Anesth Analg 2004;99:1173-1179
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130260.24433.A2
PAIN MEDICINE
Postoperative Pain After Abdominal Hysterectomy: A Double-Blind Comparison Between Placebo and Local Anesthetic Infused Intraperitoneally
Anil Gupta, MD FRCA, PhD*,
Andrea Perniola, MD*,
Kjell Axelsson, MD PhD*,
Sven E. Thörn, MD PhD*,
Kristina Crafoord, MD
, and
Narinder Rawal, MD PhD*
Department of Clinical Medicine, *Division of Anesthesiology, and
Obstetrics and Gynecology, University Hospital, Örebro, Sweden
Address correspondence and reprint requests to Anil Gupta, MD, FRCA, PhD, Department of Anesthesiology and Intensive Care, University Hospital, SE 701 85 Örebro, Sweden. Address e-mail to anil.gupta{at}orebroll.se
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Abstract
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Abdominal hysterectomy is associated with moderate to severe postoperative pain. We randomly divided 40 patients (ASA status I–II) undergoing elective abdominal hysterectomy into 2 groups: group P received an infusion of normal saline 5 mL/h via a catheter placed intraperitoneally at the end of surgery, and group L received 0.25% levobupivacaine 12.5 mg/h (5 mL/h). Ketobemidone was administered IV via a patient-controlled analgesia pump as a rescue analgesic in all patients. The catheter was removed after 24 h. Incisional pain, deep pain, and pain on coughing were assessed 1, 2, 3, 4, 8, 16, and 24 h after surgery by using a visual analog scale. Ketobemidone consumption during 0–72 h was recorded. Time to sit, walk, eat, and drink; home discharge; and plasma concentrations of levobupivacaine were also determined. Pain at the incision site, deep pain, and pain on coughing were all significantly less in group L compared with group P at 1–2 h after surgery. After 4 h, the mean visual analog scale pain scores at rest and during coughing remained <3 cm during most time periods. Total ketobemidone consumption during 4–24 h was significantly less in group L compared with group P (mean, 19 versus 31 mg, respectively). A less frequent incidence of postoperative nausea, but not vomiting, was also found during 4–24 h in group L compared with group P (P < 0.025). Total and free plasma concentrations of levobupivacaine were small. We conclude that levobupivacaine used as an infusion intraperitoneally after elective abdominal hysterectomy has significant opioid-sparing effects.
IMPLICATIONS: A double-blind study was performed to assess postoperative pain and analgesic requirements after abdominal hysterectomy. Postoperative intraperitoneal local anesthetic infusions (levobupivacaine 12.5 mg/h) had a significant opioid-sparing effect compared with placebo and had a less frequent incidence of postoperative nausea during 4–24 h.
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Introduction
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Abdominal hysterectomy with or without salpingo-oophorectomy is associated with moderate to severe postoperative pain (1). Morphine is often used via patient-controlled analgesic (PCA) pumps, but the large quantities required can lead to fatigue, nausea, and vomiting, as well as the inability to mobilize because of drowsiness (2,3). Many studies have been performed to reduce postoperative pain by using different techniques, including local anesthetic (LA) infiltration (1,4), nonsteroidal antiinflammatory drugs (5), and music and positive suggestion (6,7), but with varying results.
LAs have been infiltrated (4), infused subcutaneously (8), and injected into the peritoneal cavity (1) at the end of abdominal hysterectomy, with varying effects. However, the effect duration is limited to approximately 4 h and subsides subsequently. Intraperitoneal injection of LAs through a catheter has also been studied after laparoscopic cholecystectomy, and favorable effects were found for approximately 4 h (9). A prolonged analgesic effect was not seen in this study, possibly because of the mild character of the postoperative pain. No studies have used LAs infused into the abdomen to provide sustained postoperative pain relief.
We hypothesized that LAs infused intraperitoneally after elective abdominal hysterectomy have an opioid-sparing effect. The aim of the study was therefore to assess the efficacy of levobupivacaine in reducing opioid requirements after abdominal hysterectomy.
