure 4. Thoracic epidural anesthesia with lidocaine reduces myocardial infarct size in the epicardium and the endocardium after coronary artery ligation in the dog. *Different from control; P < 0.05. (Modified from Davis et al. [54])

Correspondingly, TEA has been found to be an effective treatment for humans with myocardial ischemia refractory to conventional medical therapy. [46,49,65,66]TEA has been used as a long-term therapy (> 3 yr) for patients not only refractory to medical therapy but also judged to be too high risk for surgical coronary bypass. [67]Initiation of TEA in patients with refractory myocardial ischemia (refractory to therapy with beta-adrenergic blocking agents, calcium antagonists, nitrates, low-dose heparin, or nitroglycerin infusion for > 24 h) resulted in rapid relief of chest pain and reduced ischemic ST-segment changes. [46,49]Relief of ischemia probably occurred both through increases in myocardial oxygen delivery by coronary artery vasodilation and also through further decreases in indexes of myocardial oxygen demand (Figure 5). [68]Hemodynamic changes after induction of TEA were mild, and in no patient did significant hypotension or bradycardia develop. The lack of significant decreases in systemic blood pressure and heart rate may be explained by the production by TEA of minimal cardiac depression in the presence of preexisting beta-adrenergic blockade (eight of nine patients were already being treated with beta-adrenergic blocking agents). [69]These results suggest that TEA not only improves the oxygen supply-demand ratio in ischemic regions of the myocardium in humans but may also be superior to conventional antianginal therapy.

Figure 5. Effect of beta-adrenergic receptor blockade (metoprolol) and thoracic epidural anesthesia (bupivacaine 0.5%) on hemodynamic variables during acute myocardial infarction in the rat. MAP = mean arterial blood pressure; SV = stroke volume; SVR = systemic vascular resistance; CO = cardiac output; LVmaxdP/dt = maximum rate of change in left ventricular pressure; LVEDP = left ventricular end-diastolic pressure. *Significantly different from control. (Modified from Blomberg and Ricksten. [68])

Figure 5. Effect of beta-adrenergic receptor blockade (metoprolol) and thoracic epidural anesthesia (bupivacaine 0.5%) on hemodynamic variables during acute myocardial infarction in the rat. MAP = mean arterial blood pressure; SV = stroke volume; SVR = systemic vascular resistance; CO = cardiac output; LVmaxdP/dt = maximum rate of change in left ventricular pressure; LVEDP = left ventricular end-diastolic pressure. *Significantly different from control. (Modified from Blomberg and Ricksten. [68])

Although TEA may be a useful therapy for angina, epidural anesthesia is more frequently used for major surgical procedures. The combination of TEA and general anesthesia has been shown to produce beneficial effects such as reduced hemodynamic correlates of myocardial oxygen consumption, [70-73]improved intraoperative hemodynamic stability, [70,74]and reduced stress response. [52,70]Obviously, combination of two anesthetic techniques also has the potential to produce detrimental hemodynamic effects and reduced coronary perfusion if anesthesia is not carefully administered. [75,76]Nonetheless, TEA with local anesthetics, with or without general anesthesia, offers potential benefits such as improved balance of myocardial oxygen supply-demand and greater intraoperative hemodynamic stability for patients with coronary artery disease undergoing surgery.

Although TEA has not been directly compared with lumbar epidural anesthesia (LEA), LEA does not appear to offer the same degree of benefits as TEA. In contrast to TEA, LEA is less commonly extended to attain block levels sufficient to produce the beneficial effects of thoracic sympathectomy (at or higher than T1). Thus, if hypotension occurs during LEA and reduces myocardial oxygen supply, this reduction in supply may not be counterbalanced by a simultaneous reduction in demand. [77]In fact, coronary blood flow may be further decreased if compensatory sympathetic activation occurs in the unblocked upper thoracic dermatomes. [78]It should then come as no surprise that the effects of LEA on myocardial ischemia are less encouraging. [71,79]Indeed, reductions in mean arterial pressure of approximately 20% during LEA with an upper level of sensory analgesia between T6-T12 may increase myocardial ischemia in some patients with coronary artery disease. [79]In contrast, similar reductions in blood pressure during TEA were not associated with myocardial ischemia during TEA. [77]Thus, the ability to selectively block cardiac sympathetic fibers (T1-T5) suggest an advantage of TEA over LEA during hypotension in patients at risk for cardiac morbidity.

In summary, animal and human data indicate that TEA with or without general anesthesia can favorably alter the balance of oxygen supply and demand in ischemic myocardium by selective thoracic sympathetic blockade. In fact, TEA may have efficacy equal to or greater than conventional antianginal therapy during acute myocardial ischemia. LEA may reduce myocardial morbidity for operations on the lower extremity or lower abdomen through a reduction in pain and the surgical stress response. However, the ability to directly inhibit cardiac sympathetic innervation may confer a physiologic advantage to TEA over LEA.

Clinical Effects. Initial efforts by anesthesiologists to reduce perioperative myocardial morbidity and mortality focused on variations in intraoperative anesthetic technique and found little ability to alter outcome. For example, neither general anesthetic technique nor routine use of intensive monitoring (pulmonary artery catheters) appears to affect postoperative cardiac morbidity significantly. [34,80,81]Similarly, intraoperative use of TEA can produce beneficial intraoperative hemodynamic effects between induction and tracheal extubation, yet it may have little effect on the incidence of postoperative myocardial ischemia. [76]A probable cause for this lack of effect is that the incidence and severity of intraoperative ischemia appears to be no greater than the incidence in the immediate preoperative period. [35]Furthermore, episodes of intraoperative myocardial ischemia most commonly occur without obvious hemodynamic causes: only 10-30% of episodes of myocardial ischemia are associated with intraoperative hemodynamic perturbations. [34-37]These results suggest that the intraoperative period is usually no more arduous than daily life and that ischemia that occurs intraoperatively may serve only to identify high-risk patient populations. Thus, although intraoperative ischemia can be correlated with postoperative cardiac morbidity, [82]it may not be a direct cause. Therefore, the disparity between beneficial intraoperative hemodynamic effects of TEA and lack of reduction in postoperative myocardial ischemia in the majority of studies is not surprising. [34-37].

On the other hand, ischemia that occurs postoperatively is more frequent, more severe, and more prolonged than ischemia occurring during pre- and intraoperative periods. [35]Furthermore, early postoperative ischemia appears to be an important correlate of cardiac morbidity in high-risk patients undergoing non cardiac surgery. [21]These observations caused Mangano et al. to conclude that "the postoperative period may warrant special attention including therapeutic trials to determine whether extended monitoring and aggressive therapy for control of pain and heart rate are warranted during the 1st 2 days after surgery." [21]This conclusion was supported by subsequent studies demonstrating that intensive perioperative analgesia with large doses of systemic opioids (high enough to require mechanical ventilation) can reduce myocardial morbidity and mortality. [4,5]However, myocardial infarction commonly occurs on the 3rd or 4th day after surgery, [83,84]suggesting that aggressive therapy may need to be extended for at least 4 days. If so, the need for prolonged ventilatory support would limit the usefulness of high-dose postoperative opioid analgesia. Thus, the greatest potential to influence cardiac outcome may result from application of analgesic techniques in the postoperative period. If epidural analgesia is expected to be beneficial, it makes sense to focus evaluations on the postoperative period.

Although administration of epidural local anesthetics or opioids in the postoperative period provides better analgesia, suppresses the stress response to surgery, and reduces incidences of myocardial ischemia and dysrhythmias when compared with systemic opioids, [6,70,85]effects of epidural analgesia on cardiac morbidity are controversial. [42,73,76,86-91]However, most studies do not have the power to detect clinically significant differences in cardiac outcomes because of the low incidence of these events and small numbers of patients studied, [89,91]and no single study to date provides a definitive answer. Consequently, conclusions at this time must be based on interpretation of trends from randomized, prospective, controlled studies that suggest that postoperative epidural analgesia is associated with reduced postoperative cardiac morbidity and mortality in high-risk populations (Table 1).

Table 1. Effect of Epidural Anesthesia and Analgesia on Postoperative Cardiac Outcomes in Controlled, Randomized, Prospective Studies

Table 1. Effect of Epidural Anesthesia and Analgesia on Postoperative Cardiac Outcomes in Controlled, Randomized, Prospective Studies
Table 1. Effect of Epidural Anesthesia and Analgesia on Postoperative Cardiac Outcomes in Controlled, Randomized, Prospective Studies

The importance of studying high-risk patient populations (i.e., patients that typically experience a high incidence of complications) cannot be overemphasized. It is in these patient groups that the greatest effects of epidural anesthesia and analgesia have been demonstrated. For example, Yeager et al. studied only patients scheduled for "intrathoracic, intraabdominal, or major (noncerebral) vascular surgery" that were also "scheduled preoperatively by the surgical staff to receive postoperative care in the intensive care unit due either to the severity of preexisting disease(s), the magnitude of the anticipated surgical procedure, or both." [73]Of note, patients in this study had an average American Society of Anesthesiologists (ASA) physical status classification of 3. Similarly, Tuman et al., studied only patients undergoing major peripheral vascular surgery (approximately 45% of operations involved the abdominal aorta). [88]Patients in these studies had high incidences of postoperative myocardial morbidity in the general anesthesia groups and statistically significant reductions in morbidity were identified in the epidural analgesia groups.

However, not all studies investigating high-risk populations have observed a benefit from epidural anesthesia or analgesia. Perhaps the best-designed study that did not find a benefit for epidural anesthesia in a high-risk patient population is a study by Baron et al. [76]No difference in the incidence of cardiac complications was observed in aortic reconstruction patients randomized to general anesthesia versus combined TEA and general anesthesia. Although many aspects of study design were excellent, postoperative analgesia techniques were not controlled or randomized. For example, only 37% of the patients in the epidural anesthesia group received epidural local anesthetics for postoperative analgesia, whereas 59% of the patients in the general anesthesia group received postoperative analgesia with epidural local anesthetic or opioid. Thus, this study assessed only the effect of intraoperative anesthetic technique on postoperative outcome. As previously discussed, there is minimal basis for believing that intraoperative TEA alone will affect postoperative cardiac morbidity. Of note, absolute morbidity rates reported by Baron et al. [76]were comparable to those reported by Yeager et al. [73]for the epidural group (Table 2). One possible conclusion is that the general anesthetic technique used by Yeager et al. was associated with increased postoperative morbidity. However, direct comparison with absolute rates of morbidity reported by Tuman et al. [88]suggests that postoperative epidural analgesia with a combination of local anesthetic and opioid may be associated with a reduction in morbidity. Although this speculation is stimulating, it seems problematic to directly compare absolute outcome data from different institutions, after different operations, performed years apart, in different countries, and with different patient populations. Nevertheless, the crux of the as-yet unanswered modern question is whether epidural analgesia produces better outcomes than an optimal general anesthetic technique followed by optimal systemic analgesia.

Table 2. Comparison of Outcomes in Studies Assessing Morbidity after Major Surgery in High Risk Patients

Table 2. Comparison of Outcomes in Studies Assessing Morbidity after Major Surgery in High Risk Patients
Table 2. Comparison of Outcomes in Studies Assessing Morbidity after Major Surgery in High Risk Patients

In contrast to these studies investigating high-risk populations, Hjortso et al. [91]studied lower-risk patient populations (> 90% ASA physical status classification 1 or 2), and Christopherson et al. [89]studied a high-risk population having a less invasive surgical procedure (infrainguinal revascularizations) with a lesser magnitude of surgical insult. [92]Both studies had low incidences of myocardial morbidity in both control and epidural groups, and neither was able to identify significant effects on cardiac morbidity. [89,91]Thus, use of postoperative epidural analgesia after intraoperative epidural anesthesia has been associated with reductions in postoperative cardiac morbidity only in high-risk patients undergoing major operations.

In summary, no current study includes a sufficient number of patients to provide definitive conclusions. However, differences appear to be largest when high-risk populations undergoing major operations are studied. Thoracic epidural catheter placement and use of local anesthetics have theoretical advantages that have not been evaluated in clinical trials. If these potential benefits are proven significant in follow up studies with larger numbers of patients, epidural analgesia has the potential to dramatically reduce perioperative myocardial morbidity after major operations in high-risk patient populations.


Major surgery is associated with a hypercoagulable state that persists well into the postoperative period. [93-95]Increases in perioperative coagulation are associated with vasoocclusive and thromboembolic events that may result in postoperative morbidity and mortality. [88,89,96,97]Although the etiology of this postoperative increase in coagulability is uncertain, the stress response appears to be an important initiator. [51,98,99]Postoperative changes occur in all arms of the coagulation system and include increased concentrations of coagulation factors, [94]decreased concentration of coagulation inhibitors, [100]enhanced platelet activity, [101]and impaired fibrinolysis. [93,102]General anesthesia with parenteral opioid analgesia has little effect on postoperative increases in coagulability. [51,88,89,103,104]However, epidural anesthesia and analgesia may reduce increases in postoperative coagulability and thus may improve clinical outcome.

Experimental Effects. Epidural administration of local anesthetic has multiple effects on coagulation that may be beneficial. [105,106]For example, general anesthesia and surgery produce a sustained reduction of blood flow in deep veins that may predispose to vascular graft occlusion and formation of deep venous thrombosis. Epidural anesthesia with local anesthetics improves lower extremity blood flow by increasing arterial inflow and venous emptying rate. [105]Addition of epinephrine to the local anesthetic increases the magnitude of these beneficial effects. [105]Second, epidural anesthesia enhances fibrinolytic activity [51,95,107-109]by prevention of postoperative increase in plasminogen activator inhibitor 1, [51]more rapid return of antithrombin III from increased to normal values, [95]and lessening of postoperative increases in platelet aggregation. [88]In addition, systemic absorption of local anesthetic during epidural anesthesia produces plasma concentrations sufficient to directly impair platelet aggregation [103,110,111]and reduce plasma and whole blood viscosity. [112]Although epidural opioids can also reduce the surgical stress response, no studies have specifically examined effects on coagulation. Finally, beneficial effects of epidural local anesthetics may be attenuated by addition of general anesthesia. [95]Thus, epidural administration of local anesthetics modifies the perioperative hypercoagulable state through several mechanisms, including blockade of sympathetic efferent nerves, attenuation of excessive coagulability, and anticoagulant properties of systemically absorbed local anesthetics.

Clinical Effects. Epidural anesthesia and analgesia appears to significantly reduce the incidence of thromboses of vascular grafts in patients undergoing lower extremity revascularization. Clinical markers for graft failure such as incidence of reoperation for graft occlusion or amputation are decreased with use of epidural anesthesia and analgesia. For example, Tuman et al. [88]randomized patients to receive either general anesthesia with parenteral opioids or general-epidural anesthesia followed by postoperative bupivacaine-fentanyl epidural infusion. Use of epidural analgesia was associated with a ninefold decrease in incidence of vascular graft occlusion. Similarly, Christopherson et al. [89]compared the effects of epidural and general anesthesia in peripheral vascular surgery patients and found that the epidural group required fivefold fewer reoperations for graft failure within 1 month. To date, impressive differences associated with epidural anesthesia and analgesia have been seen only in patients inherently at high risk for vasoocclusive events. [113]For example, patients with atherosclerotic disease are known to be hypercoagulable [88,114]and to have abnormal responses to intrinsic vasodilators. [44]Whether or not other patient groups benefit from epidural anesthesia and analgesia remains to be seen. Nonetheless, these well-conducted studies in high-risk groups demonstrate a reduction in vasoocclusive events associated with use of epidural anesthesia and analgesia.

Deep venous thrombosis with resultant pulmonary embolism is another manifestation of increased perioperative coagulability. Patients undergoing total hip replacement appear to be at especially high risk for thromboembolic complications because of immobility, decreased deep vein blood flow, [97,108]surgical manipulation of the femoral vein, decreased cardiac output from anesthetic-related effects, and prolonged surgical time. [115]Modig et al. [97,107,108]reported a series of studies on the effects of LEA followed by 24 h of analgesia with bupivacaine and epinephrine on deep venous thrombosis in patients undergoing hip replacement surgery. When compared with patients who received general anesthesia and intramuscular opioid analgesia, the epidural group had a 2.5-5-fold reduction in deep thigh venous thrombosis, a 1.5-fold reduction in calf venous thrombosis, and a 3-fold reduction in pulmonary embolism. Reduction of deep thigh venous thromboses is particularly significant, because these thromboses are almost exclusively associated with emboli to the pulmonary circulation. Similar reductions in thromboembolic complications have been reported with epidural anesthesia and analgesia (with local anesthetic) by other authors [116]and after other operations such as open prostatectomy [117]and knee arthroplasty. [118].

Thus, reduced incidences of vascular and thromboembolic complications with epidural anesthesia are well documented; however, vasoocclusive and thromboembolic events are postoperative occurrences that probably begin intraoperatively. [115]Is it the intraoperative use of epidural anesthesia or the postoperative use of epidural analgesia that diminishes hypercoagulability and reduces related complications? Christopherson et al.'s [89]finding that most reoperations occurred soon after surgery suggests that use of intraoperative epidural local anesthetic was critical. Correspondingly, their use of epidural fentanyl alone for postoperative analgesia suggests that either epidural opioids maintain a reduction in postoperative hypercoagulability or that intraoperative effects of epidural local anesthetic overshadow effects from postoperative analgesia. Further evidence for the importance of the intraoperative effect is suggested by a metaanalysis of anesthesia for hip repair (11 spinal anesthesia and 2 epidural anesthesia studies) that documented a 31% reduction in deep venous thrombosis as compared with general anesthesia. [119]Thus, the relative importance of postoperative epidural analgesia for reduction in vasoocclusive and thromboembolic complications is unclear.

