2 Outcome Studies Comparing Regional and General Anesthesia
Gabriella Iohom and George Shorten
39
Outcome Measures
Substantial increase in healthcare costs has contributed to the development of out- comes research in the United States. Outcomes research evaluates the effectiveness of healthcare interventions in many aspects of patient care (clinical outcomes, func- tional health status, patient satisfaction, health-related quality of life) and refl ects national trends in determining appropriateness, value, and quality of health care.1 Outcomes research in regional anesthesia has traditionally focused on clinically ori- ented outcomes, such as overall mortality and major morbidity (cardiovascular, pul- monary, coagulation, cognitive, gastrointestinal, immune, stress response).2 This chapter examines the currently available evidence comparing regional and general anesthesia in terms of clinically oriented outcomes.
Although postoperative pain per se is neither a traditional outcome measure nor an independent predictor of duration of hospital stay, inadequate control of postopera- tive pain is an important cause of readmission after ambulatory surgery.3 Because pain is often the predominant symptom of the postoperative period, it can be con- sidered an important outcome of surgery. Patients relate improved pain control to improved postoperative outcome.4 Therefore, the role of regional anesthesia and analgesia as part of multimodal analgesic regimens is also considered.
Challenges of Data Interpretation
Although the worth of data from prospective randomized, controlled studies (RCTs) and metaanalyses is well established, there are inherent diffi culties complicating their interpretation.
Prospective RCTs are the “gold standard” in evaluating the effect of an intervention on patient outcomes. Signifi cant drawbacks include the cost, time, and need for large sample sizes when evaluating rare outcomes.5 For example, a sample size of 24,000 patients would be needed to determine if regional anesthesia would decrease the overall mortality after a specifi c procedure by 50% (power 80%) when compared with that from general anesthesia.6 Although multicenter trials are possible, protocol devia- tion and institutional differences may affect the results.7 Other disadvantages include ethical concerns and less external validity (“generalizability” of the fi ndings of a study).5 In addition, RCTs comparing regional with general anesthesia are necessarily
unblinded (with very few exceptions), allowing for the introduction of bias.2 Other methodologic issues with studies examining outcome after regional anesthesia include the use of surrogate end points, inappropriate selection of postoperative analgesic regimens, and inadequate assessment of pain.2
Metaanalysis using strict criteria for the inclusion of studies and appropriate statisti- cal methods is a valuable means of drawing meaningful conclusions from studies with similar objectives. One of its disadvantages is that conclusions are based on data derived from studies that may vary widely in design, subject population (sample), and selected outcomes.8 Small differences in one of several factors may affect whether a trial meets the inclusion criteria, and thus potentially alter the conclusions of the metaanalysis.9 Metaanalyses may also contain publication biases (inclusion of older outdated studies, exclusion of non-English language trials, and the initial failure to publish negative results).10 These factors tend to increase the likelihood of demon- strating an effect of treatment.
Patient management has changed considerably over the last two decades, making some alleged benefi ts of regional anesthesia less impressive. For instance, low- molecular-weight heparins, used routinely for thromboprophylaxis in patients under- going hip and knee surgery, have considerably decreased the incidence of deep venous thrombosis.11 This tends to make the earlier described benefi ts of epidural analgesia less relevant in current practice. Similarly, a number of RCTs support the periopera- tive use of β-blockers to reduce the morbidity and mortality associated with noncar- diac surgery in patients at risk for cardiac complications.12 In addition, laboratory tests or radiologic investigations used to diagnose certain complications have changed (plasma concentration of troponin Ic for the diagnosis of postoperative myocardial infarction (PMI) or computed tomography for identifying pulmonary atelectasis), making the results of some earlier studies unreliable.4
In view of the above, the analysis and conclusions of metaanalyses must be inter- preted carefully.
Reliable and valid conclusions about therapies in controversial areas of clinical practice require not only that systematic reviews or metaanalyses indicate the likely sizes of effects of such therapies, but also that the fi ndings be independently confi rmed in at least one, and preferably more, high-quality RCT.13 Ideally, fi ndings of metaanalyses should be confi rmed by large RCTs to examine the effects of regional anesthesia on outcome. There are many specifi c reasons to explain why conclusions from metaanalyses may not correlate with those from subsequent large-scale RCTs.9 These include problems inherent in the study design and problems in execution.14
Neuraxial Blockade
Blockade of afferent neural stimuli from the surgical area by local infi ltration, periph- eral nerve blocks, or neuraxial (spinal and epidural) blockade decreases the endo- crine-metabolic response after major surgery. These effects are further enhanced if the blockade is maintained postoperatively.15
Hypothesis: That epidural anesthesia and analgesia is preferable in high-risk patients undergoing major surgery, because it can attenuate the neurohumoral stress response to surgery,16 improve cardiorespiratory function postoperatively, and decrease the incidence and/or severity of complications.
