Management of Postoperative Pain: Influence of Anesthetic and Analgesic Choice

Subspecialty Clinics: Anesthesiology Management of Postoperative Pain: Influence of Anesthetic and Analgesic Choice DAVID

L.

BROWN, M.D., AND DAVID

C. MACKEY, M.D.

Improved control of postoperative pain is being increasingly scrutinized yet concomitantly demanded by patients, physicians, and even the federal government. Our ever-increasing subspecialization in medicine has compartmentalized much of perioperative care and has created substantial difficulty for physicians in understanding the overall influence of other physicians' perioperative decisions, including control of pain. Clearly, intraoperative anesthetic management can affect patients' pain and perioperative course remote from the surgical procedure through modulation of analgesic and perioperative stress responses. Additionally, outcome studies show that provision of improved analgesia and minimization of the perioperative stress response enhance clinical outcome in both low- and high-risk patients. This article highlights new information on how anesthetic and analgesic management influences perioperative pain and decreases the incidence of complications in surgical patients.

Management of postoperative pain is gaining importance for patients, physicians, and the government. The Joint Commission on Accreditation of Healthcare Organizations has deemed that effective management of patients' pain is necessary for hospital accreditation, I and the US Department of Health and Human Services recently published a clinical practice guideline that addresses management of acute pain.' Although humanitarian concern for patients in pain has always existed, several reasons account for the accelerating interest in postoperative analgesia, including the growing realization that management of pain for hospitalized patients has been inadequate;" the increasing understanding of the neurophysiologic features of perioperative pain modulation and the neuroendocrine stress response to surgical injury and critical illness.v' and the sharpening focus on clinical outcome and cost containment." Relevant questions that need to be asked about management of acute postoperative pain include the following: (1) What are the typical stress-inFrom the Department of Anesthesiology (D.LB.), Mayo Clinic Rochester, Rochester, Minnesota, and Department of Anesthesiology (D.C,M.), Mayo Clinic Jacksonville, Jacksonville, Florida. Address reprint requests to Dr. D. L. Brown, Department of Anesthesiology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.

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duced physiologic perturbations associated with surgical trauma? and (2) What is the potential for intraoperative anesthetic and analgesic decisions to influence these pathophysiologic changes, the patients' postoperative pain experience, and the perioperative outcome? DOES ANESTHETIC MANAGEMENT INFLUENCE POSTOPERATIVE PAIN? During the late 19th and early 20th century, many prominent surgeons used combinations of preoperative medications, local and regional anesthesia, and general anesthetics to produce what they believed was the optimal anesthetic regimen for patient safety and operative conditions. In that era of ether and chloroform, several surgeons, including Crile, Cushing, Halsted, Matas, Fowler, Babcock, and Jonnesco, were proponents of combined anesthetic techniques, including local and regional anesthesia. Dr. George Crile? advanced the thesis that general anesthesia alone was insufficient for shielding patients from the harmful stress of major operations, and he proposed the term "anociassociation" to describe an ideal combination of sedation, local and regional anesthesia, and general anesthetic techniques that protected patients from surgical stress (Fig. 1). He subsequently showed that anesthetic prescription affected physiologic 768

© 1993 Mayo Foundationfor Medical Education and Research

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Fig. 1. Crile's schematic illustration of protective effect of anociassociation. I, Conscious patient in whom auditory, visual, olfactory, and traumatic noci-impulses reach brain. II, Patient in whom inhalation anesthesia was used; only traumatic noci-impulses reach brain. III, Patient in whom anociassociation was complete; auditory, visual,andolfactory impulses are blockedfrom brain by inhalational anesthesia. Traumatic impulses from site of injuryare blockedby procaine hydrochloride. (Redrawn from Crile and Lower.") variables not only intraoperatively and immediately postoperatively but also for several days thereafter.'? In 1924, Dr. John S. Lundy became the first chairman of the Department of Anesthesiology at the Mayo Clinic, and he subsequently coined the term "balanced anesthesia" to characterize the practice of using preoperative sedatives and opioids in combination with regional and general anesthetics." Just as the optimal diet is balanced, he reasoned that the best anesthetic is a balanced combination of small portions of differing anesthetic agents and techniques. This combined anesthetic technique paradigm initially promoted by Crile, Lundy, and others has been reexamined recently relative to the influence of preoperative and intraoperative anesthetic management on postoperative pain and outcome; indeed, the term "preemptive analgesia" has been suggested to emphasize the important effect of anesthetic prescription on postoperative pain. 12 Recently, several clinical evaluations of postoperative pain have illustrated the benefit of balanced anesthesia and preemptive analgesia. McQuay and colleagues" used the concept of balanced anesthesia as the primary study variable in patients undergoing orthopedic surgical treatment. These investigators noted that the patients' first requests for pain