In summary, reduced incidences of vascular graft occlusion and thromboembolic complications are associated with the use of epidural anesthesia and analgesia. Furthermore, there appears to a strong association between the use of intraoperative epidural anesthesia and reduction in morbidity, whereas the role of postoperative epidural analgesia remains uncertain.

Pulmonary Function

Postoperative pulmonary dysfunction occurs as a result of surgery and anesthesia-related physiologic perturbations and remains a major cause of postoperative morbidity. Thus, techniques that reduce postoperative pulmonary dysfunction may result in improved clinical outcome.

Experimental Effects. Upper abdominal and thoracic incisions significantly reduce post operative pulmonary function, [120-122]whereas laparoscopic [123,124]and peripheral operations have little effect. Pulmonary dysfunction after upper abdominal surgery occurs because of pain, [121]abnormal diaphragmatic function, [125]and increased abdominal and lower intercostal muscle tone during exhalation. [126]Pulmonary dysfunction begins with incision and remains diminished for 7-14 days postoperatively. [127]The most important alteration of respiratory function is decreased functional residual capacity, which begins about 16 h postoperatively, reaches a nadir at 24-48 h, and usually resolves within 1 week. [120,121,127,128]Decreased functional residual capacity may result in atelectasis and ventilation-perfusion abnormalities leading to hypoxemia, pneumonia, and postoperative pulmonary complications (Figure 6). [120,121,129,130]Patients especially at risk for reduction of functional residual capacity and resultant pulmonary complications include those with preexisting pulmonary disease, [122,131,132]upper abdominal and thoracic incisions, [124]advanced age, [133]obesity, [134]and those in severe pain. [135].

Figure 6. Proposed mechanisms of postoperative pulmonary complications.

Figure 6. Proposed mechanisms of postoperative pulmonary complications.

Choice of anesthetic technique affects the degree of postoperative pulmonary dysfunction. Use of general anesthesia may briefly exacerbate surgery-induced pulmonary dysfunction. [136]Mechanical ventilation, paralysis, inhaled anesthetics, and opioids all contribute to reduce pulmonary function. [137]In contrast to the exacerbation of postoperative pulmonary dysfunction seen with general anesthesia, TEA has minimal effect on pulmonary function [138-140]and may offset detrimental changes in pulmonary function induced by general anesthesia. [132]Observation of differential effects on pulmonary function between general and epidural anesthesia appears to depend on the extent of surgery. For example, laparoscopic cholecystectomy results in little postoperative pulmonary dysfunction, and thus epidural anesthesia provides little benefit after this operation. [124]Finally, most of the general anesthesia-related pulmonary dysfunction reverts to baseline early in the postoperative period and may have minor effect on postoperative pulmonary morbidity. [137]Thus, intraoperative epidural anesthesia appears to offer relatively minor advantages in preservation of early postoperative pulmonary function.

On the other hand, previous studies suggest that postoperative use of epidural analgesia has the potential to reduce pulmonary morbidity by providing better analgesia, improved diaphragmatic function, and reduced frequency and severity of postoperative hypoxemia. For example, epidural analgesia using local anesthetic, [124,135]opioid, [12,141]and especially both [142-144]provides better analgesia than systemic opioid, including delivery by intravenous PCA. [12,141]Because relief of pain improves pulmonary function after abdominal or thoracic surgery, [121,145]it is not surprising that use of epidural analgesia is associated with improved pulmonary function when compared with intramuscular and intravenous opioid. [132,134-136,146,147]That not all studies demonstrating superior analgesia in the epidural group also demonstrate improvements in pulmonary function [12,148,149]suggests that factors other than pain are also important etiologic factors for postoperative pulmonary impairment.

For example, diaphragmatic function is impaired after abdominal or thoracic surgery and may also contribute to pulmonary dysfunction. [150]Diaphragmatic dysfunction appears to result from reflex inhibition of phrenic nerve activity [125,145,150]and is not significantly altered by relief of pain. [151-153]Thus, analgesia provided with parenteral or epidural administration of opioids alone does not produce appreciable improvement in diaphragmatic function. [151]On the other hand, thoracic epidural blockade with local anesthetic may improve postoperative diaphragmatic function. This improvement in function probably results from neural blockade of the inhibitory reflex [125,145]and perhaps through changes in chest wall compliance. [152,153]Thus, epidural administration of local anesthetics for postoperative analgesia can result in improved pulmonary function in part through relief of pain but also by improving postoperative diaphragm function.

Pulmonary dysfunction may also produce morbidity through hypoxemia. Episodic hypoxemia is common in the postoperative period, particularly during sleep. [40,154-156]Postoperative hypoxemia serves as a marker for patient's with postoperative pulmonary morbidity [154]and is associated with myocardial ischemia. [40]Analgesia with either parenteral or epidural opioid is associated with equally high incidences of episodic postoperative hypoxemia. [155,157]However, use of epidural analgesia with local anesthetics is associated with a reduced incidence and severity of hypoxemia in the early postoperative period [6]perhaps because of improved pulmonary function or reduced sedation. [136].

In summary, postoperative pulmonary dysfunction can be attenuated by the intraoperative use of epidural local anesthetics. More important, continuation of epidural analgesia with local anesthetic into the postoperative period may maintain improvements in postoperative pulmonary function. These effects may be attributable to to the benefits in addition to analgesia provided by epidural administration of local anesthetics, such as limitation of the degree of postoperative diaphragmatic dysfunction, improvement of abdominal or chest wall compliance, and limitation of episodes of postoperative hypoxemia.

Clinical Effects. Although previous studies have demonstrated reduced incidence of radiologic markers of pulmonary morbidity in patients receiving epidural anesthesia and analgesia as compared with general anesthesia followed by intramuscular opioid, [158-160]effects of epidural analgesia on serious pulmonary complications remain unclear (Table 3). Several studies noted improved clinical outcome in patients receiving epidural analgesia in terms of decreased incidences of postoperative pneumonia and respiratory failure (Table 3) [73,88,134,135]Studies that observed benefit from epidural anesthesia and analgesia examined high-risk patients (e.g., obese patients undergoing upper abdominal surgery), used intraoperative epidural anesthesia (with or without general anesthesia), and continued epidural analgesia (local anesthetic or opioid) into the postoperative period.

Table 3. Comparison of Analgesia and Postoperative Pulmonary Complications in Patients Undergoing Thoracic and Major Abdominal Surgeries

Table 3. Comparison of Analgesia and Postoperative Pulmonary Complications in Patients Undergoing Thoracic and Major Abdominal Surgeries
Table 3. Comparison of Analgesia and Postoperative Pulmonary Complications in Patients Undergoing Thoracic and Major Abdominal Surgeries

On the other hand, several studies have failed to show an advantage of epidural analgesia over parenteral analgesia in incidence of pulmonary morbidity (Table 3). [16,76,91,148,149]Studies not observing differences between epidural anesthesia and analgesia versus general anesthesia and systemic opioids either used healthy patients, did not study high-risk operations, or did not control postoperative analgesia. Thus, it appears that epidural anesthesia or analgesia may be beneficial only in patients at high risk for postoperative pulmonary complications and also may be observed only when adequate epidural analgesia is maintained into the postoperative period.

Gastrointestinal System

Postoperative ileus is a temporary impairment of gastrointestinal motility that occurs after surgery. Although most common and severe after major abdominal procedures, ileus also occurs after peripheral operations, general trauma, or other stressful situations. [161,162]Ilieus delays resumption of an enteral diet, and this delay may contribute to postoperative morbidity. For example, early enteral feeding has been shown to reduce the surgical stress response, reduce postoperative septic complications, and improve wound healing. [163-166]The financial costs of postoperative ileus are substantial and have been estimated at $750,000,000 annually. [161]Ileus is thus a major surgical morbidity. Anesthetic or analgesic techniques that speed recovery from or prevent postoperative ileus have the potential to substantially reduce postoperative morbidity, duration of hospitalization, and costs of surgical care.

Experimental Effects. Postoperative ileus affects all segments of the gastrointestinal tract with variable duration and intensity. [167,168]Motility in the stomach and small intestines generally recovers within 24 h after abdominal surgery, [169,170]whereas colonic motility is inhibited for 48-72 h. [169,171]Although the pathophysiologic features of postoperative ileus remains ill defined, [161,167]the most commonly accepted theory is that abdominal pain activates a spinal reflex arc that inhibits intestinal motility. [172]In addition, surgical stress induces sympathetic hyperactivity, and excessive sympathetic stimulation of the bowel inhibits organized propulsive activity. [161,173]Thus, both nociceptive afferent and sympathetic efferent nerves are believed to be key initiators of ileus. Although stimulation of sympathetic nerves inhibits contractile activity, [174,175]therapeutic interventions with adrenergic blocking drugs do not speed resolution of ileus. [161,176]In contrast to the lack of efficacy of adrenergic-blocking drugs, section of sympathetic innervation pathways to the gastrointestinal tract can block ileus after abdominal surgery. [177]This observation provides a theoretical framework suggesting that blockade of abdominal nociceptive afferent or sympathetic efferent pathways might abolish inhibition of gastrointestinal motility induced by abdominal surgery.

Epidural local anesthetics can theoretically improve bowel motility through both of these mechanisms. Blockade of nociceptive afferent pathways may disrupt the afferent limb of the spinal reflex arc that has been postulated to mediate postoperative ileus. [172]Furthermore, epidural local anesthetics can block the efferent limb of the reflex by blocking thoracolumbar sympathetic efferent nerves. [170,177,178]Of note, activation of gastrointestinal parasympathetic nerves stimulates propulsive contractions, and parasympathetic innervation of the colon is provided by the vagus nerve and pelvic nerves originating from the sacral region of the spinal cord (Figure 7). This anatomic arrangement should make TEA with local anesthetics particularly beneficial. Segmental neural blockade of thoracic dermatomes with local anesthetics will selectively block nociceptive afferent and sympathetic efferent nerves while leaving parasympathetic innervation (by the vagus and pelvic nerves) intact. The resulting shift in autonomic balance toward a relative increase in parasympathetic tone during TEA should increase propulsive activity in the colon.

Figure 7. The effect of autonomic innervation on gastrointestinal motility. Sympathetic stimulation inhibits motility, whereas parasympathetic stimulation promotes motility.

Figure 7. The effect of autonomic innervation on gastrointestinal motility. Sympathetic stimulation inhibits motility, whereas parasympathetic stimulation promotes motility.

Another means whereby epidural local anesthetics may increase gastrointestinal function is through systemic absorption of the epidurally administered local anesthetic. For example, intraperitoneal or intravenous administration of local anesthetic speeds return of propulsive motility in the colon and shortens the duration of postoperative ileus. [179,180]Purported mechanisms for systemic effects of local anesthetics on the gastrointestinal system include a direct excitatory effect on intestinal smooth muscle, reduction of opioid dose requirement, and blockade of the inhibitory spinal reflex arc. [180]Thus, in addition to the potential beneficial effects resulting from blockade of nociceptive afferent and sympathetic efferent fibers, it appears that systemic absorption of local anesthetic can also contribute to reducing the duration of postoperative ileus.

A final potential benefit of the local anesthetic induced sympathectomy is the associated increase in gastrointestinal blood flow. [181,182]Because blood flow to the bowel is a critical factor for gastrointestinal motility [183]and for healing of gastrointestinal anastomoses, [184]some authors have suggested that increased colonic blood flow resulting from the sympathetic blockade should result in reduction of ileus [183]and improved healing of surgical anastomoses. [185]In contrast, other authors have proposed that epidural analgesia with local anesthetics can lead to excessive propulsive activity causing dehiscence of colonic anastomoses. [186,187]However, this concern is based on a few case reports, is inconsistent with animal studies that demonstrate excellent healing of anastomoses, [188]and is refuted by larger clinical studies that actually demonstrate a modest trend toward a lower incidence of dehiscence. [185,189]Thus, epidural analgesia increases intestinal blood flow that should theoretically enhance postoperative recovery of bowel motility and promote healing of gastrointestinal anastomoses.

In contrast to local anesthetics, epidural opioids may not block transmission in somatic or sympathetic nerves [190]and may thus be intrinsically less effective in reduction of ileus than local anesthetics. Furthermore, epidural opioids may directly inhibit gastrointestinal motility. For example, it is well known that systemic administration of morphine delays gastric emptying and impairs colonic transport. [176,191,192]Similarly, animal and volunteer studies suggest that actions of opioids in the spinal cord inhibit motility in both the proximal and distal colon [193,194]and prolong gastric and intestinal transit time to a similar degree as parenteral opioids. [170]On the other hand, epidural opioids may be advantageous during recovery from ileus. During the 1st 2 days after abdominal operations, opioids have no detectable effect on colonic myoelectric activity. [195]However, beginning on the 3rd day after surgery (when colonic function begins to recover) systemic administration of opioids inhibits propulsive myoelectric activity. During the same time, epidural administration of morphine does not inhibit bowel motility. [195]Thus, it appears that systemic opioid administration may contribute to and prolong postoperative ileus, whereas the effects of epidural opioid on colonic motility remains unclear.

In summary, experimental evidence suggests that epidural local anesthetics can reduce postoperative ileus through relief of pain, systemic absorption of the local anesthetic, blockade of sympathetic innervation of the bowel, and reduction of requirements for systemic opioids.

Clinical Effects. Numerous clinical studies have demonstrated more rapid recovery of bowel function when postoperative analgesia is provided with epidural local anesthetics rather than systemic opioids (Table 4). For example, postoperative TEA with bupivacaine resulted in lower pain scores and earlier passage of flatus, and earlier bowel movements than was observed with systemic opioid analgesia. [149,187,196,197]Admittedly, time to passage of flatus or first bowel movement may not be the most sensitive markers of gastrointestinal function. [198]However, more sensitive markers of gastrointestinal propulsive activity such as transit of barium contrast [199]and radiopaque markers, [200]and propulsive gastrointestinal myoelectric activity [201]also recover more rapidly when postoperative analgesia with epidural local anesthetic was compared with systemic opioid administration. Thus, studies using a variety of assessment techniques have consistently observed more rapid recovery from postoperative ileus when postoperative analgesia is provided with epidural local anesthetics.

Table 4. Randomized, Prospective Studies Comparing Effect of Epidural Analgesia and Systemic Opioids on Recovery of Colonic Function as Assessed by Passage of Flatus, Feces, or Transit of Radiopaque Markers

Table 4. Randomized, Prospective Studies Comparing Effect of Epidural Analgesia and Systemic Opioids on Recovery of Colonic Function as Assessed by Passage of Flatus, Feces, or Transit of Radiopaque Markers
Table 4. Randomized, Prospective Studies Comparing Effect of Epidural Analgesia and Systemic Opioids on Recovery of Colonic Function as Assessed by Passage of Flatus, Feces, or Transit of Radiopaque Markers

In contrast, one major study found that epidural bupivacaine did not improve recovery of bowel function when compared with systemic opioids (Table 4). However, this study administered epidural local anesthetic for only 24 h and then provided analgesia with parenteral or epidural opioids during the time that gastrointestinal function was beginning to recover (2-4 days after surgery). [91,198]Thus, it seems likely that early discontinuation of epidural local anesthetic administration may account for these negative findings. If so, these results suggest that epidural local anesthetics should be administered a minimum of 2 to 3 days after surgery to provide a beneficial effect on recovery from postoperative ileus.

Finally, few studies have directly compared epidural administration of opioids with epidural local anesthetics [197,202,203](Table 5). However, these studies indicate that epidural local anesthetics may provide greater benefit than epidural opioids. For example, postoperative analgesia provided with epidural bupivacaine was associated with more rapid return of gastric emptying [204]and shorter duration until passage of flatus and feces than when analgesia was provided with epidural morphine. [197,203]In contrast, one study did not demonstrate a benefit for epidural local anesthetics. Of note, patients in this study had a particularly prolonged postoperative ileus (Table 5), which outlasted the duration of epidural analgesia by an average of more than 2 days. Thus, the vast majority of patients in this study were receiving systemic opioids during the time that bowel function was returning to normal, and this may explain the lack of benefit observed in this study. On balance, these results suggest that epidural analgesia with local anesthetics may speed resolution of postoperative ileus when compared with epidural opioids.