Several small RCTs support this hypothesis,17–19 but none had suffi cient power to convincingly establish a benefi t in postoperative outcome.
Reviews (Metaanalyses and Systematic Reviews)
In a metaanalysis of data from 141 RCTs available before January 1, 1997 including 9559 patients (Table 2-1), Rodgers et al.20 showed that the use of epidural or spinal
Table 2-1. Metaanalyses
Intervention
Author Year Setting (groups) Outcome Result
Rodgers 2000 All types of Neuraxial Overall 30-day Neuraxial blockade superior (OR, 0.70;
et al.20 surgery blockade ± mortality 95% CI, 0.54–0.90
GA versus DVT Neuraxial superior (OR decreased by 44%) GA Pulmonary Neuraxial superior (OR decreases by 55%)
embolism
Transfusion Neuraxial superior (OR decreased by 50%)
requirements
Pneumonia Neuraxial superior (OR decreased by 39%) Respiratory Neuraxial superior (OR decreased by 59%)
depression
Urwin et al.21 2000 Hip Neuraxial 30-day Neuraxial superior (OR, 0.66; 95% CI, fracture blockade mortality 0.47–0.96)
surgery versus GA DVT Neuraxial superior (OR, 0.41; 95% CI,
0.23–0.72)
Parker et al.22 2004 Hip Neuraxial 30-day Neuraxial superior (RR, 0.69; 95% CI, fracture blockade mortality 0.71–1.21)
surgery versus GA Postoperative Neuraxial superior (RR, 0.50; 95% CI, confusion 0.26–0.95)
Liu et al.23 2004 Coronary Central Dysrhythmias Thoracic epidural superior (OR, 0.52) artery neuraxial Pulmonary Thoracic epidural superior (OR, 0.41) bypass blockade complications
surgery (thoracic Time to tracheal Thoracic epidural superior epidural, extubation
intrathecal) + Pain VAS Thoracic epidural superior GA versus scores at rest
GA and with
activity
Ballantyne 1998 Abdominal Postoperative Atelectasis Epidural opioids superior (RR, 0.54; 95%
et al.24 and epidural CI, 0.33–0.85)
thoracic opioids and Pulmonary Epidural local anesthetics superior (RR, surgery local infections 0.36; 95% CI, 0.21–0.65)
anesthetics Overall Epidural local anesthetics superior (RR, versus pulmonary 0.58; 95% CI, 0.42–0.80)
systemic complications
opioids
Beattie et al.25 2001 Abdominal, Postoperative Postoperative Epidural superior aortic, epidural analgesia
peripheral analgesia Postoperative TEA superior (rate difference, −5.3%; 95%
vascular >24 hours MI CI, −9.9%, −0.7%)
surgery
Block26 2003 All types of Postoperative Postoperative Epidural superior on each postoperative surgery epidural analgesia day
analgesia
versus
systemic
opioids
GA, general anesthesia; DVT, deep vein thrombosis; MI, myocardial infarction; VAS, visual analog scale.
block (with or without general anesthesia) resulted in a 30% reduction (P= .006) in the overall 30-day mortality after surgery [odds ratio (OR), 0.70; 95% confi dence interval (CI), 0.54–0.90]. Furthermore, neuraxial blockade reduced the odds of deep vein thrombosis by 44%, pulmonary embolism by 55%, transfusion requirements by 50%, pneumonia by 39%, and respiratory depression by 59% (all P < .001). There
were also reductions in the incidence of perioperative myocardial infarction and renal failure. Although the authors acknowledge the limited power to assess subgroup effects, they conclude that the proportional reductions in mortality did not differ by surgical group, type of neuraxial blockade (spinal or epidural), or in those trials in which neuraxial blockade was combined with general anesthesia compared with trials in which neuraxial blockade was used alone.20 Thus, it seemed that the benefi ts were principally attributable to the use of neuraxial blockade, and the technique by which this was achieved was less relevant.
