Postoperative pain is a major concern because it affects multiple systems and induces physiological, immunological, and psychological changes.1,2 Pain management in the perioperative period has been traditionally based on opiates. Considering their side effects, new drugs, opiate-sparing drugs, and novel techniques were introduced for treatment of postoperative pain, including postoperative epidural and continuous peripheral nerve block.1 A frequently used local anesthetic, lidocaine, has been introduced as part of perioperative pain management. It has been shown that IV lidocaine provides effective postoperative analgesia, reduces opiate consumption, accelerates the recovery of bowel function, and facilitates rehabilitation after surgery.3–5 Tissue and peripheral nerve injury leads to a local inflammatory reaction accompanied by increased levels of proinflammatory cytokines, including interleukin (IL)-1β and IL-6, which induce peripheral and central nervous system sensitization leading to hyperalgesia.6 IL-1β induces long-lasting synthesis and release of substance P from peripheral nerve terminals of primary afferent neurons, which may contribute to neurogenic inflammation. Lidocaine has an antiinflammatory property reflected by decreased upregulation of proinflammatory cytokines both in vitro and in vivo.7,8 Lidocaine also stimulates the secretion of the antiinflammatory cytokine IL-1 receptor antagonist (IL-1ra).9 We have previously shown the suppressive effect of opiates on the immune system10,11 and the beneficial effect of preemptive epidural analgesia, primarily based on local anesthetics, on pain, and cytokine production during the postoperative period.12 In this study, we hypothesized that IV administration of a local anesthetic (lidocaine), preincisionally and intraoperatively, may have a beneficial effect on pain intensity and immune reactivity during the postoperative period; that is, that a possible similar beneficial effect could be achieved by preoperative and intraoperative administration of local anesthetic IV rather than via the epidural route. This study was conducted in patients undergoing transabdominal hysterectomy, who were treated postoperatively with patient-controlled epidural analgesia (PCEA).
Sixty-five women aged 45–70 yr (ASA physical status I or II), undergoing transabdominal hysterectomy operation by the Pfannenstiel approach, were included in the study after obtaining approval from the Hospital Human Studies Committee and patients’ informed consent. Exclusion criteria were hypertension, arrhythmia, diabetes, and patients with previous medication with immunosuppressive drugs, nonsteroidal antiinflammatory drugs, or steroids. Two patients who needed blood transfusion during the perioperative period and 3 with fever more than 38°C during the immediate postoperative period were withdrawn from the study.
At the preoperative anesthesiology visit, the patients were randomly assigned to 1 of 2 perioperative pain management techniques: the first group (n = 32) received IV lidocaine, starting 20 min before the beginning of surgery and continued during the operation, followed postoperatively by PCEA (Lidoc + PCEA group). Patients in the second group (n = 33) were given an equal volume of saline infusion followed by PCEA in the postoperative period (Sal + PCEA group). A 10-cm visual analog scale (VAS) (with end points labeled “no pain” and “worst possible pain”) was used to assess pain intensity during rest and after coughing at 4, 8, 12, 24, 48, and 72 h after surgery.
On the morning of surgery, an anesthesiologist who did not participate in the study was instructed to prepare 2% lidocaine or saline solution in a syringe pump labeled number 1 or 2, respectively, and hand it to the anesthesiologist in charge without notifying him of the content. The patients were orally premedicated with 1–2 mg lorazepam 90 min before induction of anesthesia, followed by IV 2–3 mg midazolam on arrival at the operating room. An epidural catheter was placed in all patients via the L2-4 interspace and advanced 3–4 cm cephalad. The position of the epidural catheter was tested by injection of 3 mL 2% lidocaine. Lidoc + PCEA group patients received an IV bolus injection of 2 mg/kg lidocaine through the numbered syringe followed by a continuous IV infusion of 1.5 mg · kg−1 · h−1. Sal + PCEA group patients received a bolus and infusion of saline using the same procedure. Surgery ensued 20 min after administration of the lidocaine bolus. At completion of surgery, the lidocaine and saline infusions were terminated.
After IV administration of lidocaine bolus, general anesthesia was induced using IV fentanyl 2–3 μg/kg, propofol 1.5–2 mg/kg, and vecuronium 0.1 mg/kg. Anesthesia was maintained with N2O, isoflurane, and additional fentanyl. Mean arterial blood pressure was maintained within 20% of baseline values with isoflurane (end-tidal concentration 0.6%–1.2%) and fentanyl. Patients received upper body forced-air warming, and IV fluids were warmed to 37°C.