769

medication postoperatively were postponed when preoperative medication prescription and intraoperative regional anesthesia were used (Fig. 2). They found that opiate premedication and local anesthetic procedures performed before surgical treatment were prophylactic for postoperative pain. Almost a century after Crile initially explored his own theory of anociassociation, Tverskoy and associates" confirmed that anesthetic prescription affects conditions not only intraoperatively and immediately postoperatively but also for days afterward (Fig. 3). They concluded their investigation of three types of anesthetics for inguinal herniorrhaphy with the following comment: ... postoperative pain after inguinal herniorrhaphy can be significantly decreased if the surgery is performed with local infiltration anesthesia or spinal anesthesia instead of general anesthesia, perhaps because neural blockade prevents nociceptive impulses from entering the central nervous system during and immediately after surgery and thus suppresses formation of the sustained hyperexcitable state in the central nervous system that is responsible for the maintenance of postoperative pain. Most investigators have confirmed these findings of the preemptive value of local and regional anesthetic blockade as a component of the anesthetic plan in moderating postoperative pain.'>" In addition to local anesthetics, other medications have been shown to be efficacious in the prevention or preemptive moderation of postoperative pain. The discovery of intraspinal (intrathecal and epidural) opioid analgesia has promoted a revolution in the management of postoperative pain (Fig. 4),7,18,19 and several investigators have found that the efficacy of intraspinally administered narcotics is increased if they are used preoperatively. Katz and coworkers" demonstrated that patients who received epidural infusion of fentanyl citrate before thoracotomy experienced

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Fig. 3. Graphsof intensity of constant (A) and movement-associated (B) incisionalpain after administration of three types of anesthesia over time in patients who underwent inguinal herniorrhaphy. Pain intensity represents millimeters on a lOO-mm visual analogue scale (mean ± SEM). (FromTverskoy and associates." By permission of the International AnesthesiaResearchSociety.)

less pain and required less opioid postoperatively than did those who had the same analgesic management after thoracotomy. Bach and colleagues" found that a preoperative 72-hour epidural infusion of morphine and bupivacaine hydrochloride in patients scheduled for amputation of a lower extremity decreased the incidence of phantom limb pain at 7 days, 6 months, and I year postoperatively. Additional agents that are currently being investigated for potential modulation of perioperative pain include corticosteroids," nonsteroidal anti-inflammatory drugs," and ~­ adrenergic agonists such as clonidine hydrochloride and dexmedetomidine."

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PHENOMENON OF NEUROPLASTICITY Intraoperative anesthetic prescription can influence postoperative pain remote from the time of operation, and this phenomenon of preemptive analgesia may be understood through recent advances in neurophysiology. For many years, clinicians considered the transmission of pain solely in terms of neuroanatomic wire diagrams of sensory pathways. This depiction promoted the concept that noxious stimuli are sensed by peripheral nociceptors, transmitted to the spinal cord, and relayed directly to cortical centers of consciousness without intermediary modulation (Fig. 5). This clinical concept of pain as a relatively simple reflex

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Fig. 4. Diagramof crosssectionof spinalcord,highlighting region of dorsal hom of spinal cord containing substantia gelatinosa, whereconcentration of spinalcord opioidreceptors is highest.

Fig. 5. Diagram of traditional concept of pain transmission, highlighting details of pain circuitry from peripheral site to cerebral cortex.

