Epidural Analgesia Enhances Functional Exercise Capacity and Health-related Quality of Life after Colonic Surgery: Results of a Randomized Trial

The target population for this study was adult patients undergoing elective colorectal surgery for nonmetastatic conditions. Patients with malnutrition (serum albumin < 35 g/l), severe cardiopulmonary disease (American Society of Anesthesiologists physical status IV), sepsis (febrile on antibiotics), inflammatory bowel disease, chemotherapy or radiotherapy within the 6 months preceding surgery, and an inability to communicate or understand the aim of the project (questionnaire and consent form would need to be translated) were excluded. The study population was drawn from two adult hospital sites within the McGill University Health Centre from April 1998 and April 2000. The study was approved by the institutional ethics committees of the sites, and all 64 eligible patients agreed to participate in the study.

All patients meeting eligibility criteria were approached 1 or 2 weeks before surgery when the project was explained in detail by the investigators. The patients were not blinded, but both PCA and epidural groups were equally attractive to them. Patients agreeing to the study were evaluated for baseline variables by two study nurses specially trained in these assessments. On the morning of the surgical procedure, the group to which the subject had been randomly assigned was revealed. Two surgeons (P. B. and J. T.) with fellowship training in colorectal surgery performed the procedures in all patients. Both groups received a daily postoperative regimen whereby protein drinks and semisolid food were offered as well as assisted mobilization out of bed starting the morning after surgery. A total of 32 patients were randomized to the PCA group and 32 to the epidural group.

Assessments involved measurement of health-related outcomes, physiologic parameters, sociodemographic characteristics, compliance to regimen, adverse events, and hospitalization data. The measurement strategy varied according to the time interval from surgery (table 1).

Patients in the PCA group received general anesthesia consisting of thiopentone, 250 μg fentanyl, vecuronium, and 1–1.5% end-tidal isoflurane, nitrous oxide, and oxygen. Postoperative pain relief was with PCA morphine started at the end of surgery and continued for 4 days after surgery. The rate of infusion of intravenous morphine was set up at 1–2 mg every 5 min with no background infusion and increased if the visual analog scale (VAS; 0–100 mm) at rest was greater than 50. PCA was discontinued on days 3–4 after surgery if VAS on moving was less than 30.

In the epidural group, an epidural catheter was inserted before general anesthesia in the eighth or ninth thoracic interspace, and bupivacaine 0.5% was injected in divided doses to a maximum of 15–20 ml in the epidural space to produce a bilateral segmental sensory block to ice and pinprick between T4and S5 dermatomes. The neural blockade was maintained during surgery with additional 5 ml bupivacaine 0.5% administered hourly. A light general anesthesia included induction with thiopentone, 100 μg fentanyl, and vecuronium, and maintenance with 0.4% end-tidal isoflurane, nitrous oxide, and oxygen. An epidural infusion of bupivacaine 0.1% with 2 μg/ml fentanyl at a rate between 4 and 15 ml/h was started at the end of surgery and continued for up to 4 postoperative days.

The segmental sensory level of analgesia was assessed twice a day by the acute pain team using a blunted needle and ice, and the infusion was adjusted to maintain a sensory block between T7 and L3. The quality of pain relief was assessed using a VAS (0–100 mm; where 0 represents no pain and 100 the worst imaginable pain). If VAS at rest was greater than 50, the rate of infusion was increased to a maximum of 15 ml/h or the concentration of bupivacaine increased to 0.2% with the infusion rate decreased to 8 ml/h. If pain still persisted, the epidural catheter was resited and the block tested. If the surgical incision extended beyond the dermatome area covered by the block, epidural fentanyl was replaced by morphine (0.1 mg/ml). The epidural infusion was decreased on the third day after surgery and discontinued on day 4 if VAS on moving was less than 30. A neurologic profile was performed on a daily basis to assess sensory and motor deficit, and the epidural site was inspected for signs of infection. If the epidural block did not provide adequate analgesia, the patient continued to be included in the intention-to-treat analysis, but was excluded from analysis addressing efficacy.

Both groups also received 500 mg Naproxen either orally or rectally twice a day for 4 days. The discontinuation of epidural and PCA was decided on the following criteria: tolerance of oral diet, absence of complications, and active mobilization. Then, oral acetaminophen up to 4 g/day and codeine up to 60 mg/day were prescribed as required until discharge. The acute pain team was unaware of the results of the clinical assessment.

