How acute pain management affects outcome

How Acute Pain Management Affects Outcome James M. Moore, MD and Spencer S. Liu, MD

Many factors can contribute to patient outcome after surgery. The method of acute pain relief may be an important factor in postoperative outcome. This article discusses the pathophysiology of pain and highlights the effects of different modes of analgesia on patient outcome variables. Epidural anesthesia and analgesia can decrease the risk of vaso-occlusive complications after lower extremity vascular surgery. Currently, there is inconclusive evidence that mode of acute pain relief affects clinical outcome after thoracic surgery. After abdominal operations, both epidural analgesia and intravenous patient-controlled analgesia may reduce the incidence of pulmonary complications in selected patients, and epidural analgesia can hasten the return of gastrointestinal motility and potentially shorten the hospital stay. For patients undergoing hip or knee replacement, spinal and epidural techniques can improve clinical outcome by preventing the development of thromboembolic complications. Copyright 9 1997 by W.B. Saunders Company

n an evolutionary sense, pain and its physiologic sequelae may better enable humans to interact with their environment. However, in most clinical settings pain has deleterious effects and can often impede healing. The management of acute pain has as its goals both the alleviation of suffering and the attenuation of harmful consequences of pain. If these goals were achieved, clinical outcome might improve. Unfortunately, difficulties exist in relating acute pain management to outcome. In patients undergoing surgery, many factors that contribute to postoperative morbidity are independent of anesthetic and analgesic techniques and can be difficult to control in a prospective study. The purpose of this article is to summarize the injurious effects of acute pain on various organ systems, to review what is known about the role that acute pain management can play in lessening those effects, and to relate these benefits to patient outcome after surgery.

I

Pathophysiology of Pain Cardiovascular Effects Cardiovascular disease is a major contributor to postoperative morbidity, and cardiac morbidity is the most common cause of death after surgical anesthesia. 1 Activation of the sympathetic nervous system and the release of catecholamines because of pain may have harmful effects on myocardial oxygen balance. Increased heart rate, blood pressure, and contractility resulting from sympathetic efflux and catecholamines can increase From the Department of Anesthesiology, Virginia Mason Medical Center, Seattle, WA. Address reprint requests to James M. Moore, MD, Department of Anesthesiology, Virginia Mason Medica~Center, 1100 Ninth Avenue, P.O. Box 900, Mail Stop B2-AN, Seattle, WA 98111. Copyright 9 1997 by W.B. Saunders Company 1084-208X/97/0102-000255.00/0 64

myocardial oxygen demand. However, most episodes of perioperative myocardial ischemia occur without major hemodynamic change, with the exception of small increases in heart rate. 2 Thus, changes in perioperative myocardial oxygen supply may be the more important component of perioperative ischemia 3 (Fig 1). Myocardial oxygen supply can be decreased by several mechanisms during the perioperative period. Increased sympathetic activity accompanying pain and the stress response is associated with direct coronary vasoconstriction, 4,5 paradoxical constriction in response to vasodilators, 6 and poststenotic vasoconstriction. 7 These changes may result in ST-segment changes, angina, dysrhythmias, and increases in myocardial infarction size. 8-1z In addition, it has been postulated that sympathetic activation and the stress response can lead to a hypercoagulable state. 13 The development of coronary thrombosis may further compromise myocardial oxygen supply and promote myocardial ischemia.

Coagulative Effects The postoperative development of hypercoagulability seems to be at least partly caused by pain and the stress response. 13-~5 Changes that occur in the coagulation cascade after surgery include an increase in available coagulation factors, 16 enhanced platelet activity, 17 lesser concentrations of coagulation inhibitors, ~8 and decreased fibrinolysis) 9,2~This postoperative propensity toward coagulation is associated with vasoocclusive and thromboembolic morbidity. 21-24 In addition, prolonged bedrest because of pain is also associated with more frequent deep venous thrombosis.