Table 5. Randomized, Prospective Studies Comparing Effect of Epidural Opioids and Epidural Local Anesthetics on Recovery of Gastrointestinal Function

Table 5. Randomized, Prospective Studies Comparing Effect of Epidural Opioids and Epidural Local Anesthetics on Recovery of Gastrointestinal Function
Table 5. Randomized, Prospective Studies Comparing Effect of Epidural Opioids and Epidural Local Anesthetics on Recovery of Gastrointestinal Function

In summary, clinical studies consistently demonstrate that postoperative administration of epidural local anesthetics can reduce the duration of postoperative ileus. Although use of epidural analgesia with local anesthetics may attenuate the decrease in bowel motility that typically occurs during postoperative ileus, bowel motility does not return to the presurgical baseline after peripheral [162]or abdominal surgery. [205]These results suggest that factors other than pain and sympathetic hyperactivity also contribute to postoperative ileus. Epidural opioids may also improve recovery of gastrointestinal function when compared with parenteral opioids but more data are needed to make definitive conclusions. The benefit of local anesthetics may result from the ability not only to block pain pathways but also to block sympathetic innervation of the gastrointestinal tract. To produce a benefit reliably, it appears that epidural analgesia (with local anesthetics) should be continued until postoperative ileus is resolved (typically 48-72 h after surgery). Despite earlier recovery of bowel function, epidural analgesia has led to a shorter duration of hospitalization in only one study. [134]The lack of improvement in patient outcome may have occurred because convalescence protocols were not adjusted to take advantage of the earlier recovery of bowel motility. For example, none of the studies mention a controlled effort to remove nasogastric tubes or feed patients any earlier. A recent study supports this contention and suggests that postoperative analgesia provided with a combination epidural local anesthetic and opioid can speed recovery from colon surgery when used in conjunction with an aggressive convalescence program. [206]These preliminary results suggest that epidural analgesia may contribute not only to an earlier recovery from postoperative ileus but also to a shorter duration of hospitalization.

Stress Response

Surgical stress consistently elicits a metabolic response by activation of the sympathetic and somatic nervous system and through local trauma. [207]Responses to surgical stress include release of neuroendocrine hormones [208]and local release of cytokines (Figure 8). [207]Effects of this stress response may be detrimental: infusions of neuroendocrine hormones and cytokines provoke tachycardia, fever, shock, and increased minute ventilation. [209-211]These effects are dose related, and serum concentrations of these factors correlate with severity of injury and with outcome after injury. [92,209,212]Thus, the concept has arisen that inhibiting the stress response may improve surgical outcome.

Figure 8. The stress response involves release of neuroendocrine hormones and cytokines that may lead to detrimental physiologic responses. ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; GH = growth hormone; TSH = thyroid-stimulating hormone; IL2 = interleukin 2; IL6 = interleukin 6; TNF = tumor necrosis factor.

Figure 8. The stress response involves release of neuroendocrine hormones and cytokines that may lead to detrimental physiologic responses. ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; GH = growth hormone; TSH = thyroid-stimulating hormone; IL2 = interleukin 2; IL6 = interleukin 6; TNF = tumor necrosis factor.

Experimental Effects. The stress response can not be prevented, and may be exacerbated, by administration of general anesthetics with the exception of large doses of opioids (e.g., 50-100 micro gram/kg fentanyl) [213-216]before incision. [217]In contrast, epidural administration of either local anesthetics or opioids can blunt the surgical stress response. [3,98,218-220]Indeed, intraoperative use of epidural anesthesia with local anesthetics completely suppresses the stress response resulting from procedures below the umbilicus. [220,221]However, complete suppression of the stress response requires complete sympathetic and somatic blockade of the surgical site such as can be provided with extensive epidural anesthesia (T4-S5 to pinprick). [222]Although less extensive blockade provides anesthesia, the stress response is incompletely blocked because of incomplete suppression of sympathetic and somatic signals. [98,222,223]Thus, pain relief and prevention of the stress response do not appear to be directly coupled, and analgesia alone may not guarantee that activation of the stress response will be prevented. Further support for this concept is found when the effects of epidural opioid analgesia are considered. Virtually all opioids commonly used for epidural analgesia can attenuate the stress response. [207]However, regimens of epidural opioids that produce equivalent postoperative analgesia to epidural local anesthetics produce a less effective block of the stress response. [218,224]The relative lack of efficacy of opioids is consistent with the concept that nociceptive pathways are only partially responsible for activation of the stress response. [214,218,225]In other words, the greater efficacy of epidural local anesthetics for inhibition of the stress response may be attributable to the ability to block nociceptive and nonnociceptive pathways, such as the sympathetic innervation to the adrenal glands, whereas epidural opioids may modulate only nociceptive pathways (Figure 8). [190]Thus, previous studies indicate that epidural administration of local anesthetics can completely suppress the stress response after procedures below the umbilicus, whereas epidural opioids only lessen the stress response.

In comparison with procedures below the umbilicus, epidural anesthesia has less effect on the stress response resulting from procedures above the umbilicus. Epidural local anesthetics reduce but do not completely prevent the stress response from these operations and do not have greater efficacy than epidural opioids. [214,224,226-228]There are three likely factors for the incomplete effects of epidural anesthesia on the stress response from procedures above the umbilicus. First, doses of local anesthetic used in previous studies were unlikely to produce complete neural blockade of the surgical site. [229]Because the degree of neural blockade can be correlated with magnitude of the surgical stress response, [229,230]it is possible that greater doses of local anesthetic may be needed to more effectively inhibit the stress response from procedures above the umbilicus. Second, the type of local anesthetic used for epidural anesthesia can also affect the efficacy of attenuation of the stress response. [231]Third, some components of the stress response (cytokines) are directly released into the bloodstream by local trauma and injury (Figure 8). [232]These mediators directly activate the stress response and are released in greater quantities after surgery above the umbilicus. [223,233,234]Thus, dose-related differences in extent and density of neural blockade, choice of local anesthetic, and local release of stress response mediators may explain incomplete effects of epidural local anesthetics on the stress response for surgical procedures above the umbilicus.

Either intra- or postoperative administration of epidural local anesthetics and opioids can lessen the stress response. [98,218,224,235,236]However, only preincisional establishment of epidural anesthesia with local anesthetics can prevent the stress response and maintain mediator concentrations at preoperative values. [235]Once the stress response is initiated, postincisional administration of epidural anesthesia can only attenuate the response. Furthermore, epidural analgesia with local anesthetics or opioids should be continued into the postoperative period to maximally reduce the stress response. [220]Use of epidural analgesia in the postoperative period may be critical, as maximal increases in stress response occur immediately after surgery [237]and may continue for as long as 5 days postoperatively. [92,238]Although the necessary duration of epidural analgesia for maximal benefit is unknown, use of epidural analgesia with local anesthetic for only 24 h can suppress the catabolic component of the stress response (nitrogen balance, muscle amino acid composition) for as long as 5 days. [239-241]In contrast, use of intravenous PCA for postoperative analgesia relieves pain, but the stress response is unaltered. [242]Thus, use of epidural anesthesia followed by epidural analgesia with local anesthetic results in the greatest observed reduction of the perioperative stress response.

In summary, epidural local anesthetics or opioids effectively inhibit the stress response from surgical procedures, especially below the umbilicus. However, the greatest suppression of the stress response has been observed after epidural anesthesia with local anesthetics followed by postoperative epidural analgesia with local anesthetics. Thus, epidural local anesthetics appear to have greater efficacy than opioids in reduction of the stress response, perhaps because opioids and local anesthetics have different mechanisms of action. Opioids produce analgesia by modulating nociceptive pathways within the central nervous system, whereas local anesthetics can nonspecifically block both nociceptive and nonnociceptive pathways. The superior efficacy of local anesthetics for blunting the stress response supports the concept that relief of pain is only partially responsible for effects of epidural analgesia.

Clinical Effects. The stress response initiates potentially detrimental physiologic responses (Figure 8), peaks during the postoperative period, and is temporally associated with peak episodes of postoperative morbidity. [89,243]Thus, a popular theory is that increases in the stress response are an important marker for patients at increased risk for adverse outcome. Although there is little evidence that the stress response per se results in morbidity, several potentially detrimental physiologic effects are modulated through the stress response. For example, cardiac morbidity may be increased through release of neuroendocrine hormones with resultant reductions in myocardial oxygen supply or increases in demand. [43]In addition, the stress response enhances development of a hypercoagulable state that predisposes to vascular thrombosis both through enhancement of coagulation [99,244-246]and inhibition of fibrinolysis. [247]Furthermore, stress response mediators are potent inhibitors of the immune system [248]and may contribute to postoperative immunosuppression and infection. This concept is addressed in the following section. Thus, modulation of the surgical stress response may theoretically affect rates of morbidity in multiple organ systems.

Only a few studies have examined both stress response and postoperative morbidity in well-conducted comparisons of general anesthesia versus epidural anesthesia and analgesia. Interestingly, these studies have observed parallel movements in these measurements. [73,89,91,98]For example, Yeager et al. [73]observed marked decreases in cardiac morbidity in patients receiving epidural anesthesia and analgesia (Table 1). Urinary cortisol excretion was measured as a marker of the stress response and was significantly less in the epidural group during the first 24 h after surgery. Christopherson et al. [89,98]observed a marked increase in patency of vascular grafts in patients randomized to epidural anesthesia followed by epidural fentanyl. Plasma catecholamines were measured as markers for the stress response and were significantly decreased in the epidural group during the postoperative period. In contrast, Hjortso et al. [91]were unable to identify differences in morbidity (Table 3) between patients randomized to general anesthesia followed by on demand "systemic" morphine or general anesthesia combined with epidural anesthesia followed by epidural bupivacaine for 24 h and epidural morphine for 72 h. Serum concentrations of albumin and transferrin were measured as markers of the stress response and also did not differ between groups. Although these observations are provocative and a theoretical framework linking reduction of the stress response with reduction of cardiac and vascular morbidity exists, data are currently insufficient to establish a clear relation. More studies are needed to determine if a relation exists between the stress response and postoperative morbidity before the clinical importance of reduction of the stress response with epidural anesthesia and analgesia can be determined.

Immune Function

Both cellular and humoral immune function are suppressed after surgery. [248,249]Although the etiology of postoperative immunosuppression is unclear, many known mediators of the stress response are potent immunosuppressants. [250]Postoperative immunosuppression typically lasts for several days, may last longer in inherently immunosuppressed patients (i.e., those with malignant disease or acquired immunodeficiency syndrome), [251-253]and may predispose to the development of postoperative infections [254,255]or facilitate postoperative tumor growth and metastases. [256-259]General anesthetics (with the exception of large doses of opioids) can not suppress the stress response and may exacerbate postoperative immunosuppression by depression of cellular and humoral immune function. [260-264]For example, immunosuppression resulting from general anesthetics occurs within 15 min after induction [265]and may persist for as long as 3-11 days. [261,266]However, the clinical importance of general anesthesia induced or stress response mediated immunosuppression remains uncertain.

Experimental Effects. Although high concentrations of local anesthetics directly inhibit leukocyte activity, [267,268]epidural anesthesia followed by epidural analgesia with local anesthetics has been associated with a modest preservation of cellular and humoral immune function, especially for procedures below the umbilicus. [265,266,269,270]Preservation of immune function continues beyond the duration of epidural analgesia and is thought to result from attenuation of the stress response. [266]Addition of general anesthesia to epidural anesthesia does not appear to antagonize preservation of immune function, provided epidural analgesia is maintained into the postoperative period. [269]Finally, low plasma concentrations of amide local anesthetic, such as are seen after epidural administration, have antiinflammatory properties, [271]prevent release of tissue damaging superoxide anions and lysosomal enzymes, [272-274]and may therefore reduce wound infection through enhanced healing of tissues. [271,274,275]Thus, use of epidural anesthesia followed by epidural analgesia with local anesthetics may aid in preservation of perioperative immune function that persist beyond the duration of epidural analgesia.

Postoperative immunosuppression can promote tumor growth [276]and therefore may affect outcome after oncologic surgery. Surgery and the resultant stress response leads to suppression of natural killer (NK) cell function, [277-279]which is associated with increased tumor growth and metastases. [280,281]Even transiently immunosuppressive interventions such as blood transfusions may adversely affect outcome after oncologic surgery. [282]Thus, anesthetic and analgesic choice may also affect outcome after oncologic surgery. General anesthetics directly suppress NK cell function, [261,283]and administration of general anesthetics in animal models leads to depression of NK cell activity and increased growth and spread of inoculated tumor cells. [256,276,284]On the other hand, epidural anesthesia followed by postoperative epidural analgesia with local anesthetics attenuates stress response induced depression of NK cell function, does not directly suppress NK cell function, [266]and thus represents a theoretical means to reduce perioperative tumor growth and improve patient outcome.

Clinical Effects. The immune system is complex and difficult to assess in the perioperative period. Individual tests of cellular and humoral immune function may have little reflection on the immune system's total ability to eradicate infections and neoplasms. [264]Nevertheless, clinical studies suggest that use of epidural anesthesia followed by epidural analgesia with local anesthetics may be associated with decreased incidences of postoperative infectious complications (sepsis, wound infections, and pneumonia). [73,88,91,135,149]Studies observing a beneficial effect have consistently examined high-risk patients undergoing major surgery and have used epidural anesthesia followed by adequate postoperative epidural analgesia with local anesthetics. Currently, there are no clinical studies evaluating the influence of choice of anesthesia and analgesia on outcome after oncologic surgery. However, anesthetic and analgesic techniques may decrease the magnitude of postoperative immunosuppression and may thus affect outcome after oncologic surgery.

Cognitive Function

Transient postoperative reduction in cognitive function is common in all patients and is poorly understood. [285]Reduction in cognitive function may be especially common (10-50% incidence) and severe in the elderly. [286,287]The nadir of cognitive function typically occurs on the 2nd postoperative day with full recovery occurring within 1 week. [288]However, elderly patients may require months to return to full preoperative mental capacity. [289]Furthermore, impaired cognitive function in the elderly is associated with increased incidence of postoperative complications such as depression, decubitus ulcers, stroke, urologic complications, and delayed return to independence, all of which may lead to longer hospitalization. [286]Purported causes of postoperative cognitive dysfunction include episodes of hypoxemia, use of psychoactive medication, and preoperative affective depression. [286,290,291]However, correlation with these suggested etiologies has been inconsistent, [292]and there are no definite links between perioperative physiologic perturbations and reduction in cognition. Thus, attempts to reduce the severity of postoperative cognitive dysfunction have been hampered by lack of a definite etiology.

Initial studies comparing general and epidural anesthesia demonstrated dramatic improvement in postoperative mental status with use of epidural anesthesia in patients undergoing total hip arthroplasty. [290]However, observers were not blinded, and objective tests of psychological function were not used. In fact, subsequent studies have failed to demonstrate differences in adverse cognitive sequelae. Studies randomizing patients to epidural anesthesia, general anesthesia, and combined epidural-general anesthesia have assessed postoperative cognitive function over a 3-month period by using tests such as psychological scales, organic brain syndrome scales, and batteries of memory, psychomotor, and skilled performance tests. [286,288,293,294]These well-designed studies consistently demonstrated similar severity of postoperative cognitive dysfunction in patients regardless of anesthetic selection.

However, none of these studies addressed the effects of postoperative analgesia on cognitive function. Because the nadir in cognitive function typically occurs on the 2nd postoperative day, it seems likely that the choice of postoperative analgesic technique rather than intraoperative anesthetic technique may affect cognition. Although there are no well-conducted studies examining effects of postoperative analgesia on cognition, previous studies have demonstrated less sedation in patients receiving epidural analgesia (local anesthetic or opioid) than those receiving parenteral opioid. [136,236]No objective psychomotor tests were performed, but these data suggest potential for reduction in postoperative cognitive dysfunction from use of epidural analgesia.

In summary, patients may experience impaired cognitive function and inability to perform activities of daily living after surgery. Although the etiology remains uncertain, reduction in cognitive function may last longer and be especially severe in the elderly, intraoperative anesthetic technique does not appear to affect incidence or severity of postoperative cognitive dysfunction. On the other hand, cognitive function reaches its nadir in the postoperative period, and effects of postoperative use of epidural analgesia have not been evaluated.


Perioperative hypothermia occurs frequently and is associated with both adverse and beneficial physiologic effects. [295,296]Hypothermia may be caused by several factors including low operating room ambient temperature, [297]heat loss during skin preparation and surgical exposure, [298]and use of anesthetics. [297]Both general and epidural anesthesia are associated with impaired thermoregulation and increased heat loss. [299,300]Epidural anesthesia with local anesthetics induces several thermoregulatory changes that lead to hypothermia such as increased cutaneous blood flow, decreased input from cutaneous thermal receptors, and redistribution of central heat. [301]In addition, augmentation of general anesthesia with epidural anesthesia appears to lead to greater degrees of hypothermia than use of general anesthesia alone. [302]Surprisingly, epidural analgesia has also been associated with otherwise unexplained hyperthermia in women during labor. [303]Thus, effects of epidural analgesia on human thermoregulation are complex and incompletely understood.

Several clinical studies have attempted to determine whether use of epidural or general anesthesia resulted in greater incidences of perioperative hypothermia. The results from these studies are conflicting, as greater incidences have been found with epidural anesthesia, [304,305]with general anesthesia, [297,306]or no difference has been found. [307]Although definite conclusions can not be drawn from these results, perioperative hypothermia can be effectively prevented (e.g., by passive insulators and active warming systems). [308-310]Therefore, careful perioperative maintenance of patient temperature can effectively prevent hypothermia and may make thermoregulatory preservation a minor consideration in selection of type of anesthesia.

Risks and Complications of Epidural Anesthesia and Analgesia

Potential beneficial physiologic effects of epidural anesthesia and analgesia are accompanied by risks for potential complications. Complications from epidural analgesia may be separated into complications from placement of epidural catheters and complications from use of local anesthetics and opioids.

