Studies evaluating intraperitoneal local anesthetic instillation for pain relief after laparoscopic cholecystectomy have provided conflicting results.1–4 One of the factors that might contribute to failure of the instillation technique may be related to inadequate distribution of local anesthetic throughout the peritoneal surface. In contrast, nebulization should provide a uniform spread of local anesthetics throughout the peritoneal cavity and thus may be beneficial to improve pain relief after laparoscopic procedures.5 One study reported that bupivacaine nebulization significantly reduced pain after laparoscopic cholecystectomy in comparison with bupivacaine instillation in the gall bladder bed.6 However, these investigators used a custom-made nebulization system that required a separate gas source and tubing that is cumbersome and may not be easily available.
We reported that a microvibration-based nebulization device (Aeroneb Pro® system, Aerogen, Galway, Ireland) could be used for ropivacaine delivery into the insufflation gas required to create pneumorpeitoneum.7 We hypothesized that intraperitoneal ropivacaine nebulization would provide superior pain relief after laparoscopic cholecystectomy than intraperitoneal ropivacaine instillation. This clinical trial was designed to assess the analgesic efficacy of ropivacaine nebulization using the Aeroneb Pro® device for laparoscopic cholecystectomy in comparison with intraperitoneal ropivacaine instillation.
This single-center, randomized, parallel-group, double-blind study was approved by the ethics committee of the San Gerardo Hospital, Monza, Italy, and registered at www.clinicaltrials.gov with the number NCT01248819 (11/24/2010) by the principal investigator (P.M.I.). After obtaining written consent, 60 patients ages 18 to 70 years, ASA physical status I–III, scheduled to undergo elective laparoscopic cholecystectomy, were enrolled in this study. Patients were excluded if they had clinical diagnosis of acute pancreatitis, had acute preoperative pain other than biliary colic, required chronic pain treatment or antiepileptic drugs, had history of alcohol or drug addiction, had severe hepatic or renal impairment, had allergy to the study drugs, were pregnant or lactating, had a predictable possibility of requiring open cholecystectomy, or had cognitive impairment or communication problems.
A research assistant not involved in patient care confirmed patient eligibility, obtained written consent, and gave the sealed white envelope containing patient allocation and instructions for the solution preparation to a previously trained anesthesia nurse who was not involved in the study. The solutions were prepared in one 20-mL transparent syringe containing ropivacaine 0.5% or normal saline and two 5-mL transparent syringes containing 3 mL of ropivacaine 1% or 3 mL of normal saline according to the randomization sequence. To maintain blinding, the research assistant was not allowed to enter the operating room when the study solutions were being prepared. In case of an emergency related to or possibly related to the study or study drugs, the nurse was authorized to disclose the contents of the syringe to the anesthesiologist in charge of the case who was not involved in the study and to the research assistant.
Patients were randomized to 1 of 2 groups using a computer-generated randomization sequence. Patients in the instillation group received intraperitoneal instillation of ropivacaine 0.5%, 20 mL (100 mg) on the gall bladder after induction of pneumoperitoneum but before dissection of gall bladder plus an intraperitoneal nebulization of normal saline 3 mL before the start of gall bladder dissection and again at the end of surgery just before deflation of pneumoperitoneum. Patients in the nebulization group received intraperitoneal instillation of saline 20 mL on the gall bladder after induction of pneumoperitoneum but before dissection of the gall bladder plus intraperitoneal nebulization of ropivacaine 1% 3 mL (30 mg) before the start of gall bladder dissection and again at the end of surgery just before deflation of pneumoperitoneum (total dose of ropivacaine 60 mg). The first ropivacaine or normal saline nebulization was performed over 5 to 6 minutes using the Aeroneb Pro® device through the umbilical port while the other ports were being inserted, while the second nebulization was performed before the withdrawal of the ports.
Laparoscopic cholecystectomy was performed according to standard surgical and anesthesia protocols. A classic 4-port surgical technique that consisted of placement of a 12-mm port via the umbilical incision, a 10-mm port in the epigastric area, and two 5-mm ports on the right side of the abdomen was used for all patients. Pneumoperitoneum was achieved using nonhumidified and nonheated carbon dioxide (CO2) at an intraperitoneal pressure of 15 mm Hg.