Pulmonary Effects Incisions of the abdomen and thorax can lead to postoperative pulmonary complications. 25-27Pulmonary dysfunction is caused by pain, 26 abnormal diaphragmatic function, 28 and lower intercostal muscle tone with higher abdominal tone during expiration 29 (Fig 2). Lung dysfunction extends from the time of incision until 7 to 14 days postoperatively)~ Functional residual capacity begins decreasing at about 16 hours postoperatively, reaches a minimum at 24 to 48 hours, and usually returns to normal within a week. 25,26,3~ The resultant atelectasis and ventilation-perfusion mismatching can lead to hypoxemia, pneumonia, and other pulmonary complications, zS,z6,3z,33 Among surgical patients, higher postoperative risk of pulmonary complications occurs with preexisting pulmonary disease, 27,34,35upper abdominal or thoracic incisions, 36 advanced age, 37 obesity,38 and severe pain. 39

Gastrointestinal Effects Postoperative pain has deleterious effects on the gastrointestinal system. Pain can contribute to the postoperative develop-

Techniquesin RegionalAnesthesiaand Pain Management, Vol 1, No 2 (April), 1997: pp 64-71

MYOCARDIAL ISCHEMIA

CONSTRICTION OF

CORONARY STENOSIS

SYMPATHETIC STIMULATION

Fig 1. Effects of sympathetic stimulation on myocardial blood flow. 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. Reprinted with permission Liu SS, et al. Anesthesiology, Lippincott-Raven Publishers. 3

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ment of nausea and vomiting, which is a major factor in prolonged recovery room stays and in unplanned postoperative admissions. 4~ One of the most frequent complications after surgery is postoperative ileus, which may result in part from pain-stimulated reflex arcs. 41 Ileus may lengthen hospital stay and delay enteral feeding, whereas early enteral feeding has

been associated with a decreased stress response, better wound healing, and lesser incidence of postoperative septic complications. 42-45 Surgical stress can increase sympathetic tone, which slows gastrointestinal motility,46,47 and analgesic techniques that reduce sympathetic output may lessen the incidence and severity of postoperative ileus (Fig 3).

I•NCISION EFFE~CT,,,~ /

EXPIRATORY INTERCOSTAL AN D ABDOMINAL MUSCLE TONE ,~ DIAPHRAGMATIC FU NCTION

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Fig 2. Proposed mechanisms of postoperative pulmonary complications. Reprinted with permission Liu SS, et al. Anesthesiology, Lippincott-Raven Publishers. 3

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POSTOPERATIVE ANALGESIA AND OUTCOME

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INFERIOR MESENTERIC GANGLION

Clinical Effects of Analgesia All of the previously mentioned adverse effects of pain represent theoretical avenues for assessing a beneficial effect of analgesia on postoperative pathophysiology. In reviewing the current literature, it is useful to distinguish what might be called intermediate outcome variables from actual differences in clinical outcome after surgery. For instance, an analgesic regimen that improves postoperative pulmonary function may theoretically benefit patients, but if that regimen decreased the incidence of pneumonia, then it made a clinical difference in outcome. Thus, discussion throughout this article will include both intermediate outcome variables, (eg, pulmonary function tests, arterial blood gas measurements) and clinical outcome variables (eg, the incidence of pneumonia or myocardial infarction) in nonobstetric, adult patients.

Vascular Procedures Vascular surgery often involves patients who are at high risk for perioperative cardiac and thrombotic complications. Most analgesic studies examining cardiac outcomes in vascular surgery patients have focused on the use of either systemic opioids or epidural analgesic regimens. Use of intravenous patient-controlled analgesia (IV PCA) has been shown to provide superior analgesia over intermittent intramuscular opioid. 48 However, the use of IV PCA does not attenuate postoperative catecholamine release or activation of the sympathetic nervous system and probably offers little theoretical reason for attenuation of cardiac morbidity. 48 U: _~of continuous infusions of the potent opioid sufentanil for postoperative analgesia in coronary artery bypass patients can attenuate severity of myocardial ischemia but requires concomitant mechanical ventilation. 49 Therefore, the ability of systemic opioid regimens to attenuate postoperative cardiac morbidity in a practical manner seems doubtful. In contrast, epidural 66