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Methods
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After approval from the IRB, informed consent was obtained from 40 patients (ASA status I–II) undergoing elective abdominal hysterectomy. Patients undergoing surgery for cancer and those receiving chronic analgesic medication were excluded.
Computer-generated random numbers were obtained and inserted into opaque sealed envelopes, which were opened at the end of the operation. A nurse who did not participate in the study was asked to mix the study drugs into a sterile disposable plastic bag. The bag contained either 300 mL of 0.9% NaCl (group P) or 750 mg of levobupivacaine in 0.9% NaCl (total volume, 300 mL) (group L). The code could be broken only after all patients had been recruited into, and completed, the study.
All patients were premedicated with a tablet of diazepam 10 mg 1 h before the planned surgery; this is routine in our hospital. Paracetamol 1 g was given rectally every 6 h starting with the first dose at the time of premedication. After IV cannulation, anesthesia was induced with fentanyl 1–2 µg/kg IV and propofol 1–2 mg/kg until loss of the eyelash reflex. Tracheal intubation was performed after muscle relaxation with rocuronium 0.5 mg/kg, and anesthesia was maintained with 1%–3% sevoflurane in 33% oxygen and 66% nitrous oxide. Mechanical ventilation was used in a low-flow system to maintain an end-tidal CO2 of 4.5–5.5 kPa. Monitoring included noninvasive arterial blood pressure, heart rate, peripheral oxygen saturation, end-tidal gas monitoring, electrocardiogram, and train-of-four stimulation. Sevoflurane concentration was adjusted to maintain adequate anesthetic depth as assessed clinically, and IV fentanyl was given intermittently as an analgesic when required. At the end of the operation, muscle relaxation was reversed with glycopyrrolate (0.2 mg) and neostigmine (2.5 mg), and the gases were turned off abruptly. After satisfactory spontaneous ventilation and awakening, the trachea was extubated, and the patient was transferred to the postoperative ward.
Surgery was performed in a standardized manner by using either a lower abdominal midline incision or a Pfannenstiel incision, depending on the indication for surgery and the expected degree of surgical difficulty. Surgery could be either a supravaginal hysterectomy or a total abdominal hysterectomy (with or without salpingo-oophorectomy).
Before the peritoneum was closed, a multihole catheter was inserted percutaneously approximately 1 cm from the incision, and the tip of the catheter was placed supravaginally. No attempt was made to fix the catheter intraperitoneally. Levobupivacaine was obtained from the pharmacy in a concentration of 0.75% (volume, 20 mL/ampule). One-hundred milliliters of this was taken and mixed with 200 mL of 0.9% NaCl to provide 750 mg of levobupivacaine in 300 mL, or 2.5 mg/mL. This was infused at 5 mL/h (12.5 mg/h) for 24 h. An additional 20 mL of this solution (50 mg) was injected subcutaneously before skin closure. The total amount of levobupivacaine injected during 24 h was thus 350 mg. After surgery, patients were given ketobemidone (a narcotic analgesic equipotent with morphine) 1–2 mg IV during the first 4 h for pain relief in the postanesthesia care unit (PACU). Thereafter, a PCA pump with ketobemidone (1-mg bolus with a 6-min lockout time) was connected IV as rescue medication, and the patients were instructed in its use before surgery. The patients were specifically instructed to request analgesics or use the PCA if pain exceeded 3 cm on the visual analog scale (VAS), which is routine in our hospital. All patients were observed in the PACU for 4 h before being transferred to the general gynecological ward. After 24 h, the catheter was withdrawn, and the catheter tip was sent for bacterial culture.
For all measurements, the time at which the study drug infusion was started was considered to be Time 0 (t = 0). In addition to the routine postoperative protocols, the following measurements were made: VAS pain score (0–10 cm; 0 = no pain and 10 = worst imaginable pain) for pain at the site of incision, deep (visceral) pain, and pain on coughing at 1, 2, 3, 4, 8, 16, and 24 h; nausea or vomiting (0–4 h and 4–24 h); total ketobemidone consumption during 0–4 h and 4–24 h; ability to drink and walk; and time to home discharge. If nausea was severe or if the patient vomited, antiemetics were administered, which is routine in our hospital. Standardized discharge criteria were used. In addition, the surgical site was inspected daily for evidence of infection and registered on a scale of 0–4 (0 = no evidence of infection or inflammation; 4 = pus coming out from the incision). Blood was taken for analysis of white cell count and C-reactive protein (CRP) to exclude any evidence of infection at 24 h.