Postoperative Pain Management
On arrival to the postanesthesia care unit (PACU), patients of both groups were connected to a PCEA pump (Pain Management Provider, Abbott, Chicago, IL) and received an initial loading dose of 3–5 mL 0.1% bupivacaine + 2 μg/mL fentanyl and a bolus of 3 mL 0.1% bupivacaine + 2 μg/mL fentanyl on demand (lockout time 10 min), with continuous background infusion of 6 mL/h. The total doses of intraoperative fentanyl and PCEA during the 24 h after surgery for both groups are detailed in Table 1. Postoperative analgesia was given only by PCEA to avoid nonsteroidal antiinflammatory drugs or opiates that may have affected the study outcome.
Venous blood samples (15 mL) were collected on the morning of surgery and at 24, 48, and 72 h after surgery. Samples were prepared as previously described.13 Briefly, peripheral blood mononuclear cells (PBMCs) were isolated and frozen at −70°C until used. On the day of assay, cells were thawed quickly, washed 3 times in RPMI-1640 (Biological Industries, Beit Haemek, Israel) containing 1% penicillin, streptomycin, and nystatin and supplemented with 10% fetal calf serum, designated as complete medium, and their viability was tested by trypan blue dye exclusion. The viability was >95%.
Cytokine (IL-6 and IL-1ra) Production
PBMCs (2 × 106) suspended in 1 mL of RPMI-1640 supplemented with 5% fetal calf serum were incubated for 24 h in the presence of 10 ng/mL lipopolysaccharide (Escherichia coli, LPS, Sigma-Aldrich, Rehovot, Israel). After the incubation period, culture media were collected and kept at −70°C until assayed for cytokine content. Cytokine concentration was assessed using enzyme-linked immunosorbent assay kits specific for human IL-6 (Pharmingen, San Diego, CA) and IL-1ra (Biosource International, Camarillo, CA), as detailed in the guideline provided by the manufacturers. The detection levels of the cytokines in the assays were 15 pg/mL for IL-6 and 60 pg/mL for IL-1ra.
PBMC 0.1 mL suspension (2 × 106 cells/mL) was aliquoted and coincubated with 0.1 mL of 2% phytohemagglutinin (PHA-M, Difco Laboratories, Detroit, MI) or complete medium for 3 days. Methyl-3H-thymidine (3H-TdR) 0.5 μCi/mmol (Amersham, Buckinghamshire, UK) was added 18 h before harvesting. Radioactivity was measured with an LKB liquid scintillation counter model 3380.
The number of observations varied slightly among the assays, as a result of occasional missing samples or a problem during a particular assay. Data were analyzed for each measure, using analysis of variance with repeated measures (time periods before and after surgery). Post hoc Bonferroni procedure was considered appropriate, correcting for multiple comparisons. Probability values of P < 0.05 were considered significant. The results are expressed as mean ± sem. Post hoc power analysis revealed the power to detect a significant difference between groups in the range of 96%–99%, at an α level of 0.05, with the number of patients participating in this study.
The 2 study groups were similar in number, body weight, age, and duration of surgery (Table 1). Intraoperative fentanyl consumption was less in the Lidoc + PCEA patients, averaging 249 vs 283 μg in the Sal + PCEA group. However, the differences are quite small and this finding is not significant (P = 0.04).
There was a significant difference in VAS scores at rest and during coughing in the first 8 h between groups (Table 2). Patients of the Lidoc + PCEA group experienced less-intense postoperative pain at 4 and 8 h: VAS 4.0 (P = 0.03) and VAS 3.7 (P = 0.011) at rest and VAS 5.3 (P = 0.0001) and VAS 5.0 (P = 0.048) during coughing, respectively. VAS scores did not differ between groups for 12–72 h after surgery. Between 12 and 24 h postoperatively, the average VAS was 3.4 at rest and 4.2 during coughing. After 72 h, the VAS was 2.5 at rest and 3.2 during coughing in both groups. Over the first 24 h after surgery, patients in the Lidoc + PCEA group received a PCEA total volume of 229 mL of 0.1% bupivacaine + 2 μg/mL fentanyl using an average of 28 boluses compared with 247 mL and 35 boluses in the Sal + PCEA group. These variations are not significant. No differences were found in PCEA drug consumption during the next 48 and 72 h.
PHA-M–induced proliferation of PBMCs did not change significantly during the postoperative period in both groups as compared with before surgery (Fig. 1A). However, whereas the proliferative response induced by PHA-M was similar in the 2 groups before the operation, the mitogenic response to PHA-M was less suppressed in the Lidoc + PCEA group compared with the Sal + PCEA group, an effect observed throughout the 72 postoperative hours. Analysis of variance with repeated measures for lymphocyte proliferative response to PHA-M revealed that in the Sal + PCEA group (n = 30), it was significantly lower at 24 h (P = 0.017), 48 h (P = 0.029), and 72 h (P = 0.009) compared with that of cells from patients in the Lidoc + PCEA group (n = 25).