Bowel preparation and antibiotic prophylaxis were started the day before surgery. Nasogastric tube and abdominal drains were not inserted. The surgical incision was either a midline vertical or horizontal. All patients received an intravenous infusion of 0.9% normal saline at a rate of 6 ml · kg⁻¹· h⁻¹. No blood was transfused unless blood loss was more than 20% of the patient's circulating blood volume. Hypotension (arterial blood pressure < 80 mmHg) was treated with intravenous bolus doses of phenylephrine. A thermal blanket set up at 40°C was positioned on the exposed parts of the body to attenuate the heat loss during surgery. A bladder catheter was inserted before surgery to monitor urine output and was removed 48 h after surgery. Oxygen therapy (30% oxygen mask) was provided to all patients during the first 24 h. All patients underwent surgery during the morning hours. The patients were visited by the surgical team that was responsible for patients’ postoperative care and that was unaware of the results of the clinical or objective assessments. This team diagnosed and recorded daily gastrointestinal function (presence of abdominal sounds, passage of flatus, abdominal distension and tenderness, presence of bowel movements) and also determined the readiness for discharging patients from the hospital according to standard criteria (patients fully mobile without assistance, tolerance of semisolid and solid food, absence of infection and pain, and passage of stool). Length of hospital stay and readmission rate were also recorded. Postoperative complications were fully documented and diagnosed according to clinical and laboratory criteria. Postoperative complications to be recorded were intraabdominal sepsis, clinically apparent anastomotic leakage, wound infection, wound dehiscence, proven pulmonary emboli, pneumonia, urinary infection, myocardial infarction, cerebrovascular accidents, paralytic ileus, urinary retention necessitating bladder catheterization, and bowel obstruction. Daily assessments of VAS at rest, on coughing, and on moving were recorded by the research nurses, who were unaware of the results of the objective assessment and did not know the explicit hypothesis to be tested. Similarly, fatigue VAS response (0–5; where 0 represents no tiredness and 5 greatest tiredness) was recorded daily throughout the study.

Nutritional supplement in liquid form containing up to 60 g of protein and 1,500 calories, based on patient's body weight and formulated to personal taste, was offered from the first day after surgery to both groups by a dietitian unaware of the study and group allocation. This was done to make the two groups as similar as possible on all interventions except for the mode of analgesia. The daily nutritional support (calorie count and protein intake) was monitored and measured accurately by the ward dietitian to ensure that the nutritional supplement was provided equally to both groups and was appropriately documented. The protein and calorie intake was increased on day 2 in either liquid or solid form as tolerated by the patient. If nausea and vomiting became troublesome, the diet was temporarily discontinued, and an antiemetic (metoclopramide) was administered. In case of distended abdomen and protracted vomiting and ileus, the diet was discontinued and intravenous fluids provided.

Patients in both groups were encouraged by the research nurse to mobilize in the morning and late afternoon as of the first postoperative day. Time out of bed, either sitting or walking, was reported by the patients in their own journal. Vital capacity was measured before surgery and for the first 4 postoperative days with the patient in a semisitting position.

The primary outcome was functional exercise capacity as measured by the 6-minute walking test (6-MWT) before surgery and at 3 and 6 weeks after hospital discharge. The test has been shown to have a significant correlation with maximum oxygen consumption values obtained with other methods of exercise testing. 12Patients were asked to walk on level indoor ground as far as possible using any aid that is usually used. They were instructed to walk at a pace that would make them tired at the end of the walk. They could, however, adjust their pace as necessary and stop if they felt too tired or breathless or if they experienced pain. In this study, all subjects walked for 6 min along a 10-m course, and the total distance covered was measured. The evaluator gave encouragement during the walk using set phrases such as “good, keep going” or “keep it up, you are doing well.” When tolerable, one practice walk was performed to minimize the learning effect. The reliability of the 6-MWT has been evaluated by a number of investigators directly and indirectly, and measurement error is approximately 10%. 12 