Blood (7 mL) was taken in heparinized tubes (n = 73) after 3, 23, 25, and 27 h to measure the plasma concentration of levobupivacaine. The blood was centrifuged to separate the plasma, which was frozen to –20°C. Chromatography was performed with a Zorbax SB-C18 column (75 x 4.6 mm; 3.5-µm particle diameter). The eluent consisted of 15 mM sodium dihydrogen carbonate buffer (pH 3.0)/acetonitrile (4:1) and was pumped at 1.0 mL/min. Detection was performed at 210 nm. The free fraction was determined from the eluate, and the total concentration was determined from plasma samples before centrifugation. Results are presented as median and interquartile range.
The number of patients required for the study was calculated on the basis of total morphine consumption during 24 h, which was found to be 40 ± 10 mg in previous studies. We were interested in a reduction by 25% in the group given LA. Assuming 
= 0.05, we calculated that we would need 32 patients (16 in each group) to achieve a power of 80% (ß = 0.2). Unless otherwise stated, all results are shown as mean ± SD. Demographic data were compared by using the unpaired Student’s t-test. VAS scores were compared between the groups by using repeated-measures analysis of variance for assessment of time and treatment effects. When differences were found, a post hoc test (the Scheffé test) was used to assess these differences. For comparison of postoperative ketobemidone consumption, the unpaired Student’s t-test was used. Binomial comparisons were made with the 
2 test. A P value <0.05 was considered to be statistically significant.
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Results
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No differences were found between groups in demographic data, duration of operation and anesthesia, or the surgery performed (Table 1). The intensity of postoperative pain on the VAS is shown in Figures 1–3. Incision pain was more intense in the placebo group for the first hour after the operation but thereafter was similar between groups (P < 0.05). Deep (visceral) pain was more frequent in the placebo group for 1–2 h, and pain on coughing was severe in intensity and significantly greater in group P compared with group L for 1–2 h (P < 0.05). No differences were found between groups in VAS pain scores after 2 h. The mean incision and deep pain scores in group L were <3.5 cm at all time points during 24 h.
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Figure 1. Visual analog scores (VAS) for pain at the incision site. All results are shown as mean ± SD; *P < 0.05.
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Figure 2. Visual analog scores (VAS) for deep (visceral) pain. All results are shown as mean ± SD; *P < 0.05.
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Figure 3. Visual analog scores (VAS) for pain on coughing. All results are shown as mean ± SD; *P < 0.05.
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The supplemental requirements of ketobemidone for 0–4 h were similar between groups. Thereafter, the ketobemidone consumption via the PCA pump was significantly more in group P compared with group L for 4–24 h (mean, 31 versus 19 mg) (P < 0.012) (Table 2). The total ketobemidone consumption for 0–24 h was also significantly less in group L compared with group P (P = 0.025). No differences were found between groups at 24–72 h after surgery. No differences in ketobemidone consumption were seen in patients who had a Pfannenstiel incision as compared with a lower midline incision or in those who had a total hysterectomy with salpingo-oophorectomy compared with subtotal hysterectomy.
No significant differences were found in recovery times between groups, although there was a tendency toward earlier mobilization in group L compared with group P. The length of stay in the postoperative ward and hospital was similar in group L compared with group P (Table 3). However, one patient in group P had a prolonged stay (11 days) because of a postoperative respiratory infection.
The incidence of postoperative nausea (PON) was 40%–50% for 0–4 h and was similar between groups. However, PON was significantly less in group L compared with group P (P < 0.025) for 4–24 h after surgery. No differences were seen in the incidence of postoperative vomiting (POV) between groups (Table 4). The number of patients who received antiemetics was similar between groups. No other differences were found in any side effects between groups. No patient had any evidence of systemic infection (increase in CRP or white blood count or fever). Inspection of the surgical wound revealed redness of the wound in one patient (group P) on Day 1, and although positive cultures of isolated bacterial growth were obtained from the catheter tip in two other patients (one in each group), there was no clinical (local redness or fever) or laboratory (increase in CRP or white blood count) evidence of infection in either of these patients.