This metaanalysis has been criticized on the following grounds: the management of postoperative patients had changed over the preceding 20 years (i.e., thrombopro- phylaxis after hip and knee surgery), making some alleged benefi ts of regional anes- thesia less impressive; regional anesthesia only improved mortality in patients undergoing orthopedic surgery and had no effect in patients undergoing general, urologic, and vascular surgery (because more than half the trials with at least 10 deaths per trial involved patients with hip fracture, thus enhancing the contribution of the fi ndings of these trials to the overall result); although thoracic epidural and spinal analgesia signifi cantly improved mortality, lumbar epidural analgesia was ineffective.27
Another metaanalysis of randomized trials regarding the effects of general versus regional anesthesia on outcome after hip fracture surgery was published in 2000.21 Fifteen trials comprising a total of 2162 patients with hip fractures were included. A lesser 30-day mortality was reported in the regional anesthesia group (6.4% versus 9.4%; OR, 0.66; 95% CI, 0.47–0.96), but this advantage did not extend to 3 months or beyond. In addition, neuraxial blockade was associated with a decrease in deep vein thrombosis (30.2% versus 46.9% in the regional and general anesthesia group, respectively; OR, 0.41; 95% CI, 0.23–0.72). These results were mostly derived from trials that had used routine venography. No such difference was identifi ed for inci- dence of pulmonary embolism (OR, 0.84; 95% CI, 0.33–2.13), need for transfusion (OR, 1.02; 95% CI, 0.58–1.80), or incidence of pneumonia (OR, 0.92; 95% CI, 0.53–
1.59). However, the incidence of fatal pulmonary embolism was less in patients who had undergone regional anesthesia. Although these latter results represent a subgroup analysis, they support the contention that regional anesthesia may have a protective effect against major thromboembolism. It is recognized that routine use of thrombo- embolism prophylaxis (mentioned in only three studies) might negate such a benefi t.
This metaanalysis was recently updated to include newly available data.22 Twenty- two trials comprising a total of 2567 predominantly female and elderly patients were included. Although all trials had methodologic fl aws and many did not refl ect current anesthetic practice, pooled results from eight trials showed regional anesthesia to be associated with a lesser 30-day mortality (6.9% versus 10.0%). However, this was of borderline statistical signifi cance (relative risk, 0.69; 95% CI, 0.71–1.21). In fact, removal of data from an early study (McLaren 1978) with an unusually high mortality rate in the general anesthesia group (28%) resulted in a statistically nonsignifi cant difference in mortality at 1 month (relative risk, 0.79; 95% CI, 0.56–1.12). The decrease in the incidence of deep venous thrombosis (30% versus 47% in the regional versus general anesthesia group; relative risk, 0.64; 95% CI, 0.48–0.86) was considered inse- cure because of possible selection bias in the subgroup in whom this outcome was measured.22 Interestingly, but not unexpectedly, regional anesthesia was associated with a lesser risk of postoperative confusion (9.4% versus 19.2%; relative risk, 0.50;
95% CI, 0.26–0.95). The authors concluded that overall, there was insuffi cient evidence available from trials comparing regional versus general anesthesia to rule out clinically important differences.22
A recent systematic review of data from 24 published trials including a number of patients ranging from 30 to 9598 addressed the effect of intraoperative neuraxial
anesthesia versus general anesthesia on postoperative cognitive dysfunction (POCD) and delirium.28 The authors concluded that, in the presence of methodologic and study-design issues related to the unelucidated pathophysiology of POCD, the use of intraoperative neuraxial anesthesia does not seem to decrease the incidence of POCD when compared with general anesthesia.28
In 2004, a metaanalysis of 15 trials (comprising 1178 patients) examined the effects of perioperative central neuraxial blockade on outcome after coronary artery bypass surgery.23 Outcomes were compared in patients randomized to general anesthesia versus general anesthesia – thoracic epidural analgesia (TEA) or general anesthesia – intrathecal analgesia. TEA did not affect incidences of mortality or myocardial infarction. TEA signifi cantly reduced the risk of dysrhythmias (OR, 0.52), pulmonary complications (OR, 0.41), time to tracheal extubation by 4.5 hours, and visual analog pain scores at rest and with activity (by 7.8 and 11.6 mm, respectively). It had no sig- nifi cant effect on incidences of mortality, myocardial infarction, dysrhythmias, nausea/
vomiting, or time to tracheal extubation. It decreased systemic morphine consumption by 11 mg and visual analog scale pain scores by 16 mm.