A standard anesthetic technique was used for all patients. Patients were premedicated with diazepam 5 to 7 mg, 30 minutes before surgery. General anesthesia was induced with propofol 2 to 3 mg/kg IV, and tracheal intubation was facilitated with cisatracurium 0.15 mg/kg IV. Anesthesia was maintained with sevoflurane 1.5% to 2.5% end-tidal concentration titrated to maintain state entropy values between 45 and 60 (Entropy sensorTM, M-ENTROPYTM module, GE Healthcare, Piscataway, NJ), fentanyl boluses 1 to 2 mcg/kg titrated to maintain noninvasive mean arterial blood pressure and heart rate ±20% of basal values, and cisatracurium 0.03 mg/kg titrated to maintain a train-of-4 count of 1 to 2, as well as according to clinical needs. Ventilation was controlled to maintain end-tidal CO2 35 to 40 mm Hg. After tracheal intubation an orogastric tube and an esophageal temperature probe were placed. Operating room temperature was set at 20°C, and patients were kept warm using a forced warm-air device and warmed IV solutions. At the end of surgery, residual muscle paralysis was reversed with neostigmine 0.05 mg/kg and atropine 0.02 mg/kg, and tracheal extubation was performed once clinical and train-of-4 criteria were achieved.
All patients received dexamethasone 4 mg IV after induction of anesthesia and ondansetron 4 mg IV at the end of surgery, for postoperative nausea and vomiting (PONV) prophylaxis. Acetaminophen 15 mg/kg IV was infused during surgery and then every 6 hours for 48 hours. In addition, each 4-portal site was infiltrated with ropivacaine 0.3%, 3 mL after completion of the surgery. Upon arrival to the postanesthesia care unit (PACU), patients complaining of pain received morphine 3 mg IV boluses until the visual analog scale (VAS) score was <30 mm, after which they received IV patient-controlled analgesia with morphine 1 mg bolus, with a lockout time of 5 minutes and 4-hour dose of 20 mg. Postoperatively, patients were encouraged to ambulate as soon as possible. On the basis of our routine practice, all patients had to stay in the hospital for 48 hours.
Data collected included patient demographics (age, gender, weight, and height), intraoperative opioid use, duration of surgery, residual volume in the nebulization unit (postnebulization volume), signs of local anesthetic toxicity (e.g., intraoperative arrhythmias, unexplained hypotension, burst suppression on entropy monitor, and unexplained delayed awakening), patient temperature in the PACU, and duration of PACU stay. In addition, we collected the intensity of pain at rest (static pain) and on deep breathing, coughing, or movement (dynamic pain), assessed using a 100-mm VAS for which 0 mm represented “no pain” and 100 mm represented “worst possible pain”; incidence of significant shoulder pain (pain scores ≥ 30 mm); morphine consumption; time to unassisted walking; and incidence of PONV in the PACU and at 6, 24, and 48 hours after surgery. The research assistants involved in data collection were unaware of the study group assignment.
The primary end point of the study was the pain intensity at rest. Sample size calculations were based on data (mean ± SD [standard deviation] pain scores) from a previous investigation involving intraperitoneal local anesthetic nebulization and instillation after elective laparoscopic cholecystectomy.5 We considered a reduction in the mean intensity pain score of 20 mm as clinically significant. On the basis of the formula for normal theory and assuming a 2-sided type I error of 0.05 and a power of 0.90, a minimum sample size of 26 patients per group was required. Thirty patients were enrolled in each group to account for possible protocol violations.
Because this study evaluated the effect of intraperitoneal ropivacaine nebulization on pain intensity after laparoscopic cholecystectomy, conversion to an open technique was considered a protocol violation, and these patients were excluded from further analysis. However, the excluded patients received the same anesthesia protocol, analgesia protocol, and postoperative follow-up evaluations until their hospital discharge for the safety analysis.