The free and total plasma concentrations of levobupivacaine at 3, 23, 25, and 27 h are shown as box-and-whisker plots in Figures 4 and 5, respectively. The median (range) total and free concentrations of levobupivacaine obtained after 23 h of infusion were 2208 nmol/L (789–3998 nmol/L) (0.64 µg/mL [0.23 – 1.15 µg/mL]) and 40.3 nmol/L (19.3–119.5 nmol/L) (0.01 µg/mL [0.006 – 0.03 µg/mL]), respectively. No clinical evidence of LA toxicity was seen in any patient.
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Figure 4. Total plasma concentration of levobupivacaine is presented as median and 25th–75th percentile (box plot).
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Figure 5. Free plasma concentration of levobupivacaine is presented as median and 25th–75th percentile (box plot).
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Discussion
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We found a significant opioid-sparing effect in patients receiving levobupivacaine compared with placebo infusion for 4–24 hours. This was associated with a significant reduction in PON, but not POV, during 4–24 hours. A short-lasting reduction in VAS pain scores was also seen for 1–2 hours after surgery in the levobupivacaine group. No signs of LA toxicity or other side effects were reported by any of the patients.
Pain after abdominal hysterectomy can be multifactorial. Incision pain, pain from deeper (visceral) structures, and, particularly, dynamic pain, such as during straining, coughing, or mobilizing, can be quite severe. In one study, the authors found that visceral pain dominated during the first 48 hours after hysterectomy (10). Although LAs have been injected into the surgical wound in numerous studies, the effect is equivocal; some studies show a good effect (4,11,12), whereas others show no effect (8,10). In a systematic review of the use of incisional LAs, Møiniche et al. (13) found inconclusive results after all operations except inguinal herniorrhaphy, for which LA provided up to seven hours of analgesia. In most studies on abdominal hysterectomy, the authors have not assessed pain at different sites, and therefore it is difficult to conclude the true benefit of subcutaneously placed catheters on incisional pain during major abdominal surgery. In our study, one group was given an active substance (levobupivacaine) locally into the subcutaneous tissue as a single dose. Pain intensity characterized by VAS was less in the group given LA. However, the effect was short lived, and no differences were seen after one hour. This effect can be prolonged by using catheters inserted into the site of incision and injecting LAs (11,12).
Deep (visceral) pain after abdominal hysterectomy is often moderate to severe, particularly on straining (dynamic pain). LAs injected intraperitoneally have been found to provide pain relief, which, however, is of short duration (1,14). In one study in which the authors inserted a catheter intraperitoneally after laparoscopic cholecystectomy, reduced pain intensity was demonstrated for four hours after surgery (9). The short-lasting effect was attributed to the mild pain seen after four hours after this procedure. In this study, we found that VAS deep (visceral) pain and pain on coughing were significantly reduced in the LA group only during the first one to two hours, when analgesics were administered by nurses. Thus, nurse assessment of pain during the early postoperative period may be lower and therefore inadequately treated. Once the PCA device was connected, it is likely that patients controlled their pain appropriately and adequately with IV ketobemidone, which is why only mild pain was reported after two hours. In the absence of other methods to relieve pain, the average postoperative morphine consumption during the first 24 hours varies from 35 to 62 mg in different studies (1,6). We found a significant reduction in postoperative ketobemidone consumption for 4–24 hours in the group given an LA infusion intraperitoneally compared with placebo by almost 40%. Despite the reduction in analgesic requirement during the 24-hour period with levobupivacaine infusion, patients had moderate pain during coughing, which is not satisfactory, and this issue needs to be addressed in future studies. Factors such as the type of LA, the doses used, and the method of administration, as well as the site of catheter placement, need to be assessed. We did not find that patients with a Pfannenstiel incision had smaller ketobemidone requirements during 4–24 hours compared with those with a midline lower abdominal incision.