The authors concluded that, although no differences in the rates of mortality or myocardial infarction were observed, central neuraxial analgesia for coronary artery bypass grafting was associated with shorter intervals to tracheal extubation, fewer pulmonary complications and cardiac dysrhythmias, and less pain postoperatively.23
A comprehensive, cumulative metaanalysis published in 1998 focused on compara- tive effects of postoperative analgesic therapies on pulmonary outcome.24 Compared with systemic opioids, epidural opioids decreased the incidence of atelectasis [risk ratio (RR), 0.53; 95% CI, 0.33–0.85] and had a weak tendency to decrease the inci- dence of pulmonary infections and pulmonary complications overall. Epidural local anesthetics increased Pao2 by 4.6 mm Hg (95% CI, 0.06–9.08) and decreased the incidence of pulmonary infections (RR, 0.36; 95% CI, 0.21–0.65) and pulmonary complications overall (RR, 0.58; 95% CI, 0.42–0.80) compared with systemic opioids.
There were no clinically or statistically signifi cant differences in the surrogate mea- sures of pulmonary function such as forced expiratory volume in 1 second, functional vital capacity, or peak expiratory fl ow rate. The authors concluded that clinical mea- sures of pulmonary outcome (incidence of atelectasis, infection, and other complica- tions) were signifi cantly improved by epidural opioid and epidural local anesthetic treatments in the postoperative period.24
In 2001, a metaanalysis of 11 RCTs (comprising a total of 1173 patients) examined the effect of postoperative epidural analgesia continued for more than 24 hours on the incidence of PMI.25 Postoperative epidural analgesia resulted in superior analgesia for the fi rst 24 hours after surgery and was associated with a lesser incidence of PMI (rate difference, −3.8%; 95% CI, −7.4%, −0.2%; P = .049). The incidences of in- hospital death (3.3%) were similar in the epidural and nonepidural groups. Of note, the proportion of patients taking β-blockers was identical in the two groups. The incidence of PMI in patients who received epidural analgesia via the thoracic route was less than in those who received systemic analgesia (rate difference, −5.3%; 95%
CI, −9.9%, −0.7%; P = .04). The authors concluded that, in high-risk cardiac patients, postoperative epidural analgesia is indicated.25
In 2003, a metaanalysis of 100 RCTs examined the effi cacy of postoperative epidural analgesia in adults.26 Weighted mean pain scores, weighted mean differences in pain score, and weighted incidences of complications were determined using a fi xed-effect model. Epidural analgesia provided better overall postoperative analgesia compared with parenteral opioids (P< .001). Epidural analgesia was better than that achieved using parenteral opioids on each postoperative day (P< .001). In conclusion, epidural analgesia, regardless of analgesic agent, location of catheter placement, and type and time of pain assessment, provided superior postoperative analgesia com- pared with parenteral opioids.26
Recent, Large RCTs
A multicenter, randomized, controlled, unblinded study conducted in 15 United States Veterans Affairs hospitals set out to determine the effects of intraoperative epidural anesthesia and postoperative epidural analgesia on outcome after major abdominal surgery (Table 2-2).29 This study compared (1) general anesthesia intraop- eratively plus parenteral opioids postoperatively with (2) epidural bupivacaine anal- gesia and light general anesthesia intraoperatively plus epidural morphine postoperatively in 1021 patients undergoing four types of surgery: intraabdominal aortic, gastric, biliary, or colonic surgery. The primary outcome was the combined end point of 30-day all-cause mortality, myocardial infarction, congestive heart failure, ventricular tachyarrhythmia, complete atrioventricular block, severe hypoten- sion, cardiac arrest, pulmonary embolism, respiratory failure, stroke, and renal failure.
The secondary outcomes were angina, respiratory depression, pneumonia, sepsis, gastrointestinal bleeding, epidural hematoma, and reoperation. Postoperative pain at
Table 2-2. Recent RCTs
Author Year Setting Intervention Outcome Result
Park et al.29 2001 Major abdominal Epidural LA VAS pain score Epidural superior (P艋 .03 on the surgery analgesia + GA 30-day mortality fi rst, third, and seventh
intraoperatively Duration of postoperative day
+ epidural tracheal Epidural superior in abdominal morphine intubation and aortic surgical patients (22%
postoperatively ICU stay versus 37%,P< .01)
versus GA + Epidural superior
parenteral
opioids
postoperatively
Norris et al.30 2001 Abdominal aortic Thoracic epidural Time to Epidural PCA superior (P= .002) surgery anesthesia + extubation
light GA or GA
followed by
epidural PCA
postoperatively
or morphine
PCA (four
treatment
groups)
Rigg and the 2002 High-risk patients Intraoperative Respiratory Epidural superior (23% versus MASTER undergoing epidural failure 30%, P= .02)
group31 major anesthesia with VAS pain scores Epidural superior abdominal GA and
surgery or postoperative esophagectomy epidural
analgesia for
72 hours
Foss et al.32 2005 Hip fracture Continuous Dynamic Epidural superior surgery postoperative analgesia
epidural
analgesia with
local
anesthetics +
opioids
VAS, visual analog scale; LA, local anesthetic; GA, general anesthesia.
rest, physical mobilization, and durations of intensive care unit (ICU) and hospital stay were also evaluated.