Continuous data (age, weight, body mass index, intraoperative opioid use, temperature, postnebulization volume, duration of surgery, PACU stay, static and dynamic pain scores, morphine requirements, and time to unassisted walking) are presented as mean ± SD and analyzed with a 2-sided Student t test. Patient gender, ASA physical status, number of patients with significant postoperative pain (dynamic pain scores ≥30 mm), number of patients with shoulder pain, number of patients receiving postoperative morphine, proportion of patients walking without assistance within 12 hours after surgery, and number of patients with PONV are presented as frequency and 95% confidence interval (CI; calculated by exact mid-p binomial method) and absolute risk reduction, and analyzed with nonexact χ2 test or Fisher exact test when appropriate.
An effect size is the difference between 2 means (e.g., treatment minus control) divided by the SD of the 2 conditions. The division by the SD enables comparison of effect sizes across experiments and is used to interpret changes in health status.8 The effect size of ropivacaine nebulization was calculated through Cohen's d test to compare the relative magnitude of the experimental interventions on the intensity of postoperative pain, morphine consumption, and unassisted walking time.
Statistical comparisons were accomplished with Microsoft Excel 97 (Microsoft Inc., Redmond, WA), EPI INFO, version 2004 (EpiInfo 3.2.2, Centers for Disease Control and Prevention [CDC], Atlanta, GA), and SPSS software (version 13, Chicago, IL). A P value of <0.05 was considered to be statistically significant.
Sixty patients were enrolled in the study, and 57 were included in the data analysis. Three patients in nebulization group were excluded because the laparoscopic surgical procedures were converted to open surgery. There were no significant differences between groups with respect to age, weight, gender, body mass index (BMI), duration of surgery, postnebulization volume, intraoperative opioid use, temperature after surgery, and time to PACU discharge (Table 1).
There were no significant differences between groups with respect to static and dynamic pain scores at all time points (Cohen's d at 24-hour = 0.14, “negligible effect” −11% decrease of dynamic VAS scores) (Table 2).
There were no differences in the proportions of patients with dynamic pain scores ≥30 mm on the first postoperative day. In the PACU, 25 (83%) patients receiving ropivacaine instillation and 20 (70%) patients receiving ropivacaine nebulization reported pain scores ≥30 mm (absolute risk reduction −9.25%, 95% CI −30% to 12%; P = 0.21). At 6 hours after surgery, 8 (27%) patients on instillation group and 5 (19%) patients in the nebulization group reported pain scores ≥30 mm (absolute risk reduction −8%, 95% CI −30% to 13%; P = 0.24), and at 24 hours after surgery, 3 patients in each groups reported pain scores ≥30 mm (P = 0.61).
No patients receiving ropivacaine nebulization complained of significant shoulder pain in comparison with 25 (83%) patients in the instillation group (absolute risk reduction −83%, 95% CI −97% to −70%, P < 0.001 uncorrected for multiple comparisons).
There were no significant differences between the 2 groups with respect to morphine consumption. During the first 48 hours after surgery, patients receiving ropivacaine nebulization consumed 16 ± 12 mg (95% CI 11 mg to 21 mg) morphine in comparison with 20 ± 13 mg (95% CI 15 mg to 25 mg) in instillation group (Cohen's d = 0.32 “small effect” −20%; P = 0.32). Twenty-three (77%) patients in the instillation group and 20 (74%) patients in the nebulization group used morphine on the first postoperative day (absolute risk reduction −2.6%, 95% CI −25% to 20%; P = 0.6), whereas 16 (53%) patients in the instillation group and 11 (41%) patients in the nebulization group used morphine on the second postoperative day (absolute risk reduction −13%, 95% CI −38% to 13%; P = 0.4).
Patients receiving ropivacaine nebulization walked without assistance earlier than did those receiving ropivacaine instillation. The mean time to unassisted walking after surgery in the instillation group was 13 ± 9 hours (95% CI 10 hours to 16 hours) in comparison with 9 ± 7 hours (95% CI 6 hours to 12 hours) in the nebulization group (Cohen's d = 0.5 “medium effect,” −31%, P = 0.03). Patients receiving instillation without significant shoulder pain walked earlier (4 ± 1 hours, 95% CI 3 hours to 5 hours) than did patients complaining of shoulder pain in the same group (15 ± 9 hours, 95% CI 11 hours to 19 hours, P = 0.01).