analgesia with local anesthetics or opioids has been shown to favorably affect many intermediate variables of cardiac morbidity. Administration of thoracic epidural local anesthetics dilates stenotic coronary arteries, 5~ improves left ventricular function during stress in patients with atherosclerotic disease, 51 and successfully treats angina in patients with inoperable coronary artery disease. 52 Administration of epidural morphine has been shown to decrease postoperative hypertension 53 and to decrease frequency of postoperative myocardial ischemia when compared with IV PCA morphine. 54 Thus, epidural analgesia has altered intermediate variables affecting postoperative cardiac morbidity positively. There is some evidence that intraoperative epidural anesthesia with postoperative epidural analgesia may improve clinical cardiac outcomes as well. Tuman et al randomized patients undergoing lower extremity and aortic revascularization to general anesthesia with postoperative systemic opioids versus epidural anesthesia and analgesia. 21 They found a decrease in the frequency of cardiovascular complications in the epidural group, although many of these were dysrhythmias of unclear clinical importance. In the epidural group they also showed a decrease in postoperative vascular occlusion and a prevention of postoperative hypercoagulability (Table 1). Yeager et al randomized patients undergoing vascular surgery along with other high-risk surgical groups, to receive either general anesthesia with postoperative systemic opioid or epidural anesthesia and analgesia. 55 The epidural group also had a reduced cardiac morbidity, a shorter duration of mechanical ventilation, and a much lower hospital cost when compared to the group receiving general anesthesia with systemic opioid analgesia (Table 2). However, these patients were not exclusively a vascular surgery population, and therefore results may not be entirely generalizable to vascular surgical procedures. The importance of intraoperative versus postoperative epidural analgesia in vascular surgery may be inferred by examining MOORE AND LIU

TABLE 1. Postoperative Complications from Prospective, Randomized Comparison of Postoperative Epidural Analgesia Versus Systemic Opioid Analgesia after General Anesthesia for Lower Extremity Revascularization General Plus General Plus Systemic Epidural (n = 4O) (n = 40) P Mortality Cardiovascular complications Myocardial infarction Congestive heart failure Ventricular tachydysrhythmia Supraventricular tachydysrhythmia Hypertensive crisis Angina Heart block Respiratory complications Prolonged mechanical ventilation Reintubation Pulmonary infection Vascular occlusions Vascular graft failure Deep venous thrombosis

0 11 3 4 4 7 1 1 2 5 5 1 4 9 8 1

0 4 0 2 0 3 0 1 0 1 1 0 0 1 1 0

.045 .077 .409 .040 .176 .314 1.00 .152 .089 .089 .314 .040 .007 .013 .314

Data from Tuman et al.21

studies that looked only at intraoperative epidural anesthesia. Bode et al studied patients having lower extremity peripheral vascular surgery and found no difference in cardiac morbidity between epidural, spinal, or general anesthesia. 56 Baron et al studied patients having abdominal aortic surgery and did not demonstrate lesser morbidity with the addition of intraoperative epidural anesthesia to a standardized general anesthesia. 57 In both these studies, postoperative analgesic regimens were uncontrolled. Together, these studies suggest that intraoperative epidural regimens probably do not protect against significant cardiac morbidity during vascular surgery.58 The use of postoperative epidural analgesia may favorably affect cardiac outcome after vascular surgery but has not been fully addressed. One type of pathologic condition that epidural anesthesia and analgesia can affect is postoperative thrombosis. Tuman et al demonstrated thromboelastographic evidence of attenuation of postoperative hypercoagulability with postoperative epidural bupivacaine and fentanyl. The basic mechanism of normalized coagulation with epidural anesthesia and analgesia may involve the attenuation of the levels of plasminogen activator inhibitor-1 and other stress response mediators. 13,59 With respect to clinical differences in thrombosis, Tuman et al's study not only demonstrated thromboelastographic evidence of attenuation of coagulation but improved vascular TABLE 2. Results of Prospective, Randomized Comparison of GeneraI-Epidural Anesthesia Plus Epidural Analgesia Versus General Anesthesia Plus Systemic Opioid Analgesia in High-Risk Patients