The two groups were similar in terms of the frequencies of primary or secondary outcomes, the average postoperative physical performance scores, and durations of ICU or hospital stays. Visual analog pain scores were lesser in the epidural group (P 艋 .03) on the fi rst, third, and seventh postoperative day. For abdominal aortic surgical patients, the incidence of primary end points was less in the epidural group (22%
versus 37%, P < .01). This difference stemmed from differences in the incidence of new myocardial infarction, stroke, and respiratory failure. In the epidural group, the duration of tracheal intubation was 13 hours shorter, which translated into a 3.5 hours shorter ICU stay. The authors concluded that the effect of anesthetic and postopera- tive analgesic techniques on perioperative outcome varies with the type of operation performed. Overall, epidural analgesia provides better postoperative pain relief. In addition, epidural anesthesia and analgesia improves the overall outcome and short- ens the intubation time and intensive care stay in patients undergoing abdominal aortic operations.29 Critics of this study have argued that in addition to being under- powered (to demonstrate a reduction in major morbidity and mortality up to 30 days postoperatively), the intervention may not have been adequate.33 This study used intraoperative lumbar or thoracic epidural local anesthetic without opioids for abdom- inal surgery followed by postoperative analgesia with epidural opioids alone. As we have pointed out, two metaanalyses demonstrated that only thoracic, and not lumbar, epidural analgesia decreases the incidence of mortality20 or perioperative myocardial infarction.25 In addition, it seems that an epidural local anesthetic is essential to improve pulmonary, cardiac, and gastrointestinal outcome. Epidurally administered local anesthetics, but not opioids, produce their benefi cial effects in pulmonary outcome by promoting the postoperative recovery of diaphragmatic contractility.14
A prospective, double-blind, randomized clinical trial was designed to compare four combinations of intraoperative anesthesia and postoperative analgesia with respect to postoperative outcomes in patients undergoing surgery of the abdominal aorta.30 One hundred sixty-eight patients were randomly assigned to receive either thoracic epidural anesthesia plus a light general anesthesia or general anesthesia alone intraoperatively combined with either intravenous or epidural patient-controlled anal- gesia (PCA) postoperatively (four treatment groups). PCA was continued for at least 72 hours. Duration of hospital stay and direct medical costs for patients surviving to discharge were similar among the four treatment groups. Postoperative outcomes were similar among the four treatment groups with respect to death, myocardial infarction, myocardial ischemia, reoperation, pneumonia, and renal failure. The only difference observed was a shorter time to extubation (P= .002) in the epidural PCA group. Times to ICU discharge, ward admission, fi rst bowel sounds, fi rst fl atus, toler- ance of clear liquid intake, tolerance of regular diet, and independent ambulation were similar among the four treatment groups. Postoperative pain scores were also similar among the treatment groups.
This study concluded that in patients undergoing surgery of the abdominal aorta, thoracic epidural anesthesia combined with a light general anesthesia and followed by either intravenous or epidural PCA offers no major advantage over general anes- thesia alone followed by either intravenous or epidural PCA.30
An important limitation of this trial is that generalization of the conclusion, beyond the very select patient population studied and the very specifi c anesthetic and anal- gesic regimens used, may not be possible. When used for postoperative pain control after aortic aneurysm repair, epidural techniques may yield outcome benefi ts provided that (1) adequate concentrations are used, and (2) the infusion rates are adjusted swiftly, with boli where needed, to respond to individual patient and changing anti- nociceptive needs.34 Other authors caution against the “overstated” conclusions of Norris et al. and the more general interpretation that epidural anesthesia – analgesia is not benefi cial.35 The lack of a rigorous recovery protocol, use of opioids in all
patients, and selection of an insensitive primary outcome measure (duration of hos- pital stay) may have contributed to the negative fi ndings of this study.