Nineteen (70%) patients receiving ropivacaine nebulization were able to stand and walk without assistance within 12 hours after surgery in comparison with 14 (47%) patients receiving ropivacaine instillation (absolute risk reduction −24%, 95% CI −48% to 1%, P = 0.04). Of 32 patients without shoulder pain, 24 (75%) walked without assistance within 12 hours in comparison with 36% (9 out of 25) patients complaining of shoulder pain (absolute risk reduction −39%, 95% CI −63% to −14%, P = 0.002).
There were no significant differences between groups with respect to hospital stay (1.9 ± 0.3 days for the instillation group in comparison with 1.9 ± 0.2 days for the nebulization group (P = 0.1).
One (3%) patient in the instillation group vomited in comparison with 6 (22%) patients in the nebulization group (absolute risk reduction −19%, 95% CI −36% to −2%, P = 0.03). No patients presented signs of local anesthetic toxicity in the perioperative period.
We compared the effects of ropivacaine nebulization using the Aeroneb Pro® device before and after surgery with intraperitoneal instillation of ropivacaine before laparoscopic cholecystectomy. The main finding of this study is that in comparison with ropivacaine instillation, ropivacaine nebulization significantly reduced the incidence of shoulder pain and the time to unassisted walking, but it was associated with higher incidence of postoperative vomiting after laparoscopic cholecystectomy.
Previous studies evaluating intraperitoneal local anesthetic instillation during laparoscopic surgery have shown variable results probably due to differences in site of instillation (e.g., subdiaphragmatic versus subhepatic administration), differences in timing of administration (preoperatively versus postoperatively), differences in local anesthetic dose and concentration, and differences in perioperative analgesic regimens.1–4
Pain after laparoscopic cholecystectomy, particularly shoulder pain and diffuse abdominal pain, remains a problem.9,10 Although the exact origin of pain during laparoscopy is unclear, shoulder pain and diffuse abdominal pain may be due to peritoneal stretching and diaphragmatic irritation associated with CO2 pneumoperitoneum.11 The use of humidified insufflation gas12–14 as well as more uniform spread of ropivacaine throughout the peritoneum including the area under the diaphragm5–7 may explain the lower incidence of shoulder pain in the nebulization group. Reduced shoulder pain may have allowed earlier ambulation in the nebulization group despite similar pain levels at the incision sites.
The reduced shoulder pain observed in our study was also reported by Alkhamesi et al.6 using bupivacaine (0.5%, 10 mL) nebulized in the peritoneal cavity at the end of surgery. In contrast to our nebulization technique, these authors used a custom-made nebulization system that included a syringe pump connected to the insufflator with a double-lumen catheter that is introduced into the abdomen through a port featuring a special introducer to prevent gas leak. The authors reported that this delivery method generated a “foggy” environment, which may suggest that the peritoneal cavity was completely covered.
The nebulization system used in this study consists of a commercially available high-frequency vibrating membrane nebulizer, which is reusable and easy to assemble, can be placed in series with the insufflation tubing, and does not need a separate tubing or injection system or driving gas. It allows simultaneous and efficient delivery of the local anesthetic while the surgical procedure is being performed.7 Because the particle size generated by the Aeroneb® device is small (Mass Median Diameter <5 microns), it can be speculated from available data in pulmonary therapy15,16 and ENT research17 that the local anesthetic would spread uniformly throughout the peritoneal cavity as well as to the most remote parts of the peritoneum.
One of the limitations of the nebulization technique is that the small droplets size creates a “foggy” environment, which may interfere with the surgeon's vision. Thus, local anesthetic nebulization may not be feasible throughout the surgical procedure. Therefore, we performed the initial nebulization while the other ports were being inserted and the second nebulization after the surgery was completed just prior to exsufflation of the pneumoperitoneum.