The smaller analgesic requirements in the group with an LA infusion did not translate into earlier mobilization or home discharge. Although most recovery variables did occur earlier in the LA group, no statistically significant differences were found between groups. Because this study was not sufficiently powered to detect these differences, it is difficult to say whether the benefits to the patients in terms of better pain relief with LA truly translate into better outcome. A larger study with the primary aim of studying these variables—and that is adequately powered to detect these differences—is now needed. Although length of stay in the hospital is important, it remains very subjective, and thus differences (if any) are not easy to detect.
A good technique should not result in an increase in the incidence of side effects for patients. LAs are well tolerated by most patients and, if used in appropriate doses, have minimal side effects. In this group of 20 patients, we saw no side effects, and the overall incidence of minor complications was similar between groups. The total plasma concentration of levobupivacaine was smaller than that reported to give mild central nervous system symptoms. The free plasma concentration of levobupivacaine in this study was much smaller than that reported to produce symptoms of LA toxicity with bupivacaine (15). There are no human data on toxic concentrations of levobupivacaine after infusion. In one study, the authors infused a total dose of up to 470 mg of levobupivacaine epidurally during 24 hours without any signs or symptoms of LA toxicity (16). Because the free plasma concentration of bupivacaine required to produce cardiovascular toxicity is approximately 25%–50% less than for levobupivacaine (17), it is unlikely that LA toxicity with these doses of intraperitoneal levobupivacaine is an issue. The reduction in ketobemidone consumption should also lead to a reduction in its side effects, such as nausea, vomiting, fatigue, and drowsiness. The incidence of PON, but not POV, was less frequent in the levobupivacaine group during 4–24 hours, when the ketobemidone consumption was also less. This would confirm the benefits of reducing narcotic analgesics in the postoperative period by using alternative techniques for managing pain. Studies in which opioid-free anesthetics are used (such as during regional anesthesia) have consistently shown fewer side effects. The overall incidence of other minor complications was small in our study, which would mean that more patients would need to be studied to find any significant differences between groups.
Our study is limited in its conclusions, because we studied a small group of patients undergoing elective surgery under optimal conditions. Thus, the beneficial effects of LA seen in this study cannot be translated to other patients undergoing different types of surgery. More studies in more patients are thus needed. We did not measure the hourly postoperative consumption of analgesics, which may have been an advantage. However, we used a PCA pump under clinical limitations, which did not allow the personnel or researchers to quantify this variable hourly. Thus, we chose to assess pain during the first 4 hours (in the PACU) and during the next 20 hours (in the general ward). The catheter was removed after 24 hours because our experience had suggested that pain intensity is maximal during the first 24 hours. In hindsight, it may have been better to continue with the LA infusion up to 72 hours, because analgesic consumption continued to be moderate after 24 hours. Finally, our dosing of LA was based on equipment availability (elastometric infusion pumps) and existing knowledge of dose limitations of levobupivacaine based on epidural infusions. In view of the small plasma concentrations achieved, it is possible that larger doses may be used without leading to LA toxicity. That may provide better pain relief; therefore, future studies should address the issue of optimal doses of LAs, particularly in the early phase (zero to four hours), to provide the best pain relief in this group of patients.
In conclusion, in this double-blind study, we were able to demonstrate a significantly smaller opioid consumption with levobupivacaine infused intraperitoneally after abdominal hysterectomy. This opioid-sparing effect lasted from 4 to 24 hours and was associated with a reduced incidence of nausea. However, no other differences were found between the groups in time to eating, drinking, mobilizing, or home discharge.
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Acknowledgments
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Supported by the Clinical Research Center, University Hospital, Örebro, Sweden, and Research Funds from Örebro County Council, Örebro, Sweden.
The authors are indebted to the personnel in the PACU and the Department of Gynecology—specifically, Ingegard Welhemsson and Mikael Lood—for their constant help and enthusiasm during various stages of the study. We would also like to thank Abbott Scandinavia for financial help in the analysis of plasma concentrations of levobupivacaine.
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Accepted for publication April 9, 2004.
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Abstract
Introduction