Ex Vivo Cytokine Production
IL-1ra Cytokine Production
Sal + PCEA patients (n = 30) had increased IL-1ra production at 24 h (P = 0.0001), 48 h (P = 0.0012), and 72 h (P = 0.001) compared with before surgery (P = 0.01; Fig. 1B). The production of IL-1ra in cells from patients in the Lidoc + PCEA group (n = 26) did not change significantly during the postoperative period. There was a significant increase in IL-1ra production at 24 h only in the Sal + PCEA group versus Lidoc + PCEA group (P = 0.024).
IL-6 Cytokine Production
IL-6 production increased during the postoperative period in the Sal + PCEA group (n = 28, P = 0.025), whereas in the Lidoc + PCEA group (n = 29), the secretion of IL-6 did not change significantly (P = 0.749; Fig. 1C). At 24, 48, and 72 h, IL-6 secretion increased by 2.32 (P = 0.001), 2.16 (P = 0.0009), and 2.62 (P = 0.012) fold, respectively, compared with that produced before surgery and was significantly higher than in the Lidoc + PCEA group at the 3 timepoints examined (P = 0.0018, P = 0.0005, and P = 0.012, respectively).
The present findings indicate that the group receiving preincisional and intraoperative IV lidocaine experienced better pain relief in the immediate postoperative period, which was associated with an attenuated suppression of a lymphocyte proliferative response and attenuated production of both pro- and antiinflammatory cytokines (IL-6 and IL-1ra, respectively). IL-1β plays an important role in acute phase reactions; however, other cytokines, such as IL-1ra and IL-6, may be more sensitive to minor immune changes.13 Therefore, in this study, we chose to examine the cytokines IL-1ra and IL-6.
Surgery is associated with increased production of proinflammatory cytokines, which may lead to a systemic inflammatory response followed by a compensatory excessive antiinflammatory cytokine production. Consequently, the patient may become immune-compromised and predisposed to opportunistic infection and multiple organ failure14 and may be vulnerable to the development of postoperative ileus.15 Accordingly, attenuated levels of cytokines after perioperative lidocaine administration have been associated with improved bowel function.16 The mitogenic response of lymphocytes to PHA-M is another important tool, which mimics the activity of the immune system in response to exogenous stimulus. The mitogenic response to PHA-M was less suppressed in the Lidoc + PCEA group compared with the Sal + PCEA group, suggesting better immune function in the first group.
The main objective of postoperative pain management is, obviously, to reduce the pain experienced by the patient, but it also serves to attenuate the pain-induced physiological and metabolic changes. Among several mechanisms of pain, proinflammatory cytokines have been extensively investigated. One study indicated that there are reciprocal interactions between proinflammatory cytokines and pain in which proinflammatory cytokines modulate pain sensitivity, whereas pain affects the synthesis and release of cytokines.17
Intravenous lidocaine has analgesic,5 antihyperalgesic,18 and antiinflammatory7 properties. Local anesthetics can reduce the postoperative inflammatory response in several ways, such as blocking neural transmission at the site of tissue injury and thus attenuating neurogenic inflammation.19 In addition, because of antiinflammatory properties of their own, they may inhibit the migration of granulocytes and release of lysosomal enzymes, consequently leading to a decreased release of proinflammatory cytokines.20,21 Proinflammatory cytokines can induce peripheral and central sensitization, leading to pain augmentation (hyperalgesia).6 Thus, it is possible that the attenuated production of IL-6 observed in the Lidoc + PCEA patients could partially account for their reduced pain.
Among the study limitations, we administered local anesthetics IV preoperatively and intraoperatively and continued epidurally (rather than IV) during the postoperative period. An alternative approach would have been to continue IV lidocaine into the postoperative period. However, the safety of IV lidocaine for postoperative analgesia has not yet been clearly determined. The postoperative period is characterized by multiple influences on drug distribution and elimination, and it is still unknown whether the accumulation of IV lidocaine after a prolonged period remains below toxic levels.22 It should be noted that the 2 groups showed marginal differences in the intraoperative consumption of fentanyl and in the 24-h postoperative PCEA volume (background plus per demand). These differences are quite small and seem to be inconsequential in terms of the variables measured in this study; however, we cannot completely exclude that they may have some impact on our results.
The present findings indicate that preincisional and intraoperative IV lidocaine improves postoperative pain management and reduces surgery-induced immune alterations.
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