The Multicentre Australian Study of Epidural Anaesthesia (the MASTER Anaes- thesia Trial) was designed to have adequate power to test the proposed benefi cial effect of epidural techniques,17 while allowing for a smaller difference observed as a result of improvements in perioperative management that have occurred since 1987.31 The RCT by Yeager et al.17 conducted in the mid-1980s, comparing general anesthesia with or without perioperative epidural anesthesia and analgesia in high-risk patients undergoing major surgery, was stopped for ethical reasons after 53 patients had been studied, because of the impressive improvement in mortality and morbidity observed in patients who received epidurals. The MASTER trial targeted the highest-risk patients (with one or more of the following comorbidities: morbid obesity, diabetes mellitus, chronic renal failure, respiratory insuffi ciency, cardiac failure, acute myocar- dial infarction, exertional angina, myocardial ischemia, severe hepatocellular disease, age >75 years plus at least two criteria) undergoing major abdominal operations or esophagectomy. The authors argued that this combination of high-risk patients and high-risk procedures defi nes an area of practice in which major perioperative compli- cations are concentrated and consequently maximizes the power of a study of given size.36 Nine hundred fi fteen patients were randomly allocated to receive either intra- operative epidural anesthesia (site selected to provide optimum block) with general anesthesia and postoperative epidural analgesia for 72 hours or control (general anes- thesia and postoperative systemic opioids for analgesia). The primary end points were death at 30 days or major postsurgical morbidity.
There was no difference in the 30-day mortality rate between groups, and only one of eight categories of morbid end points in individual systems (respiratory failure;
23% versus 30%, P= .02) occurred less frequently in patients managed with epidural techniques. However, postoperative epidural analgesia was associated with lesser pain scores during the fi rst three postoperative days, despite most participants in the control group receiving multimodal analgesia.
The authors concluded that most major postoperative complications in high-risk patients undergoing major abdominal surgery are not decreased by the use of com- bined epidural and general anesthesia combined with postoperative epidural analge- sia.31 However, they advocate the use of combined general and epidural anesthesia intraoperatively with continuing postoperative epidural analgesia in high-risk patients undergoing major intraabdominal surgery, based on improvement in analgesia, and the decrease in incidence of respiratory failure.
A subsequent subgroup analysis of the data from the MASTER trial, published in 2003, identifi ed no difference in outcome between epidural and control groups in patients at increased risk of respiratory or cardiac complications or undergoing aortic surgery, nor in a subgroup with failed epidural block.37 There was a small reduction in the duration of postoperative ventilation in the epidural group compared with controls (P= .048). No differences were found in duration of intensive care or hospital stay. Perioperative epidural analgesia did not infl uence the incidence of serious mor- bidity or mortality after major abdominal surgery.37
It seems that this study lacked adequate sample size and power to demonstrate a difference in overall mortality or cardiac morbidity between epidural and systemic treatments. Mortality at 30 days was low in both groups (epidural 5.1% versus control 4.3%). It is conceivable that the true benefi t associated with the use of epidural techniques is 3.6%, as observed in this study (57.1% of patients in the epidural group and 60.7% in the control group had at least one morbidity end point or died, P= .29).
A trial of 6000 patients at high risk would be required to give an 80% chance of declaring statistically signifi cant an absolute difference of 3.6% in the rate of death or major complications.36 Similarly, to demonstrate a 30% reduction in the incidence of myocardial infarction, as suggested by Rodgers et al.,20 a study with a 5% type I
error rate and 80% power would require at least 9500 patients. Nearly 50% of patients in the epidural group were not fully compliant with the study protocol and thoracic epidural – previously shown to decrease the incidence of mortality and perioperative myocardial infarction – was not mandatory.33
More recently, a randomized, double-blind, placebo-controlled trial looked at the effect of postoperative epidural analgesia on rehabilitation and pain after hip fracture surgery.32 Sixty elderly patients were randomly allocated to receive either 4 days of continuous postoperative epidural infusion of 4 mL/hour bupivacaine 0.125% plus 50 µg/mL morphine or placebo. Both groups received balanced analgesia and intra- venous nurse-controlled analgesia with morphine. Patients followed a multimodal rehabilitation program. Postoperative epidural analgesia provided superior dynamic analgesia without motor dysfunction compared with placebo. However, under the conditions of this study, superior analgesia did not translate into enhanced rehabilitation.32
Alternatives to RCT