Mortality Cardiovascular complications Major infections Duration of mechanical ventilation (h) Hospital cost ($) Physician cost ($)

General (n = 28)

Epidural (n = 25)

0 4 2

4 13 10

.04 .007 .007

7.1 +_ 10.1 11,218 -+ 5,738 3,801 +_ 1,342

81.8 _+ 186.1 20,380 _+ 20,343 5,134 _+ 2,939

.005 .02 .05

Data from Yeager et al.55 POSTOPERATIVE ANALGESIA AND OUTCOME

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graft survival as well. 21 Christopherson et al studied patients undergoing lower extremity vascular repair and found that patients receiving intraoperative epidural anesthesia and postoperative epidural fentanyl had a lesser incidence of reoperation for regrafting or embolectomy compared with general anesthesia with intravenous opioid analgesia. 22 This study's demonstration that most reoperations occurred soon after surgery and the use of epidural fentanyl alone seem to indicate that the intraoperative regimen may be more important than the postoperative analgesic regimen, at least for peripheral vascular surgery. Epidural anesthesia does not appear to affect cardiac morbidity after vascular surgery. Postoperative epidural analgesia may decrease cardiac morbidity, but beneficial effects have not been clearly shown, although the two studies discussed earlier that showed evidence of fewer cardiac complications used postoperative epidural analgesia. Epidural anesthetic and analgesic techniques improve postoperative outcome after lower extremity peripheral vascular surgery by reducing the chance of reoperation for vascular occlusion. In contrast to cardiac morbidity, thromboembolic morbidity appears to be primarily affected by intraoperative epidural anesthesia.

Thoracic Procedures The pain produced by thoracotomy incisions has a major impact on the development of postoperative pulmonary complications, 6~ so pain relief after thoracotomy should present a significant opportunity to affect pulmonary outcome. Popular analgesic options in postthoracotomy patients include intermittent intramuscular opioid administration, patient-controlled intravenous opioids, epidural analgesia, intercostal nerve blockade, and interpleural analgesia. Traditional analgesia with systemic opioids, often given intramuscularly, results in unpredictable pain control and significant detriment to pulmonary function. 61-63 IV PCA seems to convey no major benefit to postoperative pulmonary function, but it has been associated with shorter hospital stay in one study when compared with intramuscular opioid. 64 Although this finding is intriguing, interpretation of this study is difficult because of a lack of double blinding and control of postoperative recovery. Comparisons of epidural opioid analgesia to intravenous opioid infusion have inconsistently observed improved pulmonary function with epidural analgesia. 65-68 The improvements cited include reduced hypercarbia 65 and less decrease in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow.66 Diaphragmatic dysfunction is a component of a postoperative pulmonary pathologic condition that results from a reflex inhibition of phrenic nerve activity. 2s Pain relief per se does not affect diaphragmatic dysfunction, but administration of epidural local anesthetic does attenuate this dysfunction2s and can decrease postoperative carbon dioxide retention. 69 The addition of local anesthetic to an epidural regimen may thus confer additional benefit over opioid alone. However, a clear benefit of epidural analgesia to clinical outcome after thoracotomy has not been shown. Intercostal blockade can be performed either by targeting several individual nerves by separate needle placements or by insertion of a single intercostal catheter to produce spread to multiple dermatomes. A few studies have observed short-term 67