Complications of Placement of Epidural Catheters

The most common complication from placement of epidural catheters is accidental dural puncture with resultant post-dural puncture headache. Recent large surveys encompassing 51,000 epidural catheter placements performed during the past 3 decades suggest that the incidence of dural puncture is 0.16-1.3%. [311,312]Subsequent development of post-dural puncture headache depends on several factors [313]and ranges from 16% to 86%. Less frequent complications are paresthesias and neurologic injury. The incidence of these complications is likely 0.01-0.001%. [311,314]Most of the neurologic injuries were self-limited and did not require treatment. [314].

An extremely rare but potentially disastrous complication of epidural analgesia is paraplegia. Paraplegia associated with epidural analgesia appears to result most commonly from formation of epidural hematoma. [315]Prompt recognition and surgical decompression of symptomatic epidural hematoma can prevent permanent neurologic injury. [316]Puncture of epidural vessels during placement of epidural catheters occurs in approximately 3-12% of cases. [317]Although subsequent formation of asymptomatic hematomas may be common, [318]formation of symptomatic epidural hematoma is a rare event. The incidence of symptomatic epidural hematoma associated with epidural analgesia is difficult to estimate, but combined case series of more than 100,000 epidural anesthetics have been reported without a single epidural hematoma. [319]Currently, the risk of formation of epidural hematoma after epidural analgesia appears to be increased if patients are receiving anticoagulant agents or have a coagulation disorder. [317,319,320]The majority of case reports of paraplegia resulting from epidural hematoma (with or without epidural catheters) were associated with these factors. [314-316,319,321]However, use of anticoagulants may not be an absolute contraindication to epidural analgesia. In fact, several large series have documented safe use of epidural analgesia in patients receiving antiplatelet therapy, [320,322,323]warfarin sodium, [324]and high- and low-dose heparin. [317,320,325-327]In fact, current clinical trials are examining the role of TEA in patients undergoing coronary bypass surgery. [328]These patients have epidural catheters placed preoperatively and undergo complete anticoagulation with heparin during surgery. Thus, with the possible exception of thrombolytic agents, [329]the risk of formation of symptomatic epidural hematoma in patients receiving anticoagulants may be small. Currently, it remains unclear what degree of laboratory abnormality identifies patients at increased risk [330-332]and when to remove epidural catheters if a serious coagulation disorder develops. [323,329,333]Other causes of paraplegia associated with epidural analgesia are probably even more rare and include epidural abscess, [334,335]epidural air from loss of resistance technique, [336]and preexisting medical conditions. [337].

Finally, recent surveys of more than 18,000 epidural anesthetics performed at university teaching hospitals suggest that placement of epidural catheters at thoracic vertebral levels does not confer higher risk than placement at lumbar levels. [311,338]In fact, incidences of complications resulting from placement of epidural catheters at thoracic levels were comparable to or lower than complications at the lumbar levels. Thus, risks of complications from placement of epidural catheters are small and are not higher for thoracic levels as compared with lumbar levels.

Complications of Administration of Local Anesthetics

Administration of epidural local anesthetics for surgical anesthesia frequently results in multiple hemodynamic changes including decreased chronotropy, inotropy, dromotropy, systemic vascular resistance, cardiac output, and myocardial oxygen consumption. [339,340]Hemodynamic effects from epidural administration of local anesthetics depend on the extent of neural blockade, intravascular volume status of the patient, and use of epinephrine containing local anesthetic solutions. [340,341].

Accidental intravascular or intrathecal injection of local anesthetics may cause complications including dysrhythmias, cardiovascular collapse, or high spinal anesthesia. [342,343]Use of a test dose of local anesthetic with epinephrine [344]and incremental rather than bolus injection of local anesthetics [345]may help decrease the incidence of these complications but does not eliminate the risk of complications. [346].

Complications from low concentrations of local anesthetics used for postoperative analgesia are also common. For example, postoperative use of concentrations of bupivacaine greater than 0.1% for LEA has been associated with high incidences (37-80%) of motor and autonomic blockade. [159,347]Complications resulting from motor and autonomic blockade include hypotension, urinary retention, impaired ambulation, and pressure necrosis. [347-349]The use of lower concentrations of bupivacaine such as 0.015-0.08% has been reported to result in lower incidences of complications (0-50%). [350,351]Furthermore, preliminary studies suggest that vertebral level of epidural catheter placement may significantly affect rate of local anesthetic complications (difficulty ambulating and orthostatic hypotension). [352,353],* These studies demonstrated that TEA is associated with less sympathetic block of the lower extremities than LEA. [352]Furthermore, use of thoracic epidural catheters for postoperative analgesia was associated with lower rates of complications than lumbar epidural catheters (2.5% vs. 20%) * and with equivalent rates of complications as parenteral morphine. [353]These findings are consistent with the segmental nature of epidural administration of local anesthetics. [352]TEA has relatively little effect on lumbar and sacral areas, [352]and these areas can initiate compensatory vasoconstriction. [78,354]Thus, preliminary results suggest that complications resulting from postoperative epidural analgesia with local anesthetics may be reduced when epidural catheters are inserted at a thoracic level.

Complications of Administration of Opioids

The most feared complication from epidural administration of opioids is delayed respiratory depression. The risk of respiratory depression after central neuraxial administration of opioids appears to be dose-dependent. [355,356]Although virtually all opioids commonly used for epidural analgesia have been reported to cause respiratory depression, [356]morphine is associated with the highest risk of delayed respiratory depression. Nonetheless, the incidence of delayed respiratory depression after epidural administration is small. Combined case surveys including more than 25,000 patients suggest that the incidence of delayed respiratory depression from epidural morphine is less than 1%. [356,357]This low incidence compares favorably with reported incidences of 0.9% for severe respiratory depression associated with oral and parenteral morphine. [358]Furthermore, several surveys have reported that use of epidural morphine in patient wards is safe, provided that adequate nursing monitoring is available. [357,359]Thus, risk of delayed respiratory depression after epidural opioids is small, and it appears that epidural opioids can be safely used on hospital wards.

Other complications from administration of epidural opioid include pruritus (reported incidences range from 28% to 100%), nausea (30-100%), and urinary retention (15-90%). [356,358,360-363]Incidences vary depending on specific opioid used, but in general, morphine appears to have the highest incidences of these side effects, whereas fentanyl has the lowest. It remains unclear whether these side effects are dose related. [364,365].

Finally, although analgesic synergism may exist between epidural local anesthetics and opioids, [14,15]it remains unclear whether combinations of local anesthetics and opioids reduce the incidences of respiratory depression, pruritus, nausea, and urinary retention. For example, addition of epidural bupivacaine in concentrations as low as 0.01% can reduce epidural fentanyl usage by 50% in patients receiving postthoracotomy epidural analgesia. [366]Use of small doses of local anesthetic and opioid to provide combination analgesia may lead to lower incidences of complications. [367]However, only one study has documented a reduction in side effect (pruritus) by combining local anesthetic and opioid. [368]Thus, further studies are necessary to identify optimal combinations of local anesthetics and opioids for provision of optimal analgesia, minimal complications, and reduced incidences of morbidity.

In summary, use of epidural anesthesia and analgesia may provide potential benefits but is also associated with potential detrimental effects. Currently, we have inadequate data to determine risk-benefit ratios; however, serious risks associated with epidural anesthesia and analgesia appear to be low. As in all of our practice, we must carefully weigh potential risks and benefits for each patient before initiating epidural anesthesia and analgesia.

Cost Effectiveness of Epidural Anesthesia and Analgesia

Health care consumes more than 12% of our gross national product, [369]and it appears that the United States is moving toward some form of health care reform. Competition for health care resources will increase, [370]and medical practices will undergo greater scrutiny regarding cost effectiveness by both internal and external regulators. [371]Thus, our specialty must take the initiative in examining cost effectiveness of our practice, [369,372-374]especially in new areas such as acute pain management.

Currently, fewer than 2% of published anesthesia literature include useful cost information. [372]Furthermore, cost effectiveness analyses are rarely performed. For example, Yeager et al. demonstrated a lower average hospital cost ($11,218 vs. $20,380) for high-risk patients receiving epidural anesthesia and analgesia as compared with general anesthesia. [73]However, actual cost savings may not be as large, as several direct and indirect costs are unknown. For example, direct costs of postoperative analgesia are unknown (equipment and services) and differ markedly among institutions. [359,375]Furthermore, indirect costs such as out-of-hospital costs (including home nursing, home medications, and days away from work) or expense of treating complications resulting from provision of epidural analgesia are also unknown. Finally, distribution of costs may be especially important. Yeager et al. [73]studied only high-risk patients and demonstrated impressive decreases in morbidity and cost. However, cost savings may be substantially diluted by provision of epidural analgesia to low-risk groups where there is less potential to decrease morbidity. Thus, direct costs, indirect costs, and distribution of costs can all affect cost effectiveness.

Correspondingly, long-term benefits may also magnify cost effectiveness of an intervention. For example, it is likely that the reduction of morbidity and mortality seen in Yeager's study added years of life and improved quality of life in the epidurai group. These long-lasting benefits gained through use of epidural anesthesia and analgesia may outweigh the total cost of providing epidural analgesia. However, these data are difficult to collect, [376]and there is neither a standard tool for measurement nor a consensus regarding relative weighting of outcome variables. [377].

In summary, although cost effectiveness of epidural analgesia remains unknown, potential long-term benefits from reduction in morbidity associated with epidural analgesia may outweigh total costs. Further studies are needed to identify the full extent of potential benefits from epidural analgesia, to identify optimal techniques, and especially to identify populations that receive the greatest benefit. Based on this information, our specialty can make rational decisions regarding cost-effective postoperative analgesic therapy.


Many studies have observed better pain relief with epidural analgesia than with systemic opioids. [12,91,378]Improved analgesia is particularly evident when local anesthetics and opioids are combined and analgesia is assessed during activity. [15]However, the ability of epidural analgesia to significantly alter other clinical outcomes is less easily defined. Our review indicates that use of epidurai anesthesia and analgesia may be associated with reductions in incidence and severity of many perioperative physiologic perturbations. Whether these effects will translate into improved patient outcome remains to be established. Preliminary evidence suggests that the perioperative coagulability can be reduced with epidural analgesia and this may significantly reduce the incidence of venous and arterial thromboses. [88,89,97]Similarly, significant improvements in gastrointestinal motility documented by indirect measures (e.g., passage of flatus) require further study to determine whether these intermediate benefits will result in a more rapid functional recovery from surgery. Evidence for clinically significant improvements in perioperative morbidity involving other organ systems is currently insufficient to allow conclusions.

It is clear that "epidural analgesia" is not a generic term. Its effects on outcome may differ depending on whether epidural injections consist of opioid, local anesthetic, or both. Local anesthetics may be more effective than opioids for attenuating many aspects of postoperative morbidity. However, theoretical benefits of local anesthetics on perioperative morbidity have not been confirmed in clinical studies, and the relative risk-benefit ratio for use of local anesthetics has not been defined. In addition, the insertion site for the epidural catheter (lumbar, low thoracic, or high thoracic) will significantly alter physiologic effects when local anesthetics are used. Consequently, site of catheter insertion and drugs used for analgesia must be considered when evaluating data from clinical trials.

Finally, we would like to promote the concept that improved analgesia may not be the only mechanism for improved outcome--at least not through a direct cause-and-effect relation. Epidurally administered analgesics may also produce beneficial effects through other mechanisms such as inhibition of efferent pathways (particularly sympathetic efferent pathways) or inhibition of neural reflex arcs.

Future Directions

Our ability to define conclusively the role of epidural anesthesia and analgesia in clinical practice is currently limited by a paucity of definitive data. Numerous questions remain unanswered. What is the optimal concentration, or dose, of local anesthetic? What is the necessary duration of epidural analgesia after surgery? Does the combination of local anesthetic and opioid provide benefits over the use of either drug alone? Does the site of catheter insertion make a difference? Most important, does epidural analgesia provide benefits over an optimal general anesthetic technique followed by analgesia with intravenous PCA opioid and additional systemic drugs that blunt detrimental physiologic responses to surgery (e.g., beta-adrenergic blocking agents or anticoagulants)?

Although epidural anesthesia and analgesia may improve outcome in high-risk patient populations, potential benefits in low-risk populations remains poorly defined because of the low rate of morbidity in these patient groups. In essence, our ability to detect differences is limited because of the relative safety of anesthetic care. Each intervention that successfully reduces postoperative morbidity requires even greater numbers of patients to detect beneficial effects in subsequent studies. To date, significant beneficial effects of epidural analgesia have been observed only in high-risk patient groups and often only for intermediate outcomes (e.g., myocardial ischemia). Perhaps future studies should attempt to determine the effect of analgesic therapy on ultimate patient outcome (e.g., death, myocardial infarction, or return to work). This effort will likely require formation of multicenter study groups and necessitate enrollment of thousands of patients. Although this approach is relatively uncommon in anesthesia research, it is a common practice in other medical specialties. Beneficial effects of numerous medical therapies have been conclusively documented only through multicenter trials (e.g., effect of beta-adrenergic blockade on myocardial morbidity [28]). It appears that multicenter studies will soon become necessary in anesthesia outcome research.

When designing outcome studies, we must strike a balance between two opposing goals: first, the scientific need to investigate effects of a single intervention by keeping all other aspects of care constant, and second, the clinical reality that postoperative recovery is multifaceted and that a solitary intervention is unlikely to alter outcome. For example, better pain management may not benefit ultimate recovery unless other aspects of convalescence are altered to take advantage of the improved analgesia. When designing studies, we must ask the following questions. Why does the patient need to be in the hospital today? What factors make it impossible for this patient to be discharged today (e.g., pain, ileus, or lack of mobility)? It is only after these factors have been identified that comprehensive convalescence programs can be developed. We must take a leadership role in defining which cases will benefit from aggressive analgesic management.

Finally, we must cooperate in developing postoperative analgesic regimens that are not only scientifically sound but also cost effective. Future studies should include measures of outcome and cost [373]and also adjust outcomes for quality (years of life added or improvement in quality of life). [379]Studies should include cost per increment of benefit gained (e.g., cost to save 1 day of hospitalization) or ratio of total costs to total benefits. Although many of these outcomes are relatively subjective and difficult to quantify, [377]we must expand our horizon beyond the intraoperative or even intrahospital period to see whether our interventions influence ultimate patient recovery (e.g., return to work). The changing economic environment means that it is no longer sufficient for anesthesiologists merely to determine the best method for postoperative analgesia or merely to believe that patients do better. In the future, we must also demonstrate cost effectiveness for our analgesic techniques. The challenge is ours.

The authors thank Sture G. Blomberg, M.D., Ph.D, Oscar A. De Leon-Casasola, M.D, and Christopher M. Bernards, M.D., for critical commentary.

*Wild LR: Does continuous infusion of epidural bupivacaine for postoperative pain impair functional mobility? (abstract). 7th World Congress on Pain, August 22-27, 1993, Paris, France.