In 2000, O’Hara et al.38 published a retrospective cohort study of 9425 consecutive patients with hip fracture, aged >60 years, who underwent surgical repair at one of 20 study hospitals between 1983 and 1993. They demonstrated that older and more ill patients were more likely to receive regional anesthesia. The 30-day mortality rate in the general anesthesia group was 4.4% compared with 5.4% in the regional anesthesia group (unadjusted OR, 0.80; 95% CI, 0.66–0.97). After controlling for differences in patient characteristics, the authors found no association between type of anesthesia and mortality or morbidity. Their fi ndings suggest that unadjusted differences in outcome between regional and general anesthesia are mainly a result of comorbidities, and not of a protective effect of one anesthetic technique.38
In 2003, Wu et al.39 offered an extensive database analysis (study of effectiveness) as an alternative to an RCT (study of effi cacy) in which large numbers would be needed to examine the effect of postoperative epidural analgesia on morbidity and mortality after total hip replacement surgery. From a 5% nationally random sample of Medicare claims from 1994 to 1999, 23,136 patients who underwent total hip arthro- plasty were identifi ed (of whom 2591 had and 20,545 had not received postoperative epidural analgesia). The unadjusted 7- and 30-day mortality rates were less for patients who had received epidural analgesia (1.9/1000 versus 3.9/1000, P= .04 at 7 days and 5.8/1000 versus 9.9/1000, P= .01 at 30 days). However, multivariate regression analysis revealed no difference between groups with regard to mortality or major morbidity with the exception of an increase in deep venous thrombosis in patients who received epidural analgesia. Although this is one of the largest data sets to date to examine this issue, the results should be interpreted with caution because of limitations in using such databases. The authors warn that insertion of a postoperative epidural catheter per se does not confer improved patient outcome; benefi t may only occur with appro- priate utilization of the epidural catheter.39
In summary, it seems that results from recent metaanalyses are not substantiated by subsequent large RCTs. Metaanalyses suggested advantages of (1) intraoperative neuraxial blocks such as lower 30-day mortality and less deep venous thrombosis in orthopedic patients,20,21 less transfusion requirement, and fewer incidences of pulmo- nary embolism, pneumonia, respiratory depression, myocardial infarction, and renal failure,20 fewer dysrhythmia, pulmonary complications, and better analgesia associ- ated with the use of thoracic epidural anesthesia,23 and (2) postoperative neuraxial blockade is associated with fewer pulmonary complications (atelectasis and infection),24 fewer PMIs25 (in the case of TEA), and overall better pain scores.25,26
Of these, RCTs support the contention that perioperative epidural techniques are associated with fewer incidences of respiratory failure in high-risk patients undergoing
major abdominal surgery,31 with a decrease in the incidence of 30-day mortality, respiratory failure, PMI, and stroke in patients undergoing abdominal aortic surgery,29 and superior analgesia.29,31,32
Peripheral Nerve Blocks
Despite superior analgesia and possible physiologic benefi ts provided by peripheral nerve blocks, there is no large-scale RCT that has examined the effi cacy of these techniques in decreasing perioperative mortality or morbidity in surgical patients. However, a number of individual studies have independently shown that better pain management through peripheral regional blocks may improve the functional result of surgery and shorten the duration of rehabilitation, resulting in economic benefi t.
Capdevila et al.40 tested the hypothesis that postoperative analgesic techniques infl uence surgical outcome and the duration of convalescence after major knee surgery.
They demonstrated that regional analgesic techniques (continuous femoral block or continuous epidural infusion) improved rehabilitation after major knee surgery by effectively controlling pain during continuous passive motion in the postoperative period.40
Similarly, Chelly et al.41 examined the effects of continuous femoral infusion of local anesthetic on recovery after total knee arthroplasty. Ninety-two patients were ran- domly assigned to receive general anesthesia (1) alone followed by PCA with mor- phine, (2) plus 3-in-1 and sciatic blocks followed by continuous femoral infusions of local anesthetic, or (3) plus epidural analgesia with local anesthetic followed by a continuous epidural infusion of local anesthetic and opioid. Blocks decreased postop- erative morphine requirements by 74% and 35% compared with PCA and epidurals (P< .05) and provided superior recovery. The use of blocks was associated with a reduction of postoperative bleeding and allowed better performance on continuous passive motion, which translated into a 2-day decrease in the duration of hospitaliza- tion. Also, it was associated with a 90% decrease in the total incidence of postopera- tive serious complications (including hypoxia and mental changes, hypotension, deep venous thrombosis, myocardial infarction, cerebrovascular accident, atelectasis, upper gastrointestinal bleed).41
Current Opinion
Given the diffi culty of proving effi cacy relating to rare adverse outcomes and of evalu- ating the role of one factor among many in the perioperative period, our inability to document a “global” superiority of regional techniques should not detract from their clinical use. Nor should they impede further clinical research to establish the relation- ship between these techniques and important health outcomes.