The secondary outcome was health-related quality of life (HRQL) as measured by the acute (1-week recall period) SF-36 health survey. The SF-36 is a generic measure of perceived health status that incorporates behavioral functioning, subjective well-being, and perceptions of health by assessing eight health concepts: (1) limitation in physical activities because of health problems; (2) limitations in role activities because of physical health problems; (3) pain; (4) limitations in social activities because of health problems; (5) general mental health; (6) limitations in usual role activities because of emotional problems; (7) vitality (energy and fatigue); and (8) general health perception. 13It provides a comprehensive, validated, psychometrically sound and efficient way to measure health from the patient's point of view by scoring standardized responses to standardized questions. Reliability, both retested and internal consistency, has been extensively demonstrated, as have content, criterion, and construct validity and responsiveness to clinical changes. Recently, a method of scoring two components, physical and mental health, has been developed. The two subcomponents have been standardized to have a mean of 50 and a SD of 10. It is composed of 36 items and takes 10–15 min to complete. It can be self-administered or used by a trained interviewer in person or by telephone. This scale has been used in more than 200 studies in North America and in 40 surgical outcome studies. As part of an international initiative, the SF-36 has been applied to Canadian population and translated into Canadian French using a standard protocol. 14Conceptually, better HRQL should arise secondary to better functional exercise capacity and, thus, the primary outcome was the 6-MWT, and the secondary outcome was the SF-36.

Intermediate outcomes, or those that the recovery regimen mediates to achieve measurable patient outcomes, such as respiratory muscle function, gastrointestinal function, pain, and fatigue, were assessed. For the purpose of this study, the vitality subscale of the SF-36 (energy and fatigue) was also used as a measure of the intermediate variable, fatigue.

For purpose of sample estimation, we identified that a difference of 36 m walked in 6 min produces a meaningful impact on the lives of the subject. 15This magnitude of difference with an SD of approximately 50 m would require a total of 64 subjects for a 80% power and a risk of a type 1error of 5%. A pilot study of nine patients confirmed the feasibility of the investigation as a whole and provided estimates of variability for use in the power calculation.

The impact of the treatment group on the main outcomes such as 6-MWT and HRQL were analyzed using repeated-measures analysis of variance (time, group, and group × time). With the type of analysis, a significant group effect was interpreted as the effect of group averaged over all assessments, and a significant group × time effect was interpreted as an effect of group that depends on time, which was the hypothesis under investigation. For variables that did not depend on time (length of stay, readiness for discharge), a two-group comparison was made depending on the measurement scale. The time to first passage of flatus and first bowel movement was compared using the log-rank test.

The demographic characteristics and clinical data related to surgery, preoperative health status, and nutritional status of the two groups were comparable (table 2).

There was no difference between the two groups as far as surgical diagnosis, types of surgery, type of surgical incision, need of colostomy, duration of surgery, amount of blood loss and blood transfused, number of postoperative complications, length of hospital stay, and number of hospital readmissions. In contrast, the epidural group met the criteria to be discharged from the hospital significantly earlier than the PCA group (table 3). One patient in the PCA group, although enrolled in the study, was excluded from further analysis as he did not undergo colonic resection as previously thought. There were four readmissions, one in the PCA group and three in the epidural group between days 7 and 30 after surgery. The duration of hospital stay after readmission was from 1 to 3 days. There was one readmission in the PCA group on postoperative day 23 for prostatic surgery. In the epidural group, there were three readmissions, one on the day 10 for incisional hernia and two on days 12 and 14 for perineal dressing and closure.

There were a total of 27 postoperative complications within 1 month of surgery, with 13 in the PCA group and 14 in the epidural group (table 3). Four patients in the PCA group and three patients in the epidural group had postoperative ileus that resolved between 36 and 72 h. Perineal abscess occurred in 5 patients following low anterior resection between the 5th and 10th day after surgery. Wound infection occurred in 5 patients between the 5th and 17th day after surgery. Pleural effusion with progressive oxygen desaturation was treated conservatively and improved on day 7 after surgery. Distended abdomen with vomiting in 2 patients resolved within 72 h and did not require surgery. Two patients in the PCA group had an anastomotic leakage that was diagnosed on days 3 and 4 after surgery, while one patient in the epidural group was diagnosed at day 5. In one patient the leakage was treated conservatively, while in the other two (one in the PCA group and one in the epidural group) an ileostomy was performed. Two patients in the epidural group had urinary retention requiring bladder catheterization between days 4 and 5. A bleeding gastric ulcer was diagnosed and treated surgically in one patient in the epidural group on day 5, with a delayed discharge of 4 days. One patient in the epidural group returned to the hospital on day 10 for incisional hernia repair.

The evolution of functional exercise capacity and HRQL over time is presented in table 4, according to the group assignment. The values for Physical Health and Mental Health are presented along with the SF-36 subscales. As expected, there was a dramatic decrease in these measures postoperatively with some recuperation by the last evaluation at 6 weeks.

Because of this pattern, the difference from preoperative values was calculated for each subject and used as the primary outcome for the analysis. These values are presented in table 5.