Cannon WB: The course of events in secondary wound shock. JAMA 73:174-181, 1919.
Kehlet H: The surgical stress response: Should it be prevented? Can J Surg 34:565-567, 1991.
Kehlet H: Surgical stress: The role of pain and analgesia. Br J Anaesth 63:189-195, 1989.
Anand KJ, Hickey PR: Halothane-morphine compared with high dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 326:1-9, 1992.
Mangano DT, Siliciano D, Hollenberg M, Leung JM, Browner WS, Goehner P, Merrick S, Verrier E, The Study of Perioperative Ischemia Research Group: Postoperative myocardial ischemia: Therapeutic trials using intensive analgesia following surgery. ANESTHESIOLOGY 76:342-353, 1992.
Beattie WS, Buckley DN, Forrest JB: Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth 40:532-541, 1993.
Wasylak TJ, Abbott FV, English MJM, Jeans M-E: Reduction of post-operative morbidity following patient-controlled morphine. Can J Anaesth 37:726-731, 1990.
Ballantyne JC, Carr DB, Chalmers TC, Dear KBG, Angelillo IF, Mosteller F: Postoperative patient-controlled analgesia: Meta-analyses of initial randomized controlled trials. J Clin Anesth 5:182-193, 1993.
Eisenach JC, Grice SC, Dewan DM: Patient controlled analgesia following cesarean section: A comparison with epidural and intramuscular narcotics. ANESTHESIOLOGY 68:444-448, 1988.
Ellis D, Millar W, Reisner L: A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after cesarean section. ANESTHESIOLOGY 72:981-986, 1990.
Glass P, Estok P, Ginsberg B, Goldberg J: Use of patient controlled analgesia to compare efficacy of epidural to intravenous fentanyl administration. Anesth Analg 74:345-351, 1992.
Benzon HT, Wong HY, Belavic AM, Goodman I, Mitchell D, Lefheit T, Locicero J: A randomized double-blind comparison of epidural fentanyl infusion versus patient controlled analgesia with morphine for postthoracotomy pain. Anesth Analg 76:316-322, 1992.
Parker RK, White PF: Epidural patient-controlled analgesia: An alternative to intravenous patient-controlled analgesia for pain relief after cesarean delivery. Anesth Analg 75:245-251, 1992.
Kaneko M, Saito Y, Kirihara Y, Collins JG, Kosaka Y: Synergistic antinociceptive interaction after epidural coadministration of morphine and lidocaine in rats. ANESTHESIOLOGY 80:137-150, 1994.
Kehlet H, Dahl JB: The value of multi-modal or balanced analgesia in postoperative pain relief. Anesth Analg 77:1048-1056, 1993.
Schulze S, Roikjaer O, Hasselstrom L, Jensen NH, Kehlet H: Epidural bupivacaine and morphine plus systemic indomethacin eliminates pain but not systemic response and convalescence after cholecystectomy. Surgery 103:321-327, 1988.
Schulze S, Drenck NE, Hjortso E, Kehlet H: Influence of combined neural blockade, H sub 1 -and H sub 2 -receptor and serotonin sub 2 -receptor blockade, indomethacin and tranexamic acid on leucocyte, temperature and acute-phase protein response to surgery. Acta Chirurgica Scandinavica 154:329-333, 1988.
Schulze S, Sommer P, Bigler D, Honnens M, Shenkin A, Cruickshank AM: Effect of combined prednisolone, epidural analgesia, and indomethacin on the systemic response after colonic surgery. Arch Surg 127:325-331, 1992.
Bromage PR, Joyal JC, Binney JC: Penetration from the spinal extradural space into the neuraxis. Science 140:392-394, 1963.
Yaksh TL, Rudy TA: Analgesia mediated by a direct spinal action of narcotics. Science 192:1357-1358, 1976.
Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 323:1781-1788, 1990.
Hertzer NR, Beven EG, Young JR, O'Hara PJ, Ruschhaupt WF, Graor RA, Dewolfe VG, Maljovec LC: Coronary artery disease in peripheral vascular patients: A classification of 1,000 coronary angiograms and results of surgical management. Ann Surg 199:223-233, 1984.
Hertzer N: Clinical experience with preoperative coronary angiography. J Vasc Surg 2:510-514, 1985.
Mangano DT: Perioperative cardiac morbidity. ANESTHESIOLOGY 72:153-184, 1990.
Mulcahy D, Keegan J, Cunningham D: Circadian variation of total ischemic burden and its alterations with antianginal agents. Lancet 2:755-759, 1988.
Willich SN, Pohjola-Sintonen S, Bhatia SJS, Shook TL, Tofler GH, Muller JE, Curtis DJ, Williams GH, Stone PH: Suppression of silent ischemia by metoprolol without alteration of morning increase in platelet aggregability in patients with stable coronary artery disease. Circulation 79:557-565, 1989.
Rocco M, Barry J, Campbell S, Nabel E, Cook E, Goldman L, Selwyn A: Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation 75:395-400, 1987.
beta-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. JAMA 250:2814-2819, 1983.
The International Collaborative Study Group: Reduction of infarct size with the early use of timolol in acute myocardial infarction. N Engl J Med 310:9-15, 1984.
Tofler G, Brezinski D, Schafer A: Concurrent morning increase in platelet aggregability and risk of myocardial infarction and sudden cardiac death. N Engl J Med 316:1514-1518, 1987.
Brezinski D, Tofler G, Muler J: Morning increase in platelet aggregability: Association with assumption of upright posture. Circulation 78:35-40, 1988.
Fujita M, Franklin D: Diurnal changes in coronary blood flow in conscious dogs. Circulation 76:488-491, 1987.
Millar-Craig M, Bishop C, Raftery E: Circadian variation of blood pressure. Lancet 1:795-797, 1978.
Slogoff S, Keats A: Randomized trial of primary anesthetic agents on outcome of coronary artery bypass operations. ANESTHESIOLOGY 70:179-188, 1989.
Mangano DT, Hollenberg M, Fegert G, Meyer ML, London MJ, Tubau JF: Perioperative myocardial ischemia in patients undergoing noncardiac surgery: I. Incidence and severity during the 4 day perioperative period. J Am Coll Cardiol 17:843-850, 1991.
Hollenberg M, Mangano D, Browner W, London M, Tubau J, Tateo I: Predictors of postoperative myocardial ischemia in patients undergoing noncardiac surgery. JAMA 268:205-209, 1992.
Leung J, O'Kelly B, Mangano D: Relationship of regional wall motion abnormalities to hemodynamic indices of myocardial oxygen supply and demand in patients undergoing CABG surgery. ANESTHESIOLOGY 73:802-814, 1990.
Chierchia S, Brunelli C, Simonetti I, Lazzari M, Maseri A: Sequence of events in angina at rest: Primary reduction in coronary flow. Circulation 61:759-768, 1980.
Chierchia S, Lazzari M, Freedman B, Brunelli C, Maseri A: Impairment of myocardial perfusion and function during painless myocardial ischemia. J Am Coll Cardiol 1:924-930, 1983.
Rosenberg J, Rasmussen V, von Jessen F, Ullstad T, Kehlet H: Late postoperative episodic and constant hypoxaemia and associated ECG abnormalities. Br J Anaesth 65:684-691, 1990.
Reeder MK, Muir AD, Foex P, Goldman MD, Loh L, Smart D: Postoperative myocardial ischaemia: Temporal association with nocturnal hypoxaemia. Br J Anaesth 67:626-631, 1991.
Reiz S, Balfors E, Sorenson M, Haggmark S, Nyhman H: Coronary hemodynamic effects of general anesthesia and surgery: Modification by epidural analgesia in patients with ischemic heart disease. Reg Anesth 7(suppl):8-18, 1982.
Lee DD, Kimura S, De Quattro V: Noradrenergic activity and silent ischemia in hypertensive patients with stable angina: Effect of metoprolol. Lancet 1:403-406, 1989.
Vanhoutte PM, Shimokawa H: Endothelium derived relaxing factor and coronary vasospasm. Circulation 80:1-9, 1989.
Heusch G, Deussen A, Thamer V: Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenosis: Feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 13:311-326, 1985.
Blomberg S, Emanuelsson H, Ricksten S: Thoracic epidural anesthesia and central hemodynamics in patients with unstable angina pectoris. Anesth Analg 69:558-562, 1989.
Kliks B: Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 36:45-49, 1975.
Schwartz P: Left stellectomy in prevention of ventricular fibrillation caused by acute myocardial ischemia in conscious dogs with anterior myocardial infarction. Circulation 62:1256-1265, 1980
Blomberg S, Curelaru I, Emanuelsson H, Herlitz J, Ponten J, Ricksten S-E: Thoracic epidural anaesthesia in patients with unstable angina pectoris. Eur Heart J 10:437-444, 1989.
Flatley KA, DeFily DV, Thomas JX: Effects of cardiac sympathetic nerve stimulation during adrenergic blockade on infarct size. J Cardiovasc Pharmacol 7:673-679, 1985.
Rosenfeld BA, Beattie C, Christopherson R, Norris EJ, Frank SM, Breslow MJ, Rock P, Parker SD, Gottlieb SO, Perler BA, Williams GM, Seidler A, Bell W, The Perioperative Ischemia Randomized Anesthesia Trial Study Group: The effects of different anesthetic regimens on fibrinolysis and the development of postoperative arterial thrombosis. ANESTHESIOLOGY 79:435-443, 1993.
Saada M, Catoire P, Bonnet F, Delaunay L, Gormezano G, Macquin-Mavier I, Brun P: Effect of thoracic epidural analgesia combined with general anesthesia on segmental wall motion assessed by transesophageal echocardiography. Anesth Analg 75:329-335, 1992.
Blomberg S, Emanuelsson H, Kvist H, Lamm C, Ponten J, Waagstein F, Ricksten S-E: Effects of thoracic epidural anesthesia on coronary arteries and arterioles in patients with coronary artery disease. ANESTHESIOLOGY 73:840-847, 1990.
Davis R, DeBoer LWV, Maroko PR: Thoracic epidural analgesia reduces myocardial infarct size after coronary artery occlusion in dogs. Anesth Analg 65:711-717, 1986.
Feigl ED: Coronary physiology. Physiol Rev 63:201-205, 1983.
Young MA, Vatner SF: Regulation of large coronary arteries. Circ Res 59:579-596, 1986.
Gould KL: Dynamic coronary stenosis. Am J Cardiol 45:286-292, 1980.
Brown BG: Response of normal and diseased epicardial coronary arteries to vasoactive drugs: Quantitative arteriographic studies. Am J Cardiol 56:23-29, 1985.
Feigl E: The paradox of adrenergic coronary vasoconstriction. Circulation 76:737-745, 1987.
Heusch G, Yoshimoto N, Heegemann H, Thamer V: Interaction of methoxamine with compensatory vasodilation distal to coronary stenosis. Drug Research 33:1647-1650, 1983.
Klassen G: The effect of acute sympathectomy by epidural anesthesia on the canine coronary circulation. ANESTHESIOLOGY 52:8-15, 1980.
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 Anaesthiol Scand 35:508-512, 1991.
Vik-Mo H, Ottesen S, Renck H: Cardiac effects of thoracic epidural analgesia before and during acute coronary artery occlusion in open-chest dogs. Scand J Clin Lab Invest 38:737-746, 1978.
Blomberg S, Ricksten S-E: Thoracic epidural anaesthesia decreases the incidence of ventricular arrhythmias during acute myocardial ischaemia in the anaesthetized rat. Acta Anaesthcsiol Scand 32:173-178, 1988.
Tevelenok Y: Peridural anesthesia in the acute period of myocardial infarction. Anesteziol Reanimatol 3:36-39, 1977.
Toft P, Jorgensen A: Continuous thoracic epidural analgesia for the control of pain in myocardial infarction. Intensive Care Med 13:388-389, 1987.
Blomberg S: Long-term home self treatment with high thoracic epidural anesthesia in patients with severe coronary artery disease. Anesth Analg 79:413-421, 1994.
Blomberg S, Ricksten S-E: Effects of thoracic epidural anaesthesia on central haemodynamics compared to cardiac beta adrenoceptor blockade in conscious rats with acute myocardial infarction. Acta Anaesthesiol Scand 34:1-7, 1990.
Stenseth R, Berg EM, Christensen O, Levang OW, Gisvold SE: The influence of thoracic epidural analgesia alone and in combination with general anesthesia on cardiovascular function and myocardial metabolism in patients receiving beta-adrenergic blockers. Anesth Analg 77:463-468, 1993.
Kataja J: Thoracolumbar epidural anesthesia and isoflurane to prevent hypertension and tachycardia in patients undergoing abdominal aortic surgery. Eur J Anaesthesiol 8:427-436, 1991.
Baron J-F, Coriat P, Mundler O, Fauchet M, Bousseau D, Viars P: Left ventricular global and regional function during lumbar epidural anesthesia in patients with and without angina pectoris: Influence of volume loading. ANESTHESIOLOGY 66:621-627, 1987.
Diebel L, Lange P, Schneider F, Mason K, Wilson R, Jacobs L, Dahn M: Cardiopulmonary complications after major surgery: A role for epidural analgesia. Surgery 102:660-666, 1987.
Yeager MP, Glass DD, Neff RK, Brinck-Johnson T: Epidural anesthesia and analgesia in high-risk surgical patients. ANESTHESIOLOGY 66:729-736, 1987.
Her C, Kizelshteyn G, Walker V, Hayes D, Lees D: Combined epidural and general anesthesia for abdominal aortic surgery. J Cardiothorac Anesth 4:552-557, 1990.
Mergner G, Stolte A, Frame W, Lim H: Combined epidural analgesia and general anesthesia induce ischemia distal to a severe coronary artery stenosis in swine. Anesth Analg 78:37-45, 1994.
Baron JF, Bertrand M, Barre E, Godet G, Mundler O, Coriat P, Viars P: Combined epidural and general anesthesia versus general anesthesia for abdominal aortic surgery. ANESTHESIOLOGY 75:611-618, 1991.
Saada M, Catoire P, Bonnet F, Delaunay L, Gormezano G, Macquin-Mavier I, Brun P: Effect of thoracic epidural anesthesia combined with general anesthesia on segmental wall motion assessed by transesophageal echocardiography. Anesth Analg 75:329-335, 1992.
Baron J-F, Payon D, Coriat P, Edouard D, Viars P: Forearm vascular reactivity during lumbar epidural anesthesia. Anesth Analg 67:1065-1070, 1988.
Saada M, Duval A-M, Bonnet F, Rey B, Castillon G, Macquin-Mavier I, Cabrit R, Boico O, Castaigne A: Abnormalities in myocardial segmental wall motion during lumbar epidural anesthesia. ANESTHESIOLOGY 71:26-32, 1989.
Tuman K, McCarthy R, Spiess B, DaValle M, Dabir R, Ivankovich A: Does choice of anesthetic agent significantly affect outcome after coronary artery surgery? ANESTHESIOLOGY 70:189-198, 1989.
Tuman K, McCarthy R, Spiess B, DaValle M, Hompland S, Dabir R, Ivankovich A: Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery. ANESTHESIOLOGY 70:199-206, 1989.
Slogoff S, Keats AS: Does perioperative myocardial ischemia lead to postoperative myocardial infarction? ANESTHESIOLOGY 62:107-114, 1985.
Rao TK, Jacobs KH, El-Etr AA: Reinfarction following anesthesia in patients with myocardial infarction. ANESTHESIOLOGY 59:499-505, 1983.
Steen PA, Tinker JH, Tarhan S: Myocardial reinfarction after anesthesia and surgery: An update. Incidence. mortality, and predisposing factors. JAMA 239:2566-2570, 1978.
Breslow MJ. Jordan DA, Christopherson R. Rosenfeld B, Miller CF, Hanley DF, Beattie C, Traystman RJ. Rogers MC: Epidural morphine decreases postoperative hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 261:3577-3581. 1989.
Mason R, Newton G, Cassel W, Maneksha F, Giron F: Combined epidural and general anesthesia in aortic surgery. J Cardiovasc Surg (Torino) 31:442-447, 1990.
Pecoraro J: Epidural anesthesia as all adjunct to retroperitoneal aortic surgery. Am J Surg 160: 187-191, 1990.
Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivan-kovich AD: Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 73:696-704, 1991.
Christopherson R, Beattie C, Frank SM, Norris EJ, Meinert CL, Gottlieb SO, Yates H, Rock P, Parker SD, Perler BA, Williams GM, The Perioperative Ischemia Randomized Anesthesia Trial Study Group: Perioperative morbidity in patients randomized to epidural or general anesthesia for lower-extremity vascular surgery. ANESTHESIOLOGY 79:422-434, 1993.
Gelman S: General versus regional anesthesia for peripheral vascular surgery: Is the problem solved? (editorial). ANESTHESIOLOGY 79:415-418, 1993.
Hjortso NC, Neumann P, Frosig F, Andersen T, Lindhard A, Rogon E, Kehlet H: A controlled study on the effect of epidural analgesia with local anaesthetics and morphine on morbidity after abdominal surgery. Acta Anaesthesiol Scand 29:705-716, 1985.
Chernow IL Alexander HR, Smallridge RC, Thompson WR. Cook D, Beardsley D: Hormonal responses to graded surgical stress. Arch Intern Med 147:1273-1278, 1987.