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Fig. 6. Graphs of extracellular recordings (rate in hertz versus time) of dorsal horn neurons from rat spinal cords in rats receiving injection of formalin into paw at time zero. Graphs are based on mean values for these cells, and standard errors have been omitted for clarity. A, Effects of formalin alone on spinal cord excitatory response to painful stimuli in five rat neurons. B, Effect of preemptive analgesia with DAGO (a potent opioid u-receptor agonist) 20 minutes before injection of formalin into rats; solid line illustrates three neurons measured after DAGO, and dashed line shows control measurements from A. DAGO (D) was injected 20 minutes before formalin (F). (From Dickenson and Sullivan." By permission of Elsevier Science Publishers B.V.)

mechanism has been rendered obsolete by several basic science discoveries, one of which was the gate-control hypothesis of pain modulation proposed by Melzack and Wall," which fits many clinical concepts. The current model of the physiologic aspects of acute pain acknowledges that the nervous system is capable of short- or long-term reorganization of structure or function (or both) on the basis of ongoing development or in response to prior experience or acute injury.s-" Adaptive and maladaptive alterations include sensitization of peripheral afferents and dorsal hom neurons (the latter is known as dorsal hom windup), as well as neurochemical and structural changes in central pathways. Peripheral changes in the nociceptor biochemical environment, such as the release of inflammatory mediators, may result in sensitization of primary afferent neurons." Neuropeptides, monoamines, and amino acids, such as the excitatory amino acid N-methyl-o-aspartic acid, seem to have a role in central sensitization after peripheral nociceptor stimulation.'? Neuroplasticity, the contemporary concept of nociceptive traffic transmission and processing as an activity-dependent,

dynamic, plastic phenomenon, explains the clinical use of preemptive analgesia. In the laboratory, Dickenson and Sullivan" showed that a potent and selective opioid u-receptor agonist administered intrathecally before subcutaneous injection of formalin prevents the usual biphasic response of dorsal hom neuron central sensitization after injury (Fig. 6). Woolf and WalF9demonstrated that the dose of systemically administered morphine needed to prevent C-fiber stimulus-induced excitability changes from occurring in the rat spinal cord is an order of magnitude lower than that needed to suppress these changes after they occur. Nonsteroidal anti-inflammatory drugs may prove more efficacious if they are administered preemptively in order to moderate inflammatory changes in local tissues and the resultant sensitization of peripheral nociceptors (Fig. 7), but they may also prove to have central antinociception effects. 30 Similarly, the postulated antinociceptive mechanism of action of
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Fig. 7. Diagram showing that tissue injury leads to release of substance P (sP) from nerve endings and release of algogenic substances (for example, bradykinin [BK], serotonin [5HT], histamine, and arachidonic cascade metabolites), resulting in vasodilatation, increases in vascular permeability, and sensitization of nociceptors (primary hyperalgesia). Secondary hyperalgesia probably results from functional changes in both peripheral and central nervous system. Arachidonic acid can be metabolized to prostaglandin endoperoxides (PgE) by the enzyme cyclo-oxygenase or to hydroperoxy derivatives (HPETE) and leukotrienes by lipooxygenase pathway. Nonsteroidal anti-inflammatory drugs (NSAID) inhibit biosynthesis of prostaglandins by means of acetylation and consequent inactivation of cyclo-oxygenase. (From Dahl and Kehlet." By permission of the British Journal of Anaesthesia.)

these agents may be more substantial if they are administered preemptively."

EFFECT OF ANESTHETIC MODIFICATION OF NEUROENDOCRINE STRESS RESPONSE ON PERIOPERATIVE OUTCOME Currently, the salutary effects of the management of acute postoperative pain on perioperative outcome are being emphasized." This growing recognition of analgesia as an important factor in surgical outcome derives from the appreciation of pain as one component of a wide range of neural, endocrine, metabolic, and inflammatory changes that constitute the stress response to acute surgical injury and critical illness.s-" This stress phenomenon is initiated by a wide range of perioperative stimuli, such as local tissue injury, pain, hemorrhage, infection, acidosis, hypoxia, anxiety, starvation, and hypothermia. Derangements in pituitary-adrenocortical response, antidiuretic hormone, growth hormone, renin, angiotensin, aldosterone, testosterone, insulin, glucagon, and catecholamine levels as well as in water, electrolyte, carbohydrate, protein, and fat metabolism are common. The pathophysiologic effects promoted by inflammatory mediators such as prostaglandins, leukotrienes, histamine, bradykinin, and platelet-activating factor 22,32 as well as those of various cytokines such as tumor necrosis factor (cachectin), interleukin 1, interleukin 6, interferon-y, and