benefits in analgesia 7~and respiratory function 71 with intercostal analgesia versus systemic opioid after thoracotomy. Prolonged intercostal blockade by cryoanalgesia may provide better pain relief than intercostal local anesthetic block, 72 but cryoanalgesia may produce a long-term neuralgia in some patients. 6~ No benefit in clinical outcome has been shown for intercostal blockade with either method. Another technique for pain relief after thoracotomy is interpleural analgesia. Studies of its use have yielded mixed results. 73,74 There is presently only a modicum of evidence to suggest an improvement in postoperative pulmonary function with the use of interpleural analgesia, 75 but it may provide significant pain relief and reduce the need for systemic opioid. 76 No evidence points to improved clinical outcome with interpleural analgesia. For postthoracotomy pain, substantial evidence exists that epidural analgesia can improve intermediate outcome variables, whereas inconclusive results have been observed with IV PCA, intercostal, and interpleural analgesia. However, better clinical outcome with any analgesic regimen has not been proven.

Abdominal Procedures After abdominal surgery, IV PCA may provide superior analgesia compared to intermittent systemic opioid 77 but may or may not lessen demands on nursing staff. 7s Patients undergoing abdominal operations commonly suffer pulmonary as well as gastrointestinal impairment. After hysterectomy, the use of IV PCA results in a quicker recovery of minute ventilation when compared with intramuscular morphine and leads to earlier tolerance of a solid diet and earlier ambulation. 79 Aside from these intermediate outcome benefits after hysterectomy, IV PCA may also affect clinical outcome by shortening the time to hospital discharge. 79 Epidural analgesia with local anesthetic can improve postoperative pulmonary function over the use of systemic opioids. 31'8~ Improvements cited include a higher Pa02, vital capacity,s2 and greater peak expiratory flow. s3 The use of epidural opioid alone has also been shown to improve pulmonary function, s4,s5 With respect to clinical outcome, epidural analgesia with local anesthetic can reduce the incidence of pulmonary complications in obese patients undergoing gastroplasty s6 and patients having colorectal surgery. 87 However, not all studies of epidural analgesia show a lower rate of pulmonary complications, s~ Thus, epidural analgesia probably improves pulmonary outcome after abdominal surgery but only in selected patients. Another common complication after abdominal surgery is postoperative ileus. Administration of local anesthetic (systemically or epidurally) can elicit a more rapid recovery of colonic motility after abdominal surgery, as-9~Although quicker recovery of intestinal motility might be a significant intermediate outcome, a shortened hospital stay and reduced cost of care would be important clinical outcomes, kiu et al studied patients undergoing partial colectomy with epidural morphine or bupivacaine, or a combination of both, and compared them to IV patient-controlled morphine. The patients who received either bupivacaine-containing epidural regimen had quicker recovery of gastrointestinal function and more quickly fulfilled discharge criteria 9~ (Table 3). Other studies documenting quicker gastrointestinal recovery have not shown an overall 68

T A B L E 3. Recovery of Gastrointestinal Function and Time Until Hospital Discharge After Partial Colectomy EPID MORPH + BUP Time until first flatus (h) Time until discharge criteria fulfilled (h) Time until actual hospital discharge (h)

EPID MORPH

EPID BUP

IV PCA

43 +_ 4* 67 +_ 8*

71 +_ 4 102 _+ 13

40 +_ 2* 62 -+ 5*

81 _+ 3 96 + 7

199 _+ 71 (96 _+ 12t)