Future studies evaluating the potential benefi ts of regional anesthesia and analgesia techniques should use a multimodal approach with aggressive postoperative rehabili- tation. In addition, such studies should focus on patient-meaningful and resource outcomes, rather than the occurrence of rare events (or those of intermediate rarity) with an unknown relationship to meaningful health outcomes. Progress in the evolu- tion of multimodal postoperative rehabilitation may eventually establish regional anesthesia and analgesia techniques as critical to the process.42 There is increasing evidence to suggest that postoperative ileus is decreased by continuous epidural anal- gesia with local anesthetics. Preliminary data from studies using aggressive multi- modal rehabilitation including continuous epidural analgesia after major abdominal and thoracic operations suggest that the positive impact on pain and paralytic ileus will facilitate early recovery (i.e., early mobilization and nutrition).43
The aim of analgesic regimens is not only to reduce pain intensity but also to decrease the incidences of adverse effects of analgesic agents and to improve patient comfort. Moreover, adequate pain control is a prerequisite for the use of rehabilitation programs to accelerate recovery from surgery.4
The concept of multimodal pain management or balanced analgesia is to provide suffi cient pain relief through additive and synergistic effects, using different analge- sics, with a concomitant reduction of adverse effects attributed to the lesser doses of individual drugs. Peripheral nerve blocks are the cornerstone of balanced analgesic regimens in combination with nonopioid analgesics (acetaminophen, nonsteroidal antiinfl ammatory drugs, α2-agonists, N-methyl d-aspartate antagonists, etc). They facilitate the use of opioids only when required (breakthrough pain and block resolu- tion), thus decreasing the incidence of their systemic adverse effects. Continuous regional anesthesia is likely to enhance the quality of postoperative analgesia and patient satisfaction.44 Harrop-Griffi ths and Picard45 ask, “If continuous regional anes- thesia can, with the right equipment in trained hands, provide perfect or excellent analgesia after painful limb surgery, can we afford not to use it?” The information supporting the use of these regional techniques has become so extensive that the United States Veterans’ Health Administration and the Department of Defense have made recommendations for procedure-specifi c analgesic regimens emphasizing regional analgesia.46
The clinical implications of adequately controlled postoperative pain are manifold.
After orthopedic surgery, better analgesic control can improve the functional result of surgery and shorten the duration of rehabilitation, leading to a substantial economic benefi t.40 After abdominal surgery, patients who receive epidural analgesia have a more rapid recovery of bowel motility, allowing prompt oral intake; they mobilize more rapidly and are ready for hospital discharge earlier.47
Uncontrolled postoperative pain has been identifi ed as a risk factor in the devel- opment of chronic postsurgical pain syndrome.48 Chronic postsurgical pain has been defi ned as that which develops after a surgical procedure, is of at least 2 months’
duration, for which other causes have been excluded (e.g., malignancy or chronic infection), and for which the possibility of pain continuing from a preexisting condi- tion has been explored and exclusion attempted.49 Chronic postsurgical pain has been reported after thoracotomy, mastectomy, hernia repair, and limb amputation, with all surgical procedures having the potential of developing this debilitating condition.48,49 Compared with pain-free patients, those with signifi cant acute post- operative pain are more likely to develop chronic postsurgical pain.50 Furthermore, the severity of acute pain (more importantly, movement-evoked pain) correlates with the incidence of chronic pain.51 This suggests that adequate pain relief, part- icularly movement-evoked pain relief, may reduce the risk of persistent postopera- tive pain.
Regional anesthesia techniques such as epidural analgesia and continuous periph- eral nerve blockade have been shown to provide superior dynamic pain relief. Senturk et al.52 compared the effects of TEA with bupivacaine and morphine (either initiated preoperatively or postoperatively) and those of intravenous (IV)-PCA with morphine.
Compared with patients receiving IV-PCA, patients who received preoperative TEA had a lesser incidence of pain at 6 months (78% versus 45%). Similarly, Obata et al.53 in a prospective, randomized, single-blind study demonstrated a signifi cant effect of combined intra- and postoperative epidural analgesia when compared with postopera- tive epidural analgesia alone for posterolateral thoracotomy (decreasing the incidence of pain at 6 months from 67% to 33%).
Thus, in the absence of convincing generalizable evidence that regional anesthesia and analgesia decreases mortality and morbidity, an increasing body of evidence sup- ports the excellent pain relief it provides after surgery, which alone is suffi cient to justify its use, especially in view of the long-term benefi ts of adequate intra- and postoperative pain control on rehabilitation and prevention of chronic postsurgical
pain. This is best achieved with a multimodal approach, of which regional anesthesia is an essential component.
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