granulocyte or macrophage colony-stimulating factorv-" are also important elements of surgical illness. In addition, studies have shown that the peripheral nervous system itself can promote inflammatory processes through the secretion of various neuropeptides." The perturbations in these homeostatic mechanisms, which vary in direct proportion to the degree of physiologic trespass and are presumably protective in other settings, may be deleterious in surgical patients, particularly high-risk patients. Therefore, to improve perioperative outcome, intraoperative and postoperative anesthetic management must involve more than merely relief of postoperative pain and suffering. Physicians who manage patients' postoperative pain may need to expand their focus of attention to the modulation of the broad range of neural, endocrine, metabolic, and inflammatory changes that typify the response to surgical injury and critical illness. Using anesthetic prescription to modify the neuroendocrine stress response to surgical treatment begins by acknowledging that the physiologic aspects of general and regional anesthesia differ profoundly." With the exception of very high-dose narcotic techniques, general anesthesia minimally moderates the surgical stress response; however, depending on the extent of neural block, regional anesthesia may completely obstruct neuroendocrine responses to surgical injury.V-" The use of regional anesthetic techniques and the administration of opioids, nonsteroidal anti-inflamma-

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tory drugs, and corticosteroids to moderate the stress response to surgical treatment may enable physicians to improve perioperative outcome. For example, laboratory and clinical investigators have found that epidural anesthesia is associated with decreased cardiac morbidity'v" and increased hemodynamic stability.v" Epidural anesthesia and postoperative analgesia have also been shown to improve postoperative bowel function," decrease postoperative nitrogen 10ss,44 decrease the risk of postoperative thrombotic complications.t-" and improve postoperative pulmonary function.f-" In addition, both epidural anesthesia" and infusion of local anesthetic" have been associated with improved leukocyte function. Despite these effects, however, the correlation between the extent of relief of postoperative pain as an isolated variable and the minimization of the injury response to surgical treatment is slight. Several studies have substantiated the ability of analgesics to provide excellent relief of postoperative pain; corresponding improvement in physiologic variables such as neuroendocrine stress response and pulmonary function is minimal." In addition to regional anesthesia and analgesia, other metabolic interventions have been assessed in attempts to alter the stress response to surgical injury in a favorable manner. Nonsteroidal anti-inflammatory drugs have been shown to decrease stress hormone release, protein loss, hemodynamic instability, and abnormalities of cell-mediated immunity in this setting." Schulze and associates" found that prednisolone administered preoperatively in patients undergoing cholecystectomy decreased postoperative pain, prevented the postoperative hyperthermic response, and improved postoperative pulmonary function, Apparently, the greatest opportunity to improve postoperative analgesia and to moderate the stress response to surgical injury-and thus have the maximal influence on perioperative outcome-is with use of techniques that encompass both neural block and humoral intervention (Fig. 8). Indeed, in a recent investigation by Schulze and coworkers" of patients undergoing colonic resection, postoperative pain and hyperthermic response were completely eliminated, pulmonary function was improved, and postoperative increases in prostaglandin E2 , interleukin 6, and C-reactive protein levels were significantly blunted by a regimen in which epidural analgesia, prednisolone, and indomethacin were used. OUTCOME STUDIES OF EFFECT OF ANESTHETIC PRESCRIPTION ON POSTOPERATIVE PAIN AND PERIOPERATIVE OUTCOME With our improved understanding of nociceptive plasticity and of anesthetic prescription-induced alterations in postoperative pain, another question must be asked, Have outcome studies shown that the addition of improved analgesia to

MANAGEMENT OF POSTOPERATIVE PAIN

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clinical practice translates into improved patient outcome? Four well-conducted prospective investigations directly suggest the answer. Yeager and colleagues" at Dartmouth created interest in balanced anesthesia and preemptive analgesia with their randomized, controlled clinical trial in which combined epidural and general anesthesia and postoperative epidural analgesia were compared with "standard" general anesthesia and routine parenterally administered opioid analgesia. The study group consisted of 53 high-risk patients, primarily those undergoing an intrathoracic, intra-abdominal, or major vascular (noncerebral) surgical procedure. The two groups of patients received different perioperative anesthestic care. The first group of patients received light levels of general anesthesia in combination with epidural injections of local anesthetic sufficient to maintain anesthesia and muscle relaxation intraoperatively. Postoperatively, this group of patients received analgesic concentrations of epidurally administered local anesthetics or opioids. The second group of patients received only general anesthesia by use of a highdose narcotic technique (35 ug/kg or more of fentanyl with nitrous oxide or 50 ug/kg or more of fentanyl without nitrous oxide) or a lower-dose narcotic anesthetic (35 ug/kg or less of fentanyl, or an equivalent dose of morphine, with either nitrous oxide or a low concentration of a volatile anesthetic agent such as isoflurane). Postoperatively, this second group received routine parenteral administration of narcotics as needed. Between the two groups, the outcome measures that