Ygge J: Changes in blood coagulation and fibrinolysis during the post-operative period. Am J Surg 119:225-232, 1970.
Collins GJ, Barber JA, Zajtchuk R: The effects of operative stress on the coagulation profile. Am J Surg 133:612-616. 1977.
Donadoni R, Baele G, Devulder J, Rolly G: Coagulation and fibrinolytic parameters in patients undergoing total hip replacement: Influence of anaesthesia technique. Acta Anaesthesiol Scand 33:588-592, 1989.
Scott NB, Kehlet H: Regional anaesthesia and surgical morbidity. Br J Surg 75:199-204, 1988.
Modig J, Maripuu E, Sahlstedt B: Thromboembolism following total hip replacement: A prospective investigation of 94 patients with emphasis on the efficacy of lumbar epidural anesthesia in prophylaxis. Reg Anesth 11:72-79, 1986.
Breslow MJ, Parker SD, Frank SM, Norris EJ, Yates H, Raff H, Rock P. Christopherson R, Rosenfeld BA, Beattie C, Group TPS: Determinants of catecholamine and cortisol rcsponses to lower-extremity revascularization. ANESTHESIOLOGY 79:1202-1209, 1993.
Rosenfeld BA, Faraday N, Campbell D, Dise K, Bell W, Goldschmidt P: Homostatic effects of stress hormone infusion. ANESTHESIOLOGY 81:1116-1126, 1994.
Anderson TR, Berner NS, Larsen ML, Odegarrd OR, Abdilgaard U: Plasma cofactor II, protein C, and antithrombin in elective surgery. Acta Chirurgica Scandinavica 153:291-296, 1987.
O'Brien JR, Tulevski VG, Etherington M, Madgwick T: Platelet function studies before and after operative and the effect of postoperative thrombosis. J Lab Clin Med 83:342-354, 1974.
Kluft C, Verheijen JH, Jie AFH, Rijken C, Preston FE, Sue-Ling HM, Jespersen J, Aasen AO: The postoperative fibrinolytic shutdown: A rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue type plasminogen activator after trauma. Scand J Clin Lab Invest 45:605-610, 1985.
Henny C, Odoom J, Ten Cate H, Ten Cate J, Oosterhoff R. Dabhoiwala N, Sih I: Effects of extradural bupivacaine on the haemostatic system. Br J Anaesth 58:301-305, 1986.
Lichtenfeld K, Schiffer D, Helrich M: Platelet aggregation during and after general anesthesia and surgery. Anesth Analg 58:293-296, 1979.
Modig J. Malmberg P, Karlstrom G: Effect of epidural versus general anaesthesia on calf blood flow. Acta Anaesthesiol Scand 24: 305-309, 1980.
Steele S, Slaughter T, Greenberg C, Reves J: Epidural anesthesia and analgesia: Implications for perioperative coagulability. Anesth Analg 73:683-685, 1991.
Modig J, Borg T, Bagge L, Saldeen T: Role of extradural and of general anaesthesia in fibrinolysis and coagulation after total hip replacement. Br J Anaesth 55:625-629, 1983.
Modig J, Borg T, Karlstrom G. Maripuu E, Sahlstedt B: Thromboembolism after total hip replacement: Role of epidural and general anesthesia. Anesth Analg 62:174-180, 1983.
Simpson P, Radford S, Forster S, Cooper G, Hughes A: The fibrinolytic effects of anaesthesia. Anaesthesia 37:3-8, 1982.
Feinstein M, Fickers J, Fraser C: An analysis of the mechanism of local anesthetic inhibition of platelet aggregation and secretion: J Pharmacol Exp Ther 197:215-228, 1976.
Borg T, Modig J: Potential anti-thrombotic effects of local anaesthetics due to their inhibition of platelet aggregation. Acta Anaesthesiol Scand 29:739-742, 1985.
Orr J, Lowe G, Nimmo W, Watson R, Forbes C: A haemor-heological study of lignocaine. Br J Anaesth 58:306-309, 1986.
Benzon HT, Wong CA, Wong HY, Brooke C, Wade L: The effect of low-dose bupivacaine on postoperative epidural fentanyl analgesia and thromboelastography. Anesth Analg 79:911-917, 1994.
McDaniel MD, Pearce WH, Yao JS, Rossi EC, Fahey VA, Green D, Flinn WR, Bergan JJ: Sequential changes in coagulation and platelet function following femorotibial bypass. J Vasc Surg 1:261-268, 1984.
Sharrock N, Ranawat C, Urquhart B, Peterson M: Factors influencing deep vein thrombosis following total hip arthroplasty under epidural anesthesia. Anesth Analg 76:756-771, 1993.
Sharrock NE, Haas SB, Hargett MJ, Urquhart B, Insall JN, Scuderi G: Effects of epidural anesthesia on the incidence of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg Am 73:502-506, 199l.
Hendolin H, Mattila MAK, Poikolainen E: The effect of lumbar epidural analgesia on the development of deep vein thrombosis of the legs after open prostatectomy. Acta Chirurgica Scandinavica 147: 425-429, 1981.
Jorgensen L, Rasmussen L, Nielsen P, Leffers A, Albrecht-Best E: Antithrombotic efficacy of continous extradural analgesia after knee replacement. Br J Anaesth 66:8-12, 1991.
Sorenson R, Pace N: Anesthetic techniques during surgical repair of femoral neck fractures. ANESTHESIOLOGY 77:1095-1104, 1992.
Ali J, Weisel R, Layug A, Kripke B, Hechtman H: Consequences of postoperative alterations in respiratory mechanics. Am J Surg 128:376-382, 1974.
Craig DB: Postoperative recovery of pulmonary function. Anesth Analg 60:46-52, 1981.
Tarhan S, Moffitt E, Sessler A, Douglas W, Taylor W: Risk of anesthesia and surgery in patients with chronic bronchitis and chronic obstructive pulmonary disease. Surgery 74:720-726, 1973.
Couture J, Chartrand D, Gagner M, Bellemare F: Diaphragmatic and abdominal muscle activity after endoscopic cholecystectomy. Anesth Analg 78:733-739, 1994.
Rademaker BM, Ringers J, Odoom JA, de Wit LT, Kalkman CJ, Oosting J: Pulmonary function and stress response after laparoscopic cholecystectomy: Comparison with subcostal incision and influence of thoracic epidural analgesia. Anesth Analg 75:381-385, 1992.
Pansard J-L, Mankikian B, Bertrand M, Kieffer E, Clergue F, Viars P: Effects of thoracic extradural block on diaphragmatic electrical activity and contractility after upper abdominal surgery. ANESTHESIOLOGY 78:63-71, 1993.
Duggan J, Drummond G: Activity of lower intercostal and abdominal muscle after upper abdominal surgery. Anesth Analg 66:852-855, 1987.
Meyers J, Lembeck L, O'Kane H, Baue A: Changes in functional residual capacity of the lung after operation. Arch Surg 110:576-583, 1975.
Spence AA, Smith G: Postoperative analgesia and lung function: A comparison of morphine with extradural block. Br J Anaesth 43:144-148, 1971.
Brown D, Neal J: Chronic obstructive pulmonary disease and perioperative analgesia, Problems in Anesthesia. Edited by Brown DL. Philadelphia, JB Lippincott, 1988, pp 422-434.
Hickey RF, Visick WD, Fairley HB, Fourcade HE: Effects of halothane anesthesia on functional residual capacity and alveolar-arterial oxygen tension difference. ANESTHESIOLOGY 38:20-24, 1973.
Garibaldi R, Britt M, Coleman M, Reading J, Pace N: Risk factors for postoperative pneumonia. Am J Med 70:677-680, 1981.
Hendolin H, Lahtinen J, Lansimies E, Tuppurainen T, Partanen K: The effect of thoracic epidural analgesia on respiratory function after cholecystectomy. Acta Anaesthesiol Scand 31:645-651, 1987.
Wahba WM: Influence of aging on lung function: Clinical significance of changes from age twenty. Anesth Analg 62:764-776, 1983.
Rawal N, Sjostrand U, Christoffersson E, Dahlstrom B, Arvill A, Rydman H: Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: Influence on postoperative ambulation and pulmonary function. Anesth Analg 63:583-592, 1984.
Cuschieri RJ, Morran CG, Howie JC, McArdle CS: Postoperative pain and pulmonary complications: Comparison of three analgesic regimens. Br J Surg 72:495-498, 1985.
Sydow FW: The influence of anesthesia and postoperative analgesic management on lung function. Acta Chirurgica Scandinavica 550(suppl):159-168, 1988.
Nunn J: Effects of anaesthesia on respiration. Br J Anaesth 65:54-62, 1990.
Weller R, Rosenblum M, Conrad P, Gross JA: Comparison of epidural and patient-controlled intravenous morphine following joint replacement surgery. Can J Anaesth 38:582-586, 1991.
McCarthy GS: The effects of thoracic extradural analgesia on pulmonary gas distribution, functional residual capacity, and airway closure. Br J Anaesth 48:243-247, 1976.
Groeben H, Schwalen A, Irsfeld S, Tarnow J, Lipfert P, Hopf H-B: High thoracic epidural anesthesia does not alter airway resistance and attenuates the response to an inhalational provocation test in patients with bronchial hyperreactivity. ANESTHESIOLOGY 81:868-874, 1994.
Harrison DM, Sinatra R, Morgese L, Chung JH: Epidural narcotic and patient-controlled analgesia for post-cesarean section pain relief. ANESTHESIOLOGY 68:454-457, 1988.
George KA, Chisakuta AM, Gamble JA, Browne GA: Thoracic epidural infusion for postoperative pain relief following abdominal aortic surgery: Bupivacaine, fentanyl or a mixture of both? Anaesthesia 47:388-394, 1992.
Mourisse J, Hasenbos MAWN, Gielen MJM: Epidural bupivacaine, sufentanil, or the combination for post-thoracotomy pain. Acta Anaesthesiol Scand 36:70-74, 1992.
Dahl JB, Rosenberg J, Hansen B, Hjortso N-C, Kehlet H: Differential analgesic effects of low-dose epidural morphine and morphine-bupivacaine at rest and during mobilization after major abdominal surgery. Anesth Analg 74:362-365, 1992.
Mankikian B, Cantineau JP, Bertrand M, Kieffer E, Sartene R, Viars P: Improvement of diaphragmatic function by a thoracic extradural block after upper abdominal surgery. ANESTHESIOLOGY 68:379-386, 1988.
Bromage PR, Camporesi E, Chestnut D: Epidural narcotics for postoperative analgesia. Anesth Analg 59:473-480, 1980.
Guinard J-P, Mavrocordato P, Chiolero, Carpenter RL: A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy. ANESTHESIOLOGY 77:1108-1115, 1992.
Jayr C, Mollie A, Bourgain JL, Alarcon J, Masselot J, Lasser P, Denjean A, Truffa-Bachi J, Henry-Amar M: Postoperative pulmonary complications: General anesthesia with postoperative parenteral morphine compared with epidural analgesia. Surgery 104:57-63, 1987.
Jayr C, Thomas H, Rey A, Farhat F, Lasser P, Bourgain J-L: Postoperative pulmonary complications: Epidural analgesia using bupivacaine and opioids versus parenteral opioids. ANESTHESIOLOGY 78:666-676, 1993.
Ford G, Whitelaw W, Rosenal T, Cruse PJ, Guenter CA: Diaphragm function after upper abdominal surgery in humans. Am Rev Respir Dis 127:431-436, 1987.
Simonneau G, Vivien A, Saberne R, Kuntslinger F, Samii K, Noviant Y, Duroux P: Diaphragm dysfunction induced by upper abdominal surgery: Role of postoperative pain. Am Rev Respir Dis 128: 899-903, 1983.
Fratacci M-D, Kimball WR, Wain JC, Kacmarek RM, Polaner DM, Zapol WM: Diaphragmatic shortening after thoracic surgery in humans. ANESTHESIOLOGY 79:654-665, 1993.
Lowrie A, Johnston PL, Fell D, Robinson SL: Cardiovascular and plasma catecholamine responses to tracheal extubation. Br J Anaesth 68:261-263, 1992.
Beydon L, Hassapopoulos J, Quera MA, Rauss A, Becquemin JP, Bonnet F, Harf A, Goldenberg F: Risk factors for oxygen desaturation during sleep, after abdominal surgery. Br J Anaesth 69:137-142, 1992.
Catley D, Thornton C, Jordan C, Lehane J, Royston D, Jones JG: Pronounced, episodic oxygen desaturation in the postoperative period: Its association with ventilatory pattern and analgesic regimen. ANESTHESIOLOGY 63:20-28, 1985.
Jones MJ, Piggott SE, Vaughan RS, Bayer AJ, Newcombe RG, Twining TC, Pathy J, Rosen M: Cognitive and functional competence after anesthesia in patients aged over 60: Controlled trial of general and regional anaesthesia for elective hip or knee replacement. BMJ 300:1683-1687, 1990.
Wheatley R, Somerville I, Sapsford D, Jones J: Postoperative hypoxaemia: Comparison of extradural, LM. and patient-controlled analgesia. Br J Anaesth 64:267-275, 1990.
Rybro L, Schurizek BA, Petersen TK, Wernberg M: Postoperative analgesia and lung function: A comparison of intramuscular and epidural morphine. Acta Anaesthesiol Scand 26:514-520, 1982.
Pflug AE, Murphy TM, Butler GT: The effects of postoperative epidural analgesia on pulmonary therapy and pulmonary compliance. ANESTHESIOLOGY 41:8-17, 1974.
Hasenbos M, Van Egmond J, Gielen M, Crul J: Post-operative analgesia by high thoracic epidural versus intramuscular nicomorphine after thoracotomy: III. The effects of peri- and post-operative analgesia on morbidity. Acta Anaesthesiol Scand 31:608-615, 1987.
Livingston E, Passaro E: Postoperative ileus. Dig Dis Sci 35:121-132, 1990.
Adelhoj B, Petring O, Jensen B, Ibsen M, Poulsen HE: The effect of spinal analgesia and surgery on peroperative drug absorption and gastric emptying in man. Acta Anaesthesiol Scand 31:165-167, 1987.
Moore FA, Feliciano DV, Andeassy RJ, McArdle AH, Booth FVM, Morgenstein-Wagner TB, Kellum JM, Welling RE, Moore EE: Early enteral feeding, compared with parenteral, reduces postoperative septic complications. Ann Surg 216:172-183, 1992.
Moore F, Moore E, Jones T, McCroskey B: TEN vs TPN following major abdominal trauma: Reduced septic morbidity. J Trauma 29:916-923, 1989.
Shou J, Lappin J, Minnard E, Daly J: Total parenteral nutrition, bacterial translocation, and host immune function. Am J Surg 167:145-150, 1994.
Saito H, Trocki O, Alexander J: The effect of route of nutrient administration on the nutritional state, catabolic hormone secretion, and gut mucosal integrity after burn injury. Journal of Parenteral and Enteral Nutrition 11:1-7, 1987.
Wells C, Rawlinson K, Tinckler L, Jones H, Saunders J: Ileus and postoperative intestinal motility. Lancet 2:136-137, 1961.
Condon R, Frantzides C, Cowles V, Mahoney JL, Schulte WJ, Sarna SK: Resolution of postoperative ileus in humans. Ann Surg 203:574-581, 1986.
Woods JH, Erickson LW, Condon RE, Schulte WJ, Sillin LF: Postoperative ileus: A colonic problem? Surgery 84:527-533, 1978.
Wattwi M: Postoperative pain relief and GI motility. Acta Chirurgica Scandinavica 550(suppl):140-145, 1988.
Wilson JP: Postoperative motility of the large intestine in man. Gut 16:689-692, 1975.
Furness J, Costa M: Adynamic ileus, its pathogenesis and treatment. Med Biol Eng 52:82-89, 1974.
Smith J, Kelly K: Pathophysiology of postoperative ileus. Arch Surg 112:203-209, 1977.
Jansson G, Martinson J: Studies on the ganglionic site of action of the sympathetic outflow to the stomach. Acta Physiol Scan 68:184-192, 1966.
Johansson B, Langston J: Reflex influence of mesentric afferents on renal, intestinal, and muscle blood flow and on intestinal motility. Acta Physiol Scand 61:400-412, 1964.
Heimbach D, Crout J: Treatment of paralytic ileus with adrenergic neuronal blocking drugs. Surgery 69:582-587, 1971.
Bayliss W, Starling E: The movements and innervation of the small intestine. J Physiol (Lond) 24:8-143, 1899.
Scratcherd T, Grundy D: The physiology of intestinal motility and secretion. Br J Anaesth 56:3-18, 1984.
Rimback G, Cassuto J FA, S H, Wallin G, Tollesson PO: Effect of intra-abdominal bupivacaine instillation on postoperative colonic motility. Gut 27:170-175, 1986.
Rimvack G, Cassuto J, Tollesson P: Treatment of postoperative paralytic ileus by intravenous lidocaine infusion. Anesth Analg 70:414-419, 1990.
Aitkinhead A, Gilmour D, Hothesall A, Ledingham I: Effect of subarachnoind spinal nerve block and arterial PCO2 on colon blood flow in the dog. Br J Anaesth 52:1071-1077, 1980.
Johansson K, Ahn H, Lindhagen J, Tryselius U: Effect of epidural anaesthesia on intestinal blood flow. Br J Surg 75:73-76, 1988.
Udassin R, Eimerl D, Schiffman J, Haskel Y: Epidural anesthesia accelerates the recovery of postischemic bowel motility in the rat. ANESTHESIOLOGY 80:832-836, 1994.
Shandall A, Lowndes R, Young H: Colonic anastomotic healing and oxygen tension. Br J Surg 72:606-609, 1985.
Aitkinhead A, Wishart H, Peebles-Brown D: High spinal nerve block for large bowel anastomosis: A retrospective study. Br J Anaesth 50:177-183, 1978.
Bigler D, Hjortso N-C, Kehlet H: Disruption of colonic anastamosis during continuous epidural analgesia. Anaesthesia 40:278-280, 1985.
Bredtmann RD, Herden HN, Teichmann W, Moecke HP, Kniesel B, Baetgen R, Tecklenburg A: Epidural analgesia in colonic surgery: Results of a randomized prospective study. Br J Surg 77:638-642, 1990.
