Pain, and side-effects of opioid analgesics especially, such as postoperative nausea and vomiting (PONV), sedation and delayed return of bowel function, is the common reason for prolonging hospital stay. An increasing amount of evidence suggest that perioperative intravenous lidocaine can influence pain severity, postoperative analgesic requirement, recovery of bowel function and the length of hospital stay, with fewer adverse effects than analgesics alone.1–3 A recent systematic review concluded that a continuous perioperative infusion of lidocaine has benefit for patients undergoing abdominal surgery, as it provides significant pain relief, reduces postoperative opioid requirement, decreases opioid-induced nausea and vomiting and promotes faster recovery of bowel function, allowing for a shorter hospital stay.4 In laparoscopic surgery, reports are scarce and the results conflicting.2,5–7 It seems that individual studies are needed to assess the efficacy in different surgical groups, as little to no effect was found for tonsillectomy, orthopaedic and cardiac surgery.8–10
In the few studies that evaluate the length of hospital stay, the determining factor seems to be the time to the first bowel movement.1–3,11–14 A 1-day reduction in the length of hospital stay has been reported after open and laparoscopic bowel surgery2,3,11 and after open radical prostatectomy.1
We use a transperitoneal approach for laparoscopic renal surgery which involves mobilisation of the colon to enter the retroperitoneal space. On the basis of the available data, perioperative lidocaine infusion might have a beneficial effect on the length of hospital stay due to the associated reduced opioid requirement and more rapid recovery of bowel function.
The aim of this randomised, double-blinded, placebo-controlled trial was to analyse the effect of perioperative intravenous lidocaine infusion on clinically relevant postoperative variables after laparoscopic renal surgery. Primary endpoint was the length of hospital stay, as a reflection of enhanced recovery. Secondary endpoints were the effect of lidocaine on postoperative pain, opioid requirement, sedation, incidence of PONV, return of bowel function and inflammatory and stress responses.
We undertook a double-blind, randomised, placebo-controlled trial. The study was approved by the Ethics Committee of the University Hospital Bern, Switzerland (KEK BE 155/08, 21 November 2008, Chairperson Professor N. Tüller) and by the Swiss Agency for Therapeutic Products SwissMedic (2009DR3026). It was registered at ClinicalTrials.gov (NCT00789620). All patients gave prior written informed consent. Inclusion criteria were American Society of Anesthesiologists (ASA) physical status classes I to III and laparoscopic transperitoneal renal surgery under general anaesthesia. Exclusion criteria were liver insufficiency, steroid therapy, chronic opioid therapy, known allergy to lidocaine, a pre-existing disorder of the gastrointestinal tract, an atrio-ventricular block grade II to III, congestive heart failure, a long QT syndrome and pregnancy. All patients were enrolled between July 2009 and February 2011.
Patients were assigned to receive either a lidocaine or saline infusion by computer-generated randomisation following the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) statements.15 Coded 50-ml vials of either lidocaine 1% or NaCl 0.9% were prepared by the hospital pharmacy in accordance with good manufacturing practice. The anaesthesiologist in charge, the surgeon, the nursing staff and the patients were blind to the group assignment. Lidocaine was given as a 1.5 mg kg−1 bolus during induction of anaesthesia, followed by a continuous intraoperative infusion of 2 mg kg−1 h−1. At the end of surgery, the dose was reduced to 1.3 mg kg−1 h−1 for the following 24 h, after which the infusion was discontinued. These doses were chosen from a previous study of laparoscopic colectomy in which they were associated with discharge significantly earlier (1 day) than controls.2 This approach resulted in both groups receiving an equal volume per unit of time.
During anaesthesia, arterial blood pressure, heart rate and SaO2 were measured with the Datex Ohmeda s75 monitor (Datex-Ohmeda, Helsinki, Finland) every 5 min according to institutional standards. General anaesthesia was induced with fentanyl 2 μg kg−1 and propofol 2 mg kg−1. Orotracheal intubation was facilitated with atracurium 0.5 mg kg−1. Atracurium boluses were given for intraoperative muscle relaxation to maintain no response to train-of-four stimulation. Anaesthesia was maintained with isoflurane in a mixture of oxygen and air using a closed circuit. End-tidal isoflurane concentrations were recorded every 15 min. Respiratory frequency and tidal volume were adjusted to maintain the end-tidal concentration of carbon dioxide between 32 to 35 mmHg. The use of fentanyl during surgery was limited: 1 μg kg−1 was given if mean arterial blood pressure increased more than 20% or if the heart rate was greater than 100 beats min−1 despite administration of isoflurane to 0.8 minimum alveloar concentration. Oesophageal temperature was maintained between 35.8 and 37.0°C. All patients received a Ringer lactate solution at a rate of 2 ml kg−1 h−1. The total amount of fentanyl used was recorded at the end of the procedure. No intraoperative prophylaxis against PONV was given.