130 _+ 14

101 _+ 11

122 _+ 9

Note: Values are mean -+ standard error. *Different from groups EPID MORPH and IV PCA (P < 0.005). 1"Value after exclusion of incorrectly enrolled subjects. After exclusion, groups EPID MORPH and EPID MORPH + BUP are different from groups EPID MORPH and IV PCA(P < .04). Data from Liu et al. 9~

decrease in hospital stay, but neither did they include controlled measures to shorten postoperative ileus, such as early enteral feeding91 and early removal of nasogastric tubes. 92 Intercostal analgesia has also been used after abdominal surgery: 93'94 Intercostal blockade may improve pulmonary function 94 but does so without affecting serious pulmonary complications. 95 After flank incisions, the use of intercostal blocks may facilitate earlier ambulation and a quicker return to a regular diet than intramuscular opioid, 96 but evidence for a shortened hospital stay is sparse. 97 Interpleural analgesia has also been used for postoperative abdominal pain. Some studies show a lessening of postoperative pulmonary dysfunction with interpleural analgesia, 98 but whether this leads to an overall decrease in pulmonary complications remains unclear. Compared with constant 1V opioid infusion, interpleural analgesia may prevent the decrease in P02 and the increase in PCO299 and may decrease time to passing flatus and unaided mobilization, but no better clinical outcome has been proven with interpleural analgesia. For abdominal surgery, both epidural analgesia and IV PCA may reduce the risk for postoperative pulmonary complications in selected patients. After abdominal surgery, epidural analgesia with local anesthetic can speed the return of gastrointestinal motility and may thus shorten the duration of hospital stay.

Orthopedic Procedures Because of immobility and postoperative hypercoagulability, patients having total hip replacement seem to be at high risk for thromboembolic events. In a comparison of general anesthesia with intramuscular opioid analgesia, epidural anesthesia followed by analgesia with bupivacaine and epinephrine reduced the incidence of deep thigh vein thrombosis, calf vein thrombosis, and pulmonary thromboembolism. 24,1~176 Similar reductions in thromboembolic complications were observed in other studies 1~ and after knee arthroplasty 1~ and open prostatectomy. 104 As with vascular patients, it seems that in hip replacement there is an important effect from intraoperative neuraxial blockade, because a meta-analysis of both spinal and epidural anesthesia studies showed a significant reduction in deep vein thrombosis when compared with general anesthesia. 105For hip replacement, decreased blood loss is another potential benefit of intraoperative epidural analgesia with hypotension. 1~176 Another orthopedic procedure in which analgesia may make a difference in clinical outcome is lower extremity amputation. MOORE AND LIU

This procedure can result in a high incidence of chronic phantom limb pain, 1~ whose prevention is an important clinical goal. There is preliminary evidence that epidural analgesia can decrease the incidence of phantom limb pain postoperatively, but the epidural infusion may have to be started up to 3 days before the operation. 1~ Peripheral nerve sheath analgesia after lower extremity amputation may have a role in preventing phantom pain as well, 11~but neither of these techniques has been fully explored in a large, randomized, controlled study.11 For orthopedic patients, spinal and epidural anesthetic and analgesic methods can decrease thromboembolic complications in hip or knee replacement surgery, and hypotensive epidural anesthesia can decrease blood loss during hip replacement. Other outcome benefits have yet to be elucidated, although prevention of phantom limb pain after amputation is an area open to further research.

Conclusion Postoperative pain can have detrimental effects on the cardiovascular, pulmonary, gastrointestinal, and coagulation systems leading to postoperative morbidity. On balance, epidural analgesia seems the most promising technique to improve the postoperative course, as many intermediate outcome variables are favorably affected. Unfortunately, there is less evidence of improvement in true clinical outcome after thoracic and abdominal procedures. Patients undergoing vascular and orthopedic surgery may have fewer thromboembolic complications with epidural anesthesia and analgesia. However, the contribution of intraoperative neuraxial blockade to thromboembolic outcome may be more important in vascular and orthopedic procedures than the postoperative analgesic regimen. A fundamental difficulty in assessing effects of analgesic techniques on clinical outcome is that improvement in one or even several experimental variables with a certain analgesic regimen may not necessarily demonstrate a clear difference in clinical outcome unless all aspects of recovery are controlled and large numbers of patients are enrolled. Future studies should focus on testing for clinical outcome differences in large patient series with careful control of all important postoperative factors. It is possible that studies of greater power may show differences in clinical outcome not yet evident in the current literature.

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