As can be seen in this table for the 6-MWT, at 3 weeks after discharge there was an average decrease from baseline of 62.9 m in the PCA group and 32 m in the epidural group. At 6 weeks the decrease was 21.7 and 5 m for the PCA and epidural groups, respectively. While both groups showed an expected deterioration, the decrease for the PCA group was consistently greater over time than the decrease seen in the epidural group (time × group effect = 0.0005).

A similar pattern was observed for change in SF-36 Physical Health. Both groups deteriorated and then returned to baseline, but the epidural group showed less deterioration. For mental health, the epidural group recuperated their baseline values and the PCA group did not (group effect P = 0.002).

For completeness, the results of the subscales are also presented, but, as eight comparisons are being made, it is expected that there will be many significant associations.

Table 6presents the results for these intermediate outcomes. VAS rating of pain at rest, on coughing, and on moving was significantly lower in the epidural group compared with the PCA group, as was patients’ rating of fatigue. There was no impact of type of perioperative management on vital capacity nor on frequency of nausea and vomiting (data not presented).

Twenty-one patients (66%) in the epidural group passed gas and 13 (41%) had bowel movements in the first 48 h. This in contrast with the PCA group, where 8 patients (27%) passed gas and 1 (3%) had bowel movements in the first 48 h. By day 4, 97% of patients in the epidural group passed gas and 69% had bowel movements, whereas only 73 and 28% of patients in the PCA group passed gas and had bowel movements, respectively. This difference in time to recovery of gastrointestinal motility was significant according to the log-rank test (P < 0.01).

There also was a positive impact of epidural analgesia on activity and oral intake. These data are presented descriptively in table 7. Although there were significant differences, a large number of comparisons were made, and thus many differences would have been expected by chance alone.

The results of this prospective randomized study showed that patients undergoing elective colonic surgery recuperated functional exercise capacity and HRQL faster when managed with epidural analgesia than when managed with PCA. This was most likely a result of the positive effects of epidural analgesia on postoperative pain control, mobilization, gastrointestinal motility, and intake of protein and calories. These effects were not a result of differing postoperative protocols, as these were standardized for both surgical and nursing care. In addition, nutrition and assistance to mobilization were offered equally to the two groups.

For the outcome measure used, the 6-MWT, a change in 35 m is noticeable to the individual, and even a change as low as 12 m can be detected. 15In this study, the decrease from baseline to 3 weeks in the 6-MWT was, on average, 63 m for persons in the PCA group and 32 m for those in the epidural group (table 5). In the PCA group, 61% of the 31 persons studied declined by this critical amount at the 3-week assessment compared with only 38% in the epidural group; at 6 weeks, the proportions were 39 and 31% for the PCA and epidural groups, respectively.

Again, the difference from baseline in physical health (PCS value;table 5), 13.5 points for PCA and 11.2 for the epidural group at 3 weeks and 5.5 and 3.8 for the two groups, respectively, at 6 weeks, is clinically important. At baseline, the sample studied here, on average 60 yr of age, was within the normal range for Canadians of this age group. 14However, by 3 weeks the decline to 39 put the sample well below the norms for Canadians older than 75 yr; by 6 weeks, the sample had recovered to some degree but still remained at the values for persons more than a decade older. Although the absolute difference between the two groups was numerically small, a two-point change in PCS is associated with noticeable health effects in the general population. 13 

While the data on the changes on the different subscales of the SF-36 point out interesting patterns, it must be remembered that it is unwise to make inferences when many comparisons are made at the same time. Table 5shows that pain and vitality were two subscales where the epidural analgesia appeared to have lasting benefits. This type of information would be useful in designing future studies of surgical mechanisms and outcomes.

The mechanism whereby perioperative care can produce short- and long-term effects is not fully understood. 10What is known is that thoracic epidural local anesthetics have a direct effect on the gastrointestinal innervation, thereby facilitating restoration of motility. 16,17The earlier restoration of gastrointestinal function shown in the epidural group of this study is in agreement with previous findings 18,19and represents a clinically relevant achievement as it is one of the criteria used to decide the timing of discharge. 20It could be hypothesized that enhanced gastrointestinal function reduced unpleasant symptoms such as nausea and vomiting, thereby facilitating feeding. In fact, the oral intake of protein and calories was greater in the epidural group, with a daily average of 15–26 g of proteins and 400–900 calories within the first 4 postoperative days (table 7). Early feeding following colonic surgery is delayed by many surgeons until resolution of postoperative ileus, as it might compromise the intestinal anastomosis. However, recent prospective randomized studies have demonstrated the safety and tolerability of early feeding. 21–23 