To limit differences in the surgical procedure and the duration of surgery, two staff urologists performed all operations which began between 08 : 30 and 09 : 00 a.m.
In both groups, paracetamol 1 g and metamizol 1 g intravenously were given in the intermediate care unit and repeated every 6 h for the next 2 days. Pain intensity was measured by numeric rating scale (NRS) whereby 0 = no pain and 10 = worst pain imaginable. NRS was recorded at rest and during mobilisation (walking) at 2 and 6 h postoperatively (postoperative day 0) and at 09 : 00, 13 : 00 and 19 : 00 h on postoperative days 1 and 2. Supplemental intravenous morphine was given by the nurses upon request if the patients reported a pain score at rest of 4 or more. Morphine was given intravenously during the first 24 h on the intermediate care unit in boluses of 2 mg, with a minimum interval of 10 min between two doses. On day 2, morphine was given subcutaneously in a dose of 7.5 mg, at minimal intervals of 3 h between two doses. Morphine requirement was recorded at 2 and 6 h postoperatively (postoperative day 0) and at 09 : 00, 13 : 00 and 19 : 00 h on postoperative days 1 and 2. No other analgesics were used. At the same time points, sedation was assessed by NRS in which 0 = alert and 10 = falls asleep during conversations and time of first flatus, defecation and episodes of PONV were recorded.16 For assessment of the inflammatory and stress responses, blood samples for plasma concentrations of C-reactive protein (CRP), cortisol and procalcitonin (PCT) were drawn at induction of anaesthesia (07 : 30 a.m.), and between 06 : 00 and 08 : 00 a.m. on days 1 and 2 after surgery, and were quantified by standard clinical biochemical methods in the central hospital laboratory. Patients were placed on the intermediate care unit for haemodynamic and respiratory surveillance, including continuous ECG monitoring, postoperatively for 24 h and then discharged to the ward floor.
Clear liquids were given the same evening after surgery and solid food was started the next morning. Active bedside mobilisation was enforced for the first time the evening after surgery and assisted ambulation the morning after surgery at least twice a day. Clinical and research personnel involved in the assessment of the data and patients were blind to the group assignment.
Primary outcome was the length in days of postoperative hospital stay (from the day of surgery to leaving the hospital) in which every patient was admitted 1 day before surgery according to institutional standards. For discharge, all drains had to be removed.
Criteria for discharge were as follows: absence of nausea and vomiting in the last 24 h, return of bowel function (daily defecation) and toleration of full diet, no to minimal pain (NRS 0 to 2), afebrile and no surgically associated morbidity (fever, wound dehiscence, wound infection, anastomotic leak, abscess). These variables were recorded by research personnel, blind to the allocation, every day at 09 : 00, 13 : 00 and 19 : 00 h. Patients ready for discharge after 10 : 00 a.m. were discharged on the following morning.
On the basis of retrospective data from our institution in the same surgical group (mean length of hospital stay 5 days, SD 1.5 days), a power analysis was performed using duration of hospital stay as the primary variable. For this purpose, the NCSS PASS program was used (NCSS PASS programme, NCSS, Kaysville, Utah, USA). Thirty-two patients were required in each group to detect a 1-day difference in the hospital stay between the groups, at an α-level of 0.05, with a power of 80%, expecting a SD of 1.5 days and an effect size of 0.67.
Differences between groups were compared using a two-tailed unpaired Student's t-test for normal distribution; otherwise the Mann–Whitney U-test was used. Distributional properties of all variables were evaluated with probability plots. Data are presented as mean±SD or as median with interquartile range (IQR) and range. Categorical data were expressed as numbers and percentage and analysed with χ2-test or Fisher's exact test as appropriate. The effects of time and group on the level of pain score, sedation, opioid requirement, plasma cortisol, CRP and PCT were analysed by two-way repeated analysis of variance, with time points of postoperative period as the repeated factor and group as non-repeated factor. Differences were considered statistically significant if the P value was less than 0.05. SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA) was used for statistical analyses.
Baseline data were similar between the two groups (Table 1). Of the 65 patients enrolled, one patient was excluded because the surgeon decided to convert to an open procedure. Patient flow throughout the study, according to the CONSORT statement, is shown in Fig. 1.