Surprisingly, despite reduced shoulder pain and similar pain scores and opioid consumption, the incidence of vomiting in the nebulization group was higher. The reasons for this observation are not clear because this study was not powered to assess the incidence of PONV. Future studies with appropriate sample size are necessary to specifically assess the incidence of PONV after local anesthetic nebulization during laparoscopic procedures.
This study may be criticized because it did not include a control (i.e., placebo) group in which no local anesthetic administration was performed. However, we believed that a control group was not necessary, because previous studies have shown limited (or controversial) benefit of intraperitoneal instillation. Also, the study by Alkhamesi et al.6 did not find any difference between the local anesthetic instillation group and the control group. Another criticism may be that the doses of ropivacaine in the 2 groups were different. The dose for instillation (i.e., 100 mg) was based upon our usual practice, and the lower dose of ropivacaine (i.e., 60 mg) for nebulization was based upon the nebulization time, which was determined by the time it took for our surgeons to place other ports (i.e., 5 to 6 minutes).
We did not measure the plasma concentrations of ropivacaine in our study patients. In a recent animal study the pharmacokinetics of nebulized ropivacaine 3 mg/kg was similar to that of instilled ropivacaine, and maximal ropivacaine concentrations were found within safe values.18 The total amount of ropivacaine used in this series (60 mg through nebulization plus 36 mg for the 4 surgical ports infiltration) is far below the maximum dose for infiltration anesthesia in an adult patient (3 mg/kg or 200 mg of plain solution19). Finally, laparoscopic cholecystectomy was not performed on an outpatient basis, which is a common practice in the United States. However, in our practice, patients undergoing laparoscopic cholecystectomy are hospitalized for 48 hours. Because our patients were hospitalized, we were able to use IV-PCA morphine as rescue analgesic, rather than oral opioids, which allowed us to obtain a more precise assessment of opioid consumption.
In conclusion, pain scores and opioid consumption with intraperitoneal instillation and intraperitoneal ropivacaine nebulization performed before and after laparoscopic cholecystectomy were similar. However, ropivacaine nebulization reduced shoulder pain and time to unassisted walking, but it was associated with higher incidence of postoperative vomiting.
Name: Mario Bucciero, MD.
Contribution: This author helped design the study and conduct the study.
Conflict of Interest: Mario Bucciero reported no conflict of interest.
Attestation: Mario Bucciero approved the final manuscript.
Name: Pablo M. Ingelmo, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflict of Interest: Pablo M. Ingelmo reported no conflict of interest.
Attestation: Pablo M. Ingelmo has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Roberto Fumagalli, MD.
Contribution: This author helped design the study.
Conflict of Interest: Roberto Fumagalli reported no conflict of interest.
Attestation: Roberto Fumagalli approved the final manuscript.
Name: Eric Noll, MD.
Contribution: This author helped write the manuscript.
Conflict of Interest: Eric Noll reported no conflict of interest.
Attestation: Eric Noll approved the final manuscript.
Name: Andrea Garbagnati, MD.
Contribution: This author helped design the study and conduct the study.
Conflict of Interest: Andrea Garbagnati reported no conflict of interest.
Attestation: Andrea Garbagnati approved the final manuscript.
Name: Marta Somaini, MD.
Contribution: This author helped analyze the data and write the manuscript.
Conflict of Interest: Marta Somaini reported no conflict of interest.
Attestation: Marta Somaini has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Girish P. Joshi, MB, BS, MD, FFARCSI.
Contribution: This author helped interpret the data and write the manuscript.
Conflict of Interest: Girish P. Joshi reported no conflict of interest.
Attestation: Girish P. Joshi has approved the final manuscript.
Name: Giovanni Vitale, MD.
Contribution: This author helped conduct the study.
Conflict of Interest: Giovanni Vitale reported no conflict of interest.
Attestation: Giovanni Vitale approved the final manuscript.
Name: Vittorio Giardini, MD.
Contribution: This author helped conduct the study.
Conflict of Interest: Vittorio Giardini reported no conflict of interest.
Attestation: Vittorio Giardini approved the final manuscript.
Name: Pierre Diemunsch, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Conflict of Interest: Pierre Diemunsch reported no conflict of interest.
Attestation: Pierre Diemunsch has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.