Schnitzler M, Kilbride MJ, Senagore M: Effect of epidural analgesia on colorectal anastomotic healing and colonic motility. Reg Anesth 17:143-147, 1992.
Worsley M, Wishart H, Peebles-Brown D, Aitkenhead A: High spinal nerve block for large bowel anastomosis. Br J Anaesth 60:836-840, 1988.
Lund C, Selmar P, Hansen OB, Jensen CM, Kehlet H: Effect of extradural morphine on somatosensory evoked potentials to dermatomal stimulation. Br J Anaesth 59:1408-1411, 1987.
Ingram D, Sheiner H: Postoperative gastric emptying. Br J Surg 68:572-576, 1981.
Schang J, Hemond M, Hebert M, Pilote M: How does morphine work on colonic motility? An electromyographic study in the human left and sigmoid colon. Life Sci 38:671-676, 1986.
Bardon T, Ruckebusch Y: Comparative effects of opiate agonists on proximal and distal colonic motility in dogs. Eur J Pharmacol 110:329-334, 1985.
Porreca F, Mosberg H, Hurst T, Hurby VJ, Burks TF: Role of mu, delta, kappa opioid receptors in spinal and supraspinal medication on gastrointestinal transit effects and hot-plate analgesia in the mouse. J Pharmacol Exp Ther 230:341-348, 1984.
Frantzides CT, Cowles V, Salaymeh B, Tekin E, Condon RE: Morphine effects on human colonic myoelectric activity in the postoperative period. Am J Surg 163:144-149, 1992.
Seeling W, Bruckmooser K-P, Huffner C: Continuous thoracic epidural analgesia does not diminish postoperative complications after abdominal surgery in patients at risk. Anaesthesist 39:33-38, 1990.
Scheinen B, Asantila R, Orko R: The effect of bupivacaine and morphine on pain and bowel function after colonic surgery. Acta Anaesthesiol Scand 31:161-164, 1987.
Wallin G, Cassuto J, Hogstrom S, Rimback G, Faxen A, Tollesson PO: Failure of epidural anesthesia to prevent postoperative ileus. ANESTHESIOLOGY 65:292-297, 1986.
Ahn H, Bronge A, Johansson K, Ygge H, Lindhagen J: Effect of continuous postoperative epidural analgesia on intestinal motility. Br J Surg 75:1176-1178, 1988.
Wattwil M, Thoren T, Hennerdal S, Garvil J-E: Epidural analgesia with bupivacaine reduces postoperative paralytic ileus after hysterectomy. Anesth Analg 68:353-358, 1989.
Gelman S, Feigenberg Z, Dintzman M, Levy E: Electroenterography after cholecystectomy: The role of high epidural analgesia. Arch Surg 112:580-583, 1977.
Bisgaard C, Mouridsen P, Dahl JB: Continuous lumbar epidural bupivacaine plus morphine versus epidural morphine after major abdominal surgery. Eur J Anesthesiol 7:219-225, 1990.
Thoren T, Sundberg A, Wattwil M, Garvill J-E, Jurgensen U: Effects of epidural bupivacaine and epidural morphine on bowel function and pain after hysterectomy. Acta Anaesthesiol Scand 33:181-185, 1989.
Thorn S-E, Wattwil M, Naslund I: Postoperative epidural morphine, but not epidural pubivacaine, delays gastric emptying on the first day after cholecystectomy. Reg Anesth 17:91-94, 1992.
Nimmo WS, Littlewood DG, Scott DB, Prescott LF: Gastric emptying following hysterectomy with extradural analgesia. Br J Anaesth 50:559-561, 1978.
Moiniche S, Bulow S, Hesselfeldt P, Hestboek A, Kehlet H: Convalescence and hospital stay after colonic surgery during balanced analgesia, enforced oral feeding and mobilization. Eur J Surg (in press).
Weissman C: The metabolic response to stress: An overview and update. ANESTHESIOLOGY 73:308-327, 1990.
Smiley RM, Pantuck CB, Morelli JJ, Chadburn A, Knowles DM: Alterations of the beta-adrenergic receptor system after thoracic and abdominal surgery. Anesth Analg 79:821-828, 1994.
Douglas RG, Shaw JH: Metabolic response to sepsis and trauma. Br J Surg 76:115-122, 1989.
Michie HR, Eberlein TJ, Spriggs DR, Monogue KR, Cerami A, Wilmore DW: Interleukin-2 initates metabolic responses associated with critical illness in humans. Ann Surg 208:493-503, 1988.
Michie HR, Wilmore DW: Sepsis, signals, and surgical sequelae (a hypothesis). Arch Surg 125:531-536, 1990.
Marano MA, Fong Y, Moldawer LL, Wei H, Calvano SE, Tracey KJ, Barie PS, Manogue K, Cerami A, Shires GT, Lowry SF: Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 170:32-38, 1990.
Ashburn MA, Lind GH, Stanley TH: Combined regional and general anesthesia: Is it really the answer? J Cardiothorac Anesth 4:48-57, 1990.
Weissman C, Hollinger I: Modifying systemic responses with anesthetic techniques. Anesthesiology Clinics of North America 6:221-235, 1988.
Giesecke K, Hamberger B, Jarnberg PO, Klingstedt C, Persson B: High- and low-dose fentanyl anaesthesia: Hormonal and metabolic responses during cholecystectomy. Br J Anaesth 61:575-582, 1988.
Rossano F, Tufano R, Cipollaro dLG, Servillo G, Baroni A, Tufano MA: Anesthetic agents induce human mononuclear leucocytes to release cytokines. Immunopharmacol Immunotoxicol 14:439-450, 1992.
Bent JM, Paterson JL, Mashiter K, Hall GM: Effects of high-dose fentanyl anaesthesia on the established metabolic and endocrine response to surgery. Anaesthesia 39:19-23, 1984.
Christensen P, Brandt MR, Rem J, Kehlet HK: Influence of extradural morphine on the adrenocortical and hyperglycemic response to surgery. Br J Anaesth 54:24-26, 1982.
Kehlet H: Epidural analgesia and the endocrine metabolic response to surgery: Update and perspectives. Acta Anaesthesiol Scand 28:125-127, 1984.
Kehlet H: Modification of responses to surgery by neural blockade: Clinical implications, Neural Blockade in Clinical Anesthesia and Management of Pain. Edited by Cousins MJ, Bridenbaugh PO, Philadelphia, JB Lippincott, 1988, pp 145-190.
Kehlet H: The stress response to surgery: Release mechanisms and the modifying effect of pain relief. Acta Chirurgica Scandinavica 550(suppl):22-28, 1988.
Engquist A, Brandt MR, Fernandes A, Kehlet H: The blocking effect of epidural analgesia on the adrenocortical and hyperglycemic response to surgery. Acta Anaesthesiol Scand 21:330-335, 1977.
Naito Y, Tamai S, Shingu K, Shindo K, Matsui T, Segawa H, Nakai Y, Mori K: Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery. ANESTHESIOLOGY 77:426-431, 1992.
Rutberg H, Hakanson E, Anderberg B, Jorfeldt L, Martensson J, Schildt B: Effects of the extradural administration of morphine, or bupivacaine, on the endocrine response to upper abdominal surgery. Br J Anaesth 56:223-238, 1984.
Jorgensen BC, Andersen HB, Engquist A: Influence of epidural morphine on postoperative pain, endocrine-metabolic, and renal responses to surgery: A controlled study. Acta Anaesthesiol Scand 26:63-68, 1982.
Tsuji H, Shirasaka C, Asoh T, Uchida I: Effects of epidural administration of local anaesthetics or morphine on postoperative nitrogen loss and catabolic hormones. Br J Surg 74:421-425, 1987.
Tsuji H, Asoh T, Takerchi Y: Attenuation of adrenocortical response to upper abdominal surgery with epidural blockade. Br J Surg 70:122-124, 1983.
Hjortso N-C, Christensen NJ, Andersen T, Kehlet H: Effects of the extradural administration of local anaesthetic agents and morphine on the urinary excretion of cortisol, catecholamines and nitrogen following abdominal surgery. Br J Anaesth 57:400-406, 1985.
Lund C, Hansen OB, Kehlet H, Mogensen T, Qvitzau S: Effects of etidocaine administered epidurally on changes in somatosensory evoked potentials after dermatomal stimulation. Reg Anesth 16:38-42, 1991.
Dahl JB, Rosenberg J, Kehlet H: Effect of thoracic epidural etidocaine 1.5% on somatosensory evoked potentials, cortisol and glucose during cholecystectomy. Acta Anaesthesiol Scand 36:378-382, 1992.
Stevens RA, Beardsley D, White JL, Kao T-C, Teague PJ, Spitzer L: Does the choice of local anesthetic affect the catecholamine response to stress during epidural anesthesia? ANESTHESIOLOGY 79:1219-1226, 1993.
Imura H, Fukata J, Mori T: Cytokines and endocrine function: An interaction between the immune and neuroendocrine system. J Clin Endocrinol Metab 73:111-117, 1991.
Naito Y, Fukata J, Tominaga T, Nakai Y, Tamai S, Mori K, Imura H: Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem Biophys Res Commun 155:1459-1463, 1988.
Naito Y, Fukata J, Masui Y, Hirai Y, Murakami N: Interleukin-1B analogues with markedly reduced pyrogenic activity can stimulate secretion of adrenocorticotropic hormone in rats. Biochem Biophys Res Commun 167:103-109, 1990.
Moller IW, Rem J, Brandt MR, Kehlet H: Effect of posttraumatic epidural analgesia on the cortisol and hyperglycemic response to surgery. Acta Anaesthesiol Scand 26:56-58, 1980.
Salomaki TE, Leppaluoto J, Laitinen JO, Vuolteenaho O, Nuutinen LS: Epidural versus intravenous fentanyl for reducing hormonal, metabolic, and physiologic responses after thoracotomy. ANESTHESIOLOGY 79:672-679, 1993.
Halter JB, Pflug AE, Porte D: Mechanism of catecholamine increases during surgical stress in man. J Clin Endocrinol Metab 45:936-944, 1977.
Bormann BV, Weidler B, Dennhardt R, Sturm G, Scheld HH, Hemplemann G: Influence of epidural fentanyl on stress-induced levels of vasopressin (ADH) after surgery. Anesth Analg 62:727-732, 1983.
Kehlet H: General vs. regional anesthesia, Principles and Practice of Anesthesiology. Edited by Rogers MC, Tinker JH, Covino BG, Longnecker DE. St. Louis, Mosby-Year Book, 1993, pp 1218-1234.
Carli F, Webster J, Pearson M, Pearson J, Bartlett S, Bannister P, Halliday D: Protein metabolism after abdominal surgery: Effect of 24-h extradural block with local anaesthetic. Br J Anaesth 67:729-734, 1991.
Vedrinne C, Vedrinne JM, Guiraud M, Patricot MC, Bouletreau P: Nitrogen-sparing effect of epidural administration of local anesthetics in colon surgery. Anesth Analg 69:354-359, 1989.
Moller IW, Dinesen K, Sondergard S, Knigge U, Kehlet H: Effect of patient-controlled analgesia on plasma catecholamine, cortisol, and glucose concentrations after cholecystectomy. Br J Anaesth 61:160-164, 1988.
Anand KJ, Hansen DD, Hickey PR: Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. ANESTHESIOLOGY 73:661-667, 1990.
Belcher PR, Drake HA, Hynd JW, Noble MI: Effects of trimetazidine on in vivo coronary arterial platelet thrombosis. Cardiovasc Drugs Ther 7:149-57, 1993.
Tans G, Rosing J, Thomassen MC, Heeb MJ, Zwaal RF, Griffin JH: Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 77:2641-2648, 1991.
Grant PJ: Hormonal regulation of the acute haemostatic response to stress. Blood Coagul Fibrinolysis 1:299-306, 1990.
Flinn WR, McDaniel MD, Yao JST, Fahey VA, Green D: Antithrombin III deficiency as a reflection of dynamic protein metabolism in patients undergoing vascular reconstruction. J Vasc Surg 1:888-895, 1984.
Salo M: Effects of anaesthesia and surgery on the immune response. Acta Anaesthesiol Scand 36:201-220, 1992.
Toft P, Svendsen P, Tonnesen E, Rasmussen JW, Christensen NJ: Redistribution of lymphocytes after major surgical stress. Acta Anaesthesiol Scand 37:245-249, 1993.
Davis JM, Albert JD, Tracy KJ, Calvano SE, Lowry SF, Shires GT, Yart RW: Increased neutrophil mobilization and decreased chemotaxis during cortisol and epinephrine infusions. J Trauma 31:725-732, 1991.
Lennard TWJ, Shenton BK, Borzotta A: The influence of surgical operations on components of the immune system. Br J Surg 72:771-776, 1985.
Hammer JH, Nielsen HJ, Moesgaard F, Kehlet H: Duration of postoperative immunosuppression assessed by repeated delayed type hypersensitivity skin tests. Eur Surg Res 24:133-137, 1992.
Scannell KA: Surgery and human immunodeficiency virus disease. J Acquir Immune Defic Syndr 2:43-53, 1989.
Meakins JL: Surgeons, surgery, and immunomodulation. Arch Surg 126:494-498, 1991.
Moss NM, Gough DB, Jordan AL: Temporal correlation of impaired immune response after thermal injury with susceptibility of infection in a murine model. Surgery 104:882-887, 1988.
Lundy J, Lovett EJI, Conran P: Halothane, surgery, immunosuppression and artificial pulmonary metastases. Cancer 41:827-830, 1978.
Pollock RE, Lotzova E, Stanford SD: Mechanism of surgical stress impairment of human perioperative natural killer cell cytotoxicity. Arch Surg 126:338-342, 1991.
Tanemura H, Sakata K, Kunieda T, Saji S, Yamamoto S, Takekoshi T: Influences of operative stress on cell-mediated immunity and on tumor metastasis and their prevention by non-specific immunotherapy: Experimental studies in rats. J Surg Oncol 21:189-195, 1982.
Eggermont AMM, Steller EP, Sugarbaker PH: Laparotomy enhances intraperitoneal tumor growth and abrogates the anti-tumor effects of interleukin-2 and lymphocyte activated killer cells. Surgery 102:71-78, 1987.
Kehlet H, Thomsen M, Kjaer M, Platz P: Postoperative depression of lymphocyte transformation response to microbial antigens. Br J Surg 64:890-893, 1977.
Markovic SN, Knight PR, Murasko DM: Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. ANESTHESIOLOGY 78:700-706, 1993.
Moore TC, Spruck CH, Leduc LE: Depression of lymphocyte traffic in sheep by anaesthesia and associated changes in efferent lymph PGE2 and antibody level. Immunology 63:139-143, 1988.
Salo M: Effect of anaesthesia and surgery on the number of and mitogen-induced transformation of T and B lymphocytes. Annals of Clinical Research 10:1-13, 1978.
Stevenson GW, Hall SC, Rudnick S, Seleny FL, Stevenson HC: The effect of anesthetic agents on the human immune response. ANESTHESIOLOGY 72:542-552, 1990.
Hole A: Pre- and postoperative monocyte and lymphocyte functions: Effects of sera from patients operated under general or epidural anaesthesia. Acta Anaesthesiol Scand 28:287-291, 1984.
Tonnesen E, Wahlgreen C: Influence of extradural and general anaesthesia on natural killer cell activity and lymphocyte subpopulations in patients undergoing hysterectomy. Br J Anaesth 60:500-507, 1988.
Hammer R, Dahlgren C, Stendahl O: Inhibition of human leukocyte metabolism and random mobility by local anaesthesia. Acta Anaesthesiol Scand 29:520-523, 1985.
Salo M: Effects of lignocaine and bupivacaine on immunoglobulin synthesis in vitro. Eur J Anaesthesiol 7:133-140, 1990.
Hole A, Unsgaard G: The effect of epidural and general anaesthesia on lymphocyte function during and after major orthopedic surgery. Acta Anaesthesiol Scand 27:135-141, 1983.
Rem J, Brandt MR, Kehlet H: Prevention of postoperative lymphopenia and granulocytosis by epidural analgesia. Lancet 1:283-284, 1980.
Eriksson AS, Sinclair R, Cassuto J, Thomsen P: Influence of lidocaine on leukocyte function in the surgical wound. ANESTHESIOLOGY 77:74-78, 1992.
Nakagawara M, Hirokata Y: Effects of anesthestics on superoxide releasing activity of human polymorphonuclear leukocytes. Masui 34:754-759, 1985.
Asko-Seljavaara S: Granulocyte kinetics in burns. J Burn Care Rehabil 8:492-495, 1987.
Rimback G, Cassuto J, Wallin G, Westlander G: Inhibition of peritonitis by amide local anesthetics. ANESTHESIOLOGY 69:881-886, 1988.
Cassuto J, Nellgard P, Stage L, Jonsson A: Amide local anesthetics reduce albumin extravasation in burn injuries. ANESTHESIOLOGY 72:302-307, 1990.
Radosevic-Stasic B, Udovic-Sirola M, Stojanov L, Ribaric L, Rukavina D: Growth of allogenic sarcoma in mice subjected to halothane anesthesia and/or surgical stress. Anesth Analg 69:570-574, 1989.
Tonnesen E, Brinklov M, Christensen NJ, Schmitz O: Natural killer cell activity in patients undergoing abdominal surgery: Relationship to the endocrine stress response. Acta Anaesthesiol Scand 28:654-660, 1984.
Tonnesen E, Brinklov M, Christensen NJ, Olesen AS, Madsen T: Natural killer cell activity and lymphocyte function during and after coronary artery bypass grafting in relationship to the endocrine stress response. ANESTHESIOLOGY 67:526-533, 1987.
Ader R, Felten D, Cohen N: Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol 30:561-602, 1990.
Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN, Gale RP: Stress increased metastatic spread of a mammary tumor in rats: Evidence for mediation by the immune system. Brain Behav Immun 5:193-205, 1991.