Length of hospital stay and readiness for discharge
There was no significant difference between the groups concerning the length of the postoperative hospital stay [median values: 6 days for the lidocaine group (IQR: 5 to 7; range: 2 to 8) vs. 5 days for the placebo group (IQR: 5 to 6; range: 2 to 11), P = 0.24] (Fig. 2). One patient in the lidocaine group was discharged on day 8 because of a surgical complication (need for pyelonephrostomy), and another at day 7 because of wound infection. In the placebo group, one patient was discharged on day 11 because of postoperative delirium. No cardiac or pulmonary complications were observed.
Time to achieve readiness for discharge did not differ between the two groups: 4 days for the lidocaine group (IQR: 5 to 7; range: 2 to 8) vs. 4 days for the placebo group (IQR: 5 to 7; range 2 to 11) (P = 0.26).
Opioid requirement and pain intensity
Intraoperative fentanyl doses [lidocaine group: 0.81 mg (±0.1) vs. control group: 0.68 mg (±0.2), P = 0.47], cumulative postoperative morphine consumption during the first 24 h [lidocaine group: 7 mg (±9) vs. control group: 11 mg (±12), P = 0.23)] and the total cumulative morphine consumption after surgery [lidocaine group: 8 mg (±11) vs. control group: 11 mg (±12), P = 0.26)] did not differ significantly. Morphine consumption on postoperative day 2 was significantly reduced in the lidocaine group [0.0 mg (±0.2) vs. 0.4 mg (±1.6), P = 0.02].
There were no significant differences between groups in pain scores over time at rest (P = 0.71) and during mobilisation (P = 0.13) on days 1 and 2 after surgery (Figs 3 and 4).
During the study period, nausea was recorded in 14 patients (44%) in the lidocaine group and in 15 patients (47%) in the control group (P = 0.96). Vomiting occurred in six patients (19%) in the lidocaine group and in seven patient (22%) in the control group (P = 0.78). There was no difference in sedation scores between the two groups on days 1 and 2 after surgery (P = 0.54) (Fig. 5).
No postoperative complications and no adverse events related to systemic administration of lidocaine were observed (no light headedness, drowsiness, perioral numbness, visual disturbances or metal taste). During continuous ECG monitoring, no pathological cardiac rhythm disturbances were detected and no seizures occurred.
Groups were similar with regard to time to first flatus (lidocaine group: 34.5 ± 14.9 h vs. placebo group: 30.2 ± 16.4 h; P = 0.23) and first defecation (lidocaine group: 48.7 ± 15.4 h vs. placebo group: 45.8 ± 11.3 h; P = 0.18). On day 2, 31 patients (31 of 32) in the lidocaine group and all patients (32 of 32) in the placebo group were able to defecate, whereas the last patient in the lidocaine group defecated on day 3.
Inflammatory and stress responses
Plasma concentrations of cortisol, CRP and PCT did not differ significantly between the two groups (Table 2). Plasma CRP and PCT increased significantly compared with baseline on days 1 and 2 after surgery (P < 0.001 and P = 0.025, respectively), whereas plasma cortisol concentration did not change significantly (P = 0.19).
To our knowledge, this is the first study evaluating the effect of systemic lidocaine infusion on perioperative outcome in major laparoscopic renal surgery. We were unable to find any significant influence on the length of hospital stay, time to readiness for discharge, postoperative pain, side-effects, return of bowel function or inflammatory and stress responses. There was, however, a significant decrease in opioid requirement on day 2 in the lidocaine group.
The observation that lidocaine application has no influence on the length of hospital stay is in line with studies on laparoscopic prostatectomy, major open abdominal surgery and non-abdominal surgery.5,9,17 The majority of studies that found a significant difference in the length of hospital stay were on bowel surgery and the main factor related to a reduction in the length of hospital stay was the return of bowel function.2,3,11 There are two studies of the length of hospital stay in laparoscopic surgery, and they have conflicting outcomes. In laparoscopic prostatectomy, no difference was found,5 whereas following laparoscopic colectomy the hospital stay was significantly reduced in the lidocaine group.2
On postoperative day 2, a significant decrease in morphine consumption in the lidocaine group was observed, but up to that time no difference was found. However, overall pain scores and morphine consumption were very low. We cannot rule out that the low level of pain may have prevented detection of a possible benefit from lidocaine. Here again, findings from the published science are contradictory.4 There is one report on laparoscopic prostatectomy with a reduced (although not significant) morphine consumption on day 2.5 Three other studies on laparoscopic colectomy and cholecystectomy found a significant reduction in analgesic requirement, but with wide variability that may be partly explained by different protocols, doses, length of lidocaine infusion and variable postoperative analgesic prescriptions.2,6,7 However, the protocol used here is one well established in this field. The fixed postoperative pain treatment with paracetamol and metamizol may be another factor contributing to the minor difference in opioid requirement and pain scores noted in this study, but many other studies reporting a difference have used NSAIDs, sometimes with paracetamol.1–3 Here again, a positive influence of systemic lidocaine on postoperative pain scores was observed more frequently in patients undergoing major abdominal and colonic surgery.2,12,17 One reason for the more pronounced effect observed in major bowel surgery may be a central anti-hyperalgesic effect of lidocaine, something which has been seen in experimental studies.18,19 Hyperalgesia is found in patients undergoing bowel surgery with peritoneal irritation which induces inhibitory gastrointestinal reflexes. In animal studies, lidocaine has been shown to modulate visceral pain.20 In our patients, a relatively low extent of intestinal mobilisation and no extended peritoneal reflection occurred, in contrast to major abdominal and colonic surgery, possibly explaining the minor differences observed.