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Fig, 8. Diagram of varied nociceptive (neuroendocrine) processing sitesthatmaybe modified by drugs or otheranalgesic interventions during perioperative period, epi = epidural; GABA = y-aminobutyric acid; intrathec =intrathecal; TENS =transcutaneous electrical nerve stimulation. (Redrawn from Kehlet H, Modification of responses to surgery by neural blockade: clinical implications. In: Cousins MI, Bridenbaugh PO,editors. Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd ed. Philadelphia: Lippincott, 1988: 152,)

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differed the most significantly were mortality, complication rate, time to postoperative extubation, and hospital costs: all were lower in the group that received the combination of general and epidural anesthesia and epidural analgesia (Table 1). Although the applicability of these data to other institutions has been questioned, partly because of the high mortality rate of 16% in the group that received general anesthesia and "traditional" analgesia postoperatively, this well-designed study suggests that anesthetic and analgesic decisions influence perioperative outcome. Tuman and associates" designed a study similar to that of Yeager and coworkers," although they focused their investigation on patients undergoing major vascular surgical procedures that involved the abdominal aorta or lower extremities. In their study, 80 patients were randomly assigned to receive either general anesthesia in combination with epidural anesthesia and analgesia or general anesthesia plus postoperative parenterally or orally administered (or both) narcotic analgesia. The patients who received general anesthesia were given nitrous oxide, oxygen, isoflurane (1.5% or less inspired), and 15 ug/kg or less of intravenously administered fentanyl. Postoperatively, these patients received parenterally administered narcotics on demand for pain relief. The patients in the combined general and epidural anesthesia group received epidural anesthesia with 1.5% lidocaine through an epidural catheter in association with a general anesthetic that consisted of nitrous oxide, low concentrations of isoflurane (0.5% or less inspired), and 5 ug/kg or less of intravenously administered fentanyl. Additionally, this patient group received a continuous postoperative infusion of bupivacaine and fentanyl through the epidural catheter. Tuman and coworkers studied many of the variables that Yeager and colleagues studied, but they also evaluated the coagulation state of their patients undergoing vascular operations; a group of 40 patients undergoing noncardiovascular procedures were coagulation control subjects. They found that the patients who underwent vascular procedures

had hypercoagulability in comparison with the control patients and that the use of combined general and epidural anesthesia in conjunction with postoperative epidural analgesia attenuated this hypercoagulability state and decreased the incidence of thrombotic events. The group that received the combination of general and epidural anesthesia also had significantly decreased rates of cardiovascular, infectious, and other postoperative complications (Table 2), and the duration of stay in the intensive-care unit was significantly reduced. The criticism of a high mortality rate in the report by Yeager and associates did not apply to the study by Tuman and coworkers because the latter investigation had no associated deaths. Mangano and colleagues'? of the Perioperative Ischemia Research Group at the University of California at San Francisco and the Department of Veterans Affairs Medical Center in San Francisco investigated preemptive administration of sufentanil, a potent opioid, in an evaluation of perioperative myocardial ischemia in adults undergoing elective myocardial revascularization. In that study, 106 patients received the same anesthetic (sufentanil) intraoperatively before bypass grafting (prebypass) and then were randomized either to a control group that received morphine intraoperatively and during the postbypass period and nurse-directed parenterally administered morphine in the intensive-care unit or to an intensive, preemptive analgesia group that received a continuous infusion of sufentanil intraoperatively and during the postbypass period, as well as infusion of sufentanil for 18 hours postoperatively in the intensive-care unit. During the prebypass (similar anesthetic) period, both groups had a similar incidence and duration of myocardial ischemia, although the patient group that subsequently received analgesia continuously in the intensive-care unit experienced more severe ischemic episodes during the baseline time interval. During the postbypass intraoperative period, both groups had a similar incidence of ischemia, but the episodes in the intensive analgesia

Table I.-Comparison of Significantly Different Variables in a Study of High-Risk Surgical Patients Who Were Randomized to Receive Two Different Combinations of Anesthesiaand Analgesiaat Dartmouth-Hitchcock Medical Center

Variable

Epidural anesthesia and analgesia group

Mortality Complication rate Majorinfection Cardiovascular problem Postoperative intubation (h) Hospital costs Datafrom Yeager and associates."