Herberman RB, Ortaldo JR: Natural killer cells: Their role in defense against disease. Science 214:24-30, 1981.
Parrott NR, Lennard TWJ, Taylor RMR, Proud G, Shenton BK, Johnston IDA: Effect of perioperative blood transfusion on recurrence of colorectal cancer. Br J Surg 73:970-973, 1986.
Beilin B, Martin FC, Shavit Y, Gale RP, Liebeskind JC: Supression of natural killer cell activity by high-dose narcotic anesthesia in rats. Brain Behav Immun 3:129-137, 1989.
Lundy J, Lovett EJHI, Conran P: Pulmonary metastases, a potential biologic consequence of anesthetic induced immunosuppression by thiopental. Surgery 82:254-256, 1977.
Chung F, Seyone C, Dyck B, Chung A, Ong D, Taylor A, Stone R: Age-related cognitive recovery after general anesthesia. Anesth Analg 71:217-224, 1990.
Berggren D, Gustafson Y, Eriksson B, Bucht G, Hansson L-I, Reiz S, Winblad B: Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 66:497-504, 1987.
Bedford P: Adverse cerebral effects of anaesthesia in old people. Lancet 2:259-263, 1955.
Riis J, Lomholt B, Haxholdt O, Kehlet H: Immediate and long term mental recovery from general versus epidural anesthesia in elderly patients. Acta Anaesthesiol Scand 27:44-49, 1983.
Muravchick S: Anesthesia for the elderly, Anesthesia. 3rd edition. Edited by Miller R. New York, Churchill Livingstone, 1990, pp 1969-1985.
Hole A, Terjesen T, Breivik H: Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anaesthesiol Scand 24:279-287, 1980.
Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, Katz N, Cook EF, Orav EJ, Lee TH: The relationship of postoperative delirium with psychoactive medications. JAMA 272:1518-1522, 1994.
Moller J, Svennild I, Johannessen N, Jensen P, Espersen K, Gravenstein J, Cooper J, Djernes M, Johansen S: Perioperative monitoring with pulse oximetry and late postoperative cognitive dysfunction. Br J Anaesth 71:340-347, 1993.
Ghoneim M, Hinrichs J, O'Hara M, Mehta M, Pathak D, Kurnar V, Clark C: Comparison of psychologic and cognitive functions after general or regional anesthesia. ANESTHESIOLOGY 69:507-515, 1988.
Asbjorn J, Jakobsen BW, Pilegarrd HK, Blom L, Ostergaard A, Brandt MR: Mental function in elderly men after surgery during epidural analgesia. Acta Anaesthesiol Scand 33:369-373, 1989.
Coniam SW: Accidental hypothermia. Anaesthesia 34:250-256, 1979.
Corneli HM: Accidental hypothermia. J Pediatr 120:671-679, 1992.
Frank SM, Beattie C, Christopherson R, Norris EJ, Rock P, Parker S, Kimball AJ: Epidural versus general anesthesia, ambient operating room temperature, and patient age as predictors of inadvertent hypothermia. ANESTHESIOLOGY 77:252-257, 1992.
Sessler DI, Sessler AM, Hudson S, Moayeri A: Heat loss during surgical skin preparation. ANESTHESIOLOGY 78:1055-1064, 1993.
Imrie MM, Hall GH: Body temperature and anaesthesia. Br J Anaesth 64:346-354, 1990.
Ozaki M, Kurz A, Sessler DI, Lenhardt R, Schroeder M, Moayeri A, Noyes K, Rotheneder E: Thermoregulatory thresholds during epidural and spinal anesthesia. ANESTHESIOLOGY 81:282-288, 1994.
Hynson JM, Sessler DI, Glosten B, McGuire J: Thermal balance and tremor patterns during epidural anesthesia. ANESTHESIOLOGY 74:680-690, 1991.
Joris J, Ozaki M, Sessler DI, Hardy AF, Lamy M, McGuire J, Blanchard D, Schroeder M, Moayeri A: Epidural anesthesia impairs both central and peripheral thermoregulatory control during general anesthesia. ANESTHESIOLOGY 80:268-277, 1994.
Camann WR, Hortvet LA, Hughes N, Bader AM, Datta S: Maternal temperature regulation during extradural analgesia for labour. Br J Anaesth 67:565-568, 1991.
Holdcroft A, Hall GM, Cooper GM: Redistribution of body heat during anesthesia: A comparison of halothane, fentanyl, and epidural anesthesia. Anaesthesia 34:758-764, 1979.
Jenkins J, Fox J, Sharwood-Smith G: Changes in body heat during transvesical prostatectomy: A comparison of general and epidural anesthesia. Anaesthesia 38:748-753, 1983.
Hendolin H, Lansimies E: Skin and central temperatures during continuous epidural analgesia and general anesthesia in patients subject to open prostatectomy. Annals of Clinical Research 14:181-186, 1982.
Frank SM, Shir Y, Raja SN, Fleisher LA, Beattie C: Core hypothermia and skin surface temperature gradients: Epidural versus general anesthesia and the effects of age. ANESTHESIOLOGY 80:502-508, 1994.
Just B, Trevien VED, Lienhart A: Prevention of intraoperative hypothermia by preoperative skin-surface warming. ANESTHESIOLOGY 79:214-218, 1993.
Hynson JM, Sessler DI, Moayeri A, McGuire J, Schroeder M: The effects of preinduction warming on temperature and blood pressure during propofol/nitrous oxide anesthesia. ANESTHESIOLOGY 79:219-228, 1993.
Giesbrecht GG, Ducharme MB, McGuire JP: Comparison of forced-air patient warming systems for perioperative use. ANESTHESIOLOGY 80:671-679, 1994.
Tanaka K, Watanabe R, Harada T, Dan K: Extensive application of epidural anesthesia and analgesia in a university hospital: Incidence of complications related to technique. Reg Anesth 18:34-38, 1993.
Stride PC, Cooper GM: Dural taps revisited: A 20 year survey from Birmingham Maternity Hospital. Anaesthesia 48:247-255, 1993.
Neal JM: Management of postdural puncture headache, Epidural and Spinal Analgesia and Anesthesia: Contemporary Issues. Anesthesiology Clinics of North America. Edited by Batra MS, Benumof JL. Philadelphia, WB Saunders, 1992, pp 163-178.
Kane RF: Neurodeficits following epidural or spinal anesthesia. Anesth Analg 60:150-161, 1981.
Schmidt A, Nolte H: Subdural and epidural hematomas following epidural anesthesia: A literature review. Anaesthesist 41:276-284, 1992.
Metzger G, Singbartl G: Spinal epidural hematoma following epidural anesthesia versus spontaneous spinal subdural hematoma: Two case reports. Acta Anaesthesiol Scand 35:105-107, 1991.
Schwander D, Bachmann F: Heparin and spinal or epidural anesthesia: Decision analysis. Ann Fr Anesth Reanim 10:284-296, 1991.
Wulf H, Striepling E: Postmortem findings after epidural anaesthesia. Anaesthesia 45:357-361, 1990.
Sage DJ: Epidurals, spinals and bleeding disorders in pregnancy: A review. Anaesth Intensive Care 18:319-326, 1990.
Jorgensen LN: Lumbar analgesia in patients receiving anticoagulation therapy: Pro et contra. Ugeskr Laeger 153:1491-1494, 1991.
Dickman CA, Shedd SA, Spetzler RF, Shetter AG, Sonntag VK: Spinal epidural hematoma associated with epidural anesthesia: Complications of systemic heparinization in patients receiving peripheral vascular thrombolytic therapy. ANESTHESIOLOGY 72:947-950, 1990.
Horlocker TT, Wedel DJ, Offord KP: Does preoperative antiplatelet therapy increase risk of hemorrhagic complications associated with regional anesthesia? Anesth Analg 70:631-634, 1990.
Horlocker TT, Wedel DJ: Anticoagulation, antiplatelet therapy, and neuraxis blockade, Epidural and Spinal Analgesia and Anesthesia: Contemporary Issues. Anesthesiology Clinics of North America. Edited by Batra MS, Benumof JL. Philadelphia, WB Saunders, 1992, pp 1-11.
Odoom JA, Sih IL: Epidural analgesia and anticoagulant therapy. Anaesthesia 38:254-259, 1983.
Rao TK, El-Etr AA: Anticoagulation following placement of epidural and subarachnoid catheters. ANESTHESIOLOGY 55:618-620, 1981.
Wille JP, Jorgensen LN, Rasmussen LS: Lumbar regional anaesthesia and prophylactic anticoagulant therapy: Is the combination safe? Anaesthesia 46:623-627, 1991.
Bergqvist D, Linblad B, Matzsch T: Low molecular weight heparin for thromboprophylaxis and epidural/spinal anesthesia: Is there a risk? Acta Anaesthesiol Scand 36:605-609, 1992.
Liem TH, Booij LH, Hasenbos MA, Gielen MJ: Coronary artery bypass grafting using two different anesthetic techniques: I. Hemodynamic results. J Cardiothorac Vasc Anesth 6:148-155, 1992.
Onishchuk JL, Carlsson C: Epidural hematoma associated with epidural anesthesia: Complications of anticoagulant therapy. ANESTHESIOLOGY 77:1221-1223, 1992.
Lind SE: The bleeding time does not predict surgical bleeding. Blood 77:2547-2552, 1991.
Aster RH: 'Gestational thrombocytopenia': A plea for conservative management. N Engl J Med 323:264-266, 1990.
Ramanathan J, Sibai BM, Vu T, Chauhan D: Correlation between bleeding times and platelet counts in women with preeclampsia undergoing cesarean section. ANESTHESIOLOGY 71:188-191, 1989.
Stevens DS: Epidural hematoma: Was the catheter removed during complete anticoagulation? Anesth Analg 75:863-864, 1992.
Sowter MC, Burgess NA, Woodsford PV, Lewis MH: Delayed presentation of an extradural abscess complicating thoracic extradural analgesia. Br J Anaesth 68:103-105, 1992.
Danner RL, Hartman BJ: Update on spinal epidural abscess: 35 cases and review of the literature. Review of Infectious Disease 9:265-274, 1987.
Nay PG, Milaszkiewicz R, Jothilingam S: Extradural air as a cause of paraplegia following lumbar analgesia. Anaesthesia 48:402-404, 1993.
Richardson J, Bedder M: Transient anterior spinal cord syndrome with continuous postoperative epidural analgesia. ANESTHESIOLOGY 72:764-766, 1990.
Scherer R, Schmutzler M, Giebler R, Erhard J, Stocker L, Kox WJ: Complications related to thoracic epidural analgesia: A prospective study in 1071 surgical patients. Acta Anaesthesiol Scand 37:370-374, 1993.
Callesen T, Lund C: Hemodynamic aspects of thoracic epidural analgesia. Ugeskr Laeger 155:149-154, 1993.
Cousins MJ, Bromage PR: Epidural neural blockade, Neural Blockade in Clinical Anesthesia and Management of Pain. Edited by Cousins MJ, Bridenbaugh PO. Philadelphia, JB Lippincott, 1988, pp 253-360.
Tanaka K, Harada T, Dan K: Low-dose thoracic epidural anesthesia induces discrete thoracic anesthesia without reduction in cardiac output. Reg Anesth 16:318-321, 1991.
Albright GA: Cardiac arrest following regional anesthesia with etidocaine and bupivacaine. ANESTHESIOLOGY 51:285-287, 1979.
Russell IF, 1982: Intrathecal bupivacaine for cesarean (letter). Anaesthesia 37:346-347, 1982.
Moore DS, Batra MS: The components of an effective test dose prior to epidural block. ANESTHESIOLOGY 55:693-696, 1981.
Van Zundert A, Vaes L, Soetens M, De Vel M, Van Der Aa P, Van Der Donck A, Meeuwis H, De Wolf A: Every dose given in epidural analgesia for vaginal delivery can be a test dose. ANESTHESIOLOGY 67:436-440, 1987.
Kim YI: Massive spinal block with hemicranial palsy after a 'test dose' for extradural analgesia. ANESTHESIOLOGY 43:370-371, 1975.
Conacher ID, Paers MI, Jacobsen L, Philips PD, Heaviside DW: Epidural analgesia following thoracic surgery. Anaesthesia 38:546-551, 1983.
Punt CD, van Neer PAFA, de Lange S: Pressure sores as a possible complication of epidural analgesia. Anesth Analg 73:657-659, 1991.
Cohen S, Amar D, Pantuck CB, Pantuck EJ, Weissman AB: Adverse effects of epidural 0.03% bupivacaine during analgesia after cesarean section. Anesth Analg 75:753-756, 1992.
Cohen S, Amar D, Pantuck CB, Pantuck EJ, Weissman AM, Landa S, Singer N: Epidural patient-controlled analgesia after cesarean section: Buprenorphine-0.015% bupivacaine with epinephrine versus fentanyl-0.015% bupivacaine with and without epinephrine. Anesth Analg 74:226-230, 1992.
Parker RK, Sawaki Y, White PF: Epidural patient-controlled analgesia: Influence of bupivacaine and hydromorphone basal infusion on pain control after cesarean delivery. Anesth Analg 75:740-746, 1992.
Hopf H-B, Weibach B, Peters J: High thoracic segmental epidural anesthesia diminishes sympathetic outflow to the legs, despite restriction of sensory blockade to the upper thorax. ANESTHESIOLOGY 73:882-889, 1990.
Moiniche S, Hjortso N-C, Blemmer T, Dahl JB, Kehlet H: Blood pressure and heart rate during orthostatic stress and walking with continuous postoperative thoracic epidural bupivacaine/morphine. Acta Anaesthesiol Scand 37:65-69, 1993.
Wattwil M, Sundberg A, Arvill A, Lennquist C: Circulatory changes during high thoracic epidural anesthesia: Influence of sympathetic block and systemic effect of the local anesthetic. Acta Anaesthesiol Scand 29:849-855, 1985.
Bailey PL, Rhondeau S, Schafer PG, Lu JK, Timmins BS, Foster W, Pace NL, Stanley TH: Dose-response pharmacology of intrathecal morphine in human volunteers. ANESTHESIOLOGY 79:49-59, 1993.
Morgan M: The rational use of intrathecal and extradural opioids. Br J Anaesth 63:165-188, 1989.
Ready LB, Loper KA, Nessly M, Wild L: Postoperative epidural morphine is safe on surgical wards. ANESTHESIOLOGY 75:452-456, 1991.
Ready LB: Intraspinal opioid analgesia in the perioperative period, Epidural and Spinal Analgesia and Anesthesia: Contemporary Issues. Anesthesiology Clinics of North America. Edited by Batra MS, Benumof JL. Philadelphia, WB Saunders, 1992, pp 145-159.
Cross DA, Hunt JB: Feasibility of epidural morphine for postoperative analgesia in a small community hospital. Anesth Analg 72:765-768, 1991.
Cousins MJ, Mather LE: Intrathecal and epidural administration of opioids. ANESTHESIOLOGY 61:276-310, 1984.
White MJ, Berghausen EJ, Dumont SW, Tsueda K, Schroeder JA, Vogel RL, Heine MF, Huang KC: Side effects during continuous epidural infusion of morphine and fentanyl. Can J Anaesth 39:576-582, 1992.
Hansen BJ, Rosenberg J, Andersen JT: Urinary retention in connection with postoperative pain treatment with epidural opioids. Ugeskr Laeger 152:1574-1577, 1990.
Chaplan SR, Duncan SR, Brodsky JB, Brose WG: Morphine and hydromorphone epidural analgesia. ANESTHESIOLOGY 77:1090-1094, 1992.
Borgeat A, Wilder-Smith OHG, Saiah M, Rifat K: Subhypnotic doses of propofol relieve pruritis induced by epidural and intrathecal morphine. ANESTHESIOLOGY 76:510-512, 1992.
Rawal N, Mollefors K, Axelsson K, Lingardh G, Widman B: An experimental study of urodynamic effects of epidural morphine and of naloxone reversal. Anesth Analg 62:641-647, 1983.
Liu S, Angel J, Owens BD, Carpenter RL: 0.05% bupivacaine is an optimal concentration for use with fentanyl for postthoracotomy analgesia (abstract). ANESTHESIOLOGY 81:A975, 1994.
de Leon-Cassasola OA, Parker B, Lema MJ, Harrison P, Massey J: Postoperative epidural bupivacaine-morphine therapy. ANESTHESIOLOGY 81:368-375, 1994.
Cullen ML, Staren ED, El-Ganzouri A, Logas WG, Ivankovich AD, Economou SG: Continuous epidural infusion for analgesia after major abdominal operations: A randomized, prospective, double-blind study. Surgery 98:718-728, 1985.
Wetchler BV: Economic impact of anesthesia decision making: They pay the money, we make the choice (suppl). J Clin Anesth 4:20S-24S, 1992.
Matloff JM: The practice of medicine in the year 2010. Ann Thorac Surg 55:1311-1325, 1993.
Winickoff RN, Fischer MA, August BJ: Appropriateness of short-stay admissions for procedures in six Veterans Affairs hospitals. QRB: Quality Review Bulletin 17:386-391, 1991.
Johnstone RE, Martinec CL: Costs of anesthesia. Anesth Analg 76:840-848, 1993.
Bulpitt CJ, Fletcher AE: Measuring costs and financial benefits in randomized controlled trials. Am Heart J 119:766-770, 1990.
Johnstone RE, Jozefczyk KG: Costs of anesthetic drugs: Experiences with a cost education trial. Anesth Analg 78:766-771, 1994.
Ready LB, Oden R, Chadwick HS: Development of an anesthesiology-based postoperative pain management service. ANESTHESIOLOGY 68:100-106, 1988.
Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, Klerman GL, Williams GH: The effects of antihypertensive therapy on the quality of life. N Engl J Med 314:1657-1664, 1986.
Coast J: Reprocessing data to form QALYs. BMJ 305:87-90, 1992.
Negre I, Gueneron JP, Jamali SJ, Monin S, Ecoffey C: Preoperative analgesia with epidural morphine. Anesth Analg 79:298-302, 1994.
Detsky A, Naglie I: A clinician's guide to cost-effectiveness analysis. Ann Intern Med 113:147-154, 1990.