Another beneficial effect of epidural analgesia is the optimal pain relief provided not only at rest but also during mobilization out of bed. These results are in agreement with other investigations confirming the superiority of epidural local anesthetic and opioid mixture in the pain management of patients undergoing colonic surgery. 19This intervention made it possible for the patients in the epidural group to be out of bed for a greater period of time. In fact, during the first 4 postoperative days, the patients in this group spent between 2 and 5 h out of bed, with most of the time spent walking. In contrast, patients in the PCA group spent much of their time out of bed, sitting rather than walking (table 7). It appears logical to attribute limited activity to the presence of pain on movement and, in fact, the VAS rating of pain on moving was significantly greater for patients in the PCA group than for those in the epidural group (table 6).

The potential benefits of activity have been demonstrated in many disabling conditions, 24,25and one might infer from the current study that excellent pain relief, by facilitating mobilization, would contribute to a reduction of side effects associated with bed rest, such as muscle wasting 26and impairment of homeostatic mechanisms. Unfortunately, little data are available on the effect of mobilization on the speed and quality of recuperation from surgery. Basse et al.  8reported daily mobilization greater than 8 h on the second postoperative day; however, it is not clear from their study how much of this activity was sitting or walking.

The challenge in assessing outcome following surgery is in choosing an appropriate measurement strategy both for short- and long-term outcomes. 10The outcomes must have a biologically plausible relation to the intervention being offered. In this study, the intervention was epidural analgesia, which is known to have an impact on pain. Because of the relation between pain and mobilization, measuring the time spent out of bed and walking was considered key in this study. We hypothesized that enhanced early mobilization would have a positive effect throughout the recuperation phase and translate into a better functional exercise capacity in the long term. The choice of the 6-MWT as the primary outcome was based on this premise. Although HRQL is increasingly being measured as an outcome following surgery, it is influenced by many factors (function, pain, social role, emotional role, physical role, mental health, energy, and general health). Of these, only a few are directly under the influence of our intervention, epidural analgesia.

The focus of this study was to evaluate whether the impact of the type of analgesia chosen would extend beyond the immediate short term and produce effects that would be noticeable to patients when they left the hospital and began their normal activities. This necessitated using outcome measures that were related to constructs relevant to people functioning in their own environments. The challenge in using these measures is in understanding what constitutes important change. When using physiologic measures, clinicians are familiar with values that indicate change.

Although criteria for discharge were achieved earlier in the epidural group, patients in this group went home at the same time as the PCA group (table 2). The reasons for keeping patients in hospital vary, and length of stay is influenced by the health care system, the administrative culture of the hospital, and patients’ expectations. While hospital stay is often used as an indicator of recovery, 9it is a poor proxy measure of this complex outcome. The implementation of standardized perioperative care plans that eliminate variation in intraoperative and postoperative care have been shown to influence positively hospital stay and morbidity. 27,28 

A key contributor to postoperative outcome is the number of complications. The rate of postoperative complications in the current study was twice the rate reported by Basse et al.  in a similar population. 8It has to be said that the study by Basse et al. , in contrast to ours, adopted a standardized and multimodal approach to perioperative care, suggesting that both strategies need to be present to modulate surgical pathophysiology.

Several mechanisms can be proposed to explain how a perioperative intervention, such as epidural anesthesia and analgesia, could influence postoperative functional exercise capacity and vitality. Evidence is mounting that epidural anesthesia has a positive influence on protein and glucose metabolism, leading to preservation of muscle protein, 29a decrease in whole body protein catabolism, 30an improved use of nutritional substrate, 31,32and amelioration of insulin sensitivity. 31However, a direct relation between the metabolic changes and functional outcome has not yet been demonstrated.

While the mechanisms relating short-term surgical recovery to long-term function are not fully understood, this study has shown that a relation is plausible. By manipulating the mode of analgesia, an immediate impact on pain, bowel function, and ability to mobilize was observed. In addition, the effects on exercise capacity and HRQL were evident even as long as 6 weeks after surgery.

The authors thank Rose De Angelis, R.N., M.Sc., and Louise Lamb, R.N. (Research Nurses, Department of Anesthesia, McGill University Health Centre), for their valuable assistance with data collection, and Lyne Nadeau (Data Manager, Division of Clinical Epidemiology, McGill University Health Centre), for conducting the data analysis.