In contrast to prior studies, there was no difference between the groups concerning the return of bowel function.1–3 One explanation may be that the opioid requirement did not differ between the groups. Another is that our patients did not undergo major bowel surgery and that a relatively low extent of tissue damage and peritoneal reflection occurred, in contrast to major abdominal surgery. In laparoscopic surgery, colectomy and cholecystectomy, systemic lidocaine administration resulted in a more rapid return of bowel function, whereas in laparoscopic prostatectomy it did not.2,5–7 Another explanation may be the more central anti-hyperalgesic effect of lidocaine considered above.
Moderate increases in serum PCT and CRP following laparoscopic renal surgery were observed in our study, which were not influenced by lidocaine. There were similar changes in plasma cortisol level between groups in line with previous studies.2,21,22 PCT is not only a sensitive early marker for infection (peak level day 1 or 2 after surgery) but is also increased in patients with systemic inflammation induced by trauma.23 In our patients, a slight increase of PCT levels was noted on day 2, when the values measured were slightly above the normal value of 0.5 ng ml−1. The lack of significant changes in PCT and CRP values observed here may reflect the absence of systemic inflammatory response following this type of minimally invasive surgery. This is in line with the observation that intestinal surgery is more likely to induce an increase in PCT than other potentially aseptic procedures.24 However, plasma cytokine levels of pro-inflammatory and anti-inflammatory interleukins were not measured in this study: these markers of inflammatory response might have been more sensitive to this minimal invasive surgery.2
This study was powered to determine a difference in hospital stay, the main socioeconomic factor. The choice of length of hospital stay as primary endpoint may be considered as a limitation, given the variability of this measure across different institutions and health systems. However, all clinically relevant variables were additionally recorded and there was no difference between the two groups in any other endpoints. The duration of the hospital stay reported here may be somewhat longer than that observed elsewhere; however, the length of hospital stay varies greatly in published studies.12,25,26 Another potential point of criticism could be that other factors, such as institutional standards or insurance issues, influenced the length of hospital stay. However, patients were discharged at the earliest possible moment after achieving readiness for discharge and the groups were similar in this respect. Perhaps continuous monitoring might have revealed a discrete difference which, however, would be of questionable clinical impact.
Another limitation could be the failure to use patient-controlled analgesia which might have been more sensitive than nurse-controlled analgesia.
Finally, the low pain scores and low postoperative morphine consumption may have allowed little scope for systemic lidocaine to show benefit. The study lacks power to detect differences in the secondary endpoints. However, in all other studies, the differences in pain scores and opioid requirement were the most significant differences observed, more so than the length of hospital stay. Also, all other studies showing differences had smaller patient numbers.
Overall in our study, systemic lidocaine failed to influence the length of hospital stay in patients undergoing laparoscopic transperitoneal renal surgery. Lidocaine infusion did not reduce pain intensity, overall opioid requirement, side-effects, gastrointestinal function or inflammatory response. This prospective, double-blind, placebo-controlled trial implies that individual studies on systemic lidocaine administration are necessary for specific surgical techniques.
Assistance with the study: the authors would like to thank the nurses of the intermediate care unit and of the Department of Urology for their valued collaboration, Philippe Frascarolo (PhD) of the Department of Anaesthesiology of the Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland) for statistical support/advice and the Pharmacy of the University Hospital of Berne (Marco Eschenmoser) for randomisation, blinding, storage and packaging of the drugs.
Financial support and sponsorship: support was provided solely from departmental sources.
Conflicts of interest: none declared.
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