(N =28)

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General anesthesia and routine analgesia group (N = 25)

4 19 10 13 81.8 ± 186.1 $20,380 ± $20,343

P value <0.04 <0.002 <0.005 <0.02

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Table 2.-Comparison of Significantly Different Variables in a Study of Patients Undergoing Major Vascular Surgical Procedures Who Were Randomized to Receive Two Different Combinations of Anesthesia and Analgesia at Rush-Presbyterian-St. Luke's Medical Center

Variable

Epidural + general anesthesia and epidural analgesia group (N =40)

Mortality Total complications Infection Vascular occlusion Cardiovascularproblem

General anesthesia and on-demand narcotic analgesia group (N =40)

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Data from Tuman and associates." (sufentanil infusion) group were less severe. During the therapy period in the intensive-care unit, both the incidence and severity of the ischemic episodes were less severe in the intensive analgesia group (Table 3). After discontinuation of the intensive analgesia therapy, the incidence of ischemia again became similar in both groups. No significant difference in adverse cardiac outcomes (heart failure, myocardial infarction, and death) was found between the two groups, although this result may have occurred because the study size was too small to achieve statistical significance. Although most investigations of preemptive analgesia have focused on elderly patients undergoing high-risk surgical procedures, Anand and Hickey" used a preemptive analgesia and anesthetic technique to minimize the perioperative stress response in neonates undergoing cardiac surgical procedures. These high-risk patients were randomized to receive either inhalational anesthesia (halothane) and nursedirected postoperative morphine analgesia or deep intraoperative anesthesia with high doses of sufentanil and infusions of opiates during the first 24 hours postoperatively. The neonates who received deep anesthesia with sufentanil had significant decreases in perioperative hormonal stress

responses, incidence of sepsis, metabolic acidosis, and disseminated intravascular coagulation; no deaths occurred in this group (Table 4).

CONCLUSION Several implications may be drawn from the influence of anesthetic and analgesic prescription on postoperative pain and the neuroendocrine stress response to surgical injury. Because most perioperative complications occur postoperatively, with contributions from the stress response to operation (including inadequately treated postoperative pain), a better understanding of the importance of these potentially maladaptive pathophysiologic changes is necessary, as is a greater willingness to use anesthetic and analgesic modalities proactively to attempt to moderate their deleterious effects. In additional perioperative outcome studies, costs and complication rates must be included in the comparison of preemptive and traditional anesthetic and analgesic methods. Furthermore, a concerted interdisciplinary coordination. of patient management is needed. Almost a century ago, surgeons such as George Crile may have been better able to appreciate the effect of surgical

Table 3.-Comparison of Incidence and Severity of Myocardial Ischemia in Adult Patients Undergoing Myocardial Revascularization Who Were Randomized to Receive Two Different Methods of Analgesia During the Intrabypass and Postbypass Periods and While in the Intensive-Care Unit Period Prebypass(anestheticcontrol) Drug study lntrabypass and postbypass (maximalST-segmentdepression) lCU-therapy* (area-under-curve ST change) *ICU = intensive-care unit. Data from Mangano and associates."

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Morphine-on-demand analgesia group

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Table 4.-Comparison of Significantly Different Variables in a Study of Neonates Who Underwent Cardiac Operation and Received Two Different Combinations of Anesthesia and Analgesia

Variable Mortality Complications Infection Metabolic acidosis DIC*

Halothane anesthesia and routine morphine analgesia group (N = IS)

Sufentanil anesthesia and analgesia group (N 30)

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*DIC = disseminated intravascular coagulation. Data from Anand and Hickey."

illness and trauma on what is increasingly recognized as a dynamic, plastic nociceptive system because they functioned as surgeons, intensivists, and anesthesiologists (and analgesiologists). Those who are responsible for the care of surgical patients need to maintain a holistic concept of management so that the various pathophysiologic phenomena comprising the global stress response of the perioperative milieu can be better anticipated and preemptively treated.

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