World J Surg DOI 10.1007/s00268-015-2973-0
ORIGINAL SCIENTIFIC REPORT
Aerosolized Intraperitoneal Local Anesthetic for Laparoscopic Surgery: A Randomized, Double-Blinded, Placebo-Controlled Trial Ailbhe M. McDermott • Kah Hoong Chang • Kelly Mieske • Peter F. McAnena Brian Kinirons • Abdelaly Abeidi • Brian H. Harte • Michael J. Kerin • Oliver J. McAnena
•
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background Postoperative pain remains a significant challenge following laparoscopy. Aerosolized intraperitoneal local anesthetic (AILA) is a novel method to deliver local anesthetic. The aim was to evaluate aerosolized ropivacaine in pain management following laparoscopic Nissen fundoplication (LNF) and cholecystectomy (LC). Methods This prospective randomized double-blinded placebo-controlled trial enrolled consecutive patients undergoing LNF and LC. The treatment group (TG) received intraperitoneal ropivacaine (5 mL 1 %NaropinÒ) at CO2 insufflation via the AeroSurgeÒ aerosolizer device through the camera port. The control group (CG) received 5 mL of saline in the same manner. Postoperative shoulder tip pain at rest 6 h postoperatively was the primary study endpoint, with secondary endpoints of shoulder and abdominal pain within the first 24 h, recovery room stay, hospital stay, and postoperative analgesia use. Pain scores were collected using the Verbal Rating Score. Results Eighty-seven patients were included in the final analysis (TG n = 40, CG n = 47). There was no significant difference between CG and TG at the primary endpoint. In the LC group, AILA significantly reduced shoulder tip pain at rest at 10 (p = 0.030) and 30 min (p = 0.040) and shoulder tip pain on movement at 10 (p = 0.030) and 30 min (p = 0.037). In the LNF group, AILA significantly reduced postoperative abdominal pain at rest at 6 h (p = 0.009). AILA reduced overall incidence of shoulder tip pain in the LC group (11.8 vs. 57.9 %, p = 0.004). Conclusion This study did not demonstrate a significant difference between TG and CG in the primary endpoint, pain at 6 h postoperatively.
Trial Registration: European Medicines Agency European Clinical Trials Database, EudraCT 2009-015236-15. A. M. McDermott K. H. Chang K. Mieske P. F. McAnena M. J. Kerin O. J. McAnena (&) Discipline of Surgery, National University of Ireland, Galway, Ireland e-mail: [email protected] A. M. McDermott e-mail: [email protected]
Abbreviations AILA Aerosolized intraperitoneal local anesthetic ASA American Society of Anesthesiologists BMI Body mass index B. Kinirons B. H. Harte Department of Anesthesia, Galway University Hospital, Galway, Ireland O. J. McAnena Department of Surgery, Galway Clinic, Doughiska, Galway, Ireland
B. Kinirons A. Abeidi B. H. Harte Department of Anesthesia, Galway Clinic, Doughiska, Galway, Ireland
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CG CO2 CONSORT CNS GERD IV Kg LC LNF Mg NSAID O2 PCA TG US VRS
Control group Carbon dioxide Consolidated standards of reporting of trials Central nervous system Gastro-esophageal reflux disease Intravenous Kilogram Laparoscopic cholecystectomy Laparoscopic Nissen fundoplication Milligram Non-steroidal anti-inflammatory drug Oxygen Patient-controlled analgesia Treatment group United States Verbal rating score
Introduction Laparoscopy is a commonly performed procedure. Favor of a laparoscopic approach over an open procedure for several benign and malignant pathologies has been corroborated extensively in the literature over the past two decades. While associated with reduced postoperative pain, laparoscopy is not pain free, particularly in the immediate postoperative period [1, 2]. Postoperative abdominal and shoulder tip pain often prolongs patient hospitalization resulting in additional costs [3, 4]. Increasing understanding of the mechanisms of postlaparoscopy pain has led to the use of intraperitoneal local anesthetic agents, which provide pain relief without the side-effect profile of opioids. Studies evaluating different techniques of local anesthetic delivery including peri-portal infiltration [5, 6], diaphragmatic irrigation [7], instillation into the sub-diaphragmatic area [8], or diffuse instillation [2, 9] have shown conflicting results to date. Intraperitoneal delivery of a local anesthetic in a nebulized or aerosolized form has shown promising results thus far [10, 11]. The AeroSurgeÒ device delivers preemptive aerosolized local anesthetic (ropivacaine) at the time of peritoneal insufflation with carbon dioxide (CO2). Initial experimental studies on early designs of this aerosolization device (AeronebÒ) confirmed its superiority over evaporation devices, with over 90 % of the total volume of ropivacaine being delivered to the peritoneal cavity [12]. Animal studies have demonstrated the pharmacokinetic safety of intraperitoneal ropivacaine delivery using an early design of this device (Aeroneb ProÒ) [13]. The AeroSurgeÒ comprised of an aerosolizer chamber, and modified trocar is a novel device, capable of producing a
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faster flow rate (1 mL/min) than earlier AeronebÒ models (0.3 mL/min). The aim of this study was to evaluate aerosolized ropivacaine delivered using the AeroSurge Ò device in the management of postoperative pain following laparoscopic Nissen fundoplication (LNF) and cholecystectomy (LC).
Materials and methods This was a randomized double-blinded placebo-controlled trial, registered with the European Clinical Trials Database (EudraCT 2009-015236-15). Ethical approval was granted by the Irish Medicines Board and local research ethics committee. Written informed consent was obtained from all participants. Sample size was calculated from pain scores collected during a pilot study based on a power of 0.9 and type I error 0.05. In order to detect a 20 % reduction in the shoulder tip pain score at 6 h postoperatively in the treatment group (TG), 70 patients were required, with 35 in each arm. Additional patients were recruited to allow for mechanical device, laparoscopic equipment malfunction, or deviation from the strict study protocol. Participants Consecutive patients undergoing LNF and LC between May 2011 and August 2012 were assessed for eligibility. Inclusion criteria included: American Society of Anesthesiologist (ASA) grade I or II, between 18 and 70 years of age, free from pain preoperatively, ability to understand and comply with the protocol, and ability to provide informed consent. Exclusion criteria included: renal or hepatic impairment, pregnant or breast feeding, taking regular analgesia, prior laparoscopic surgery, allergy or suspected allergy to local anesthetic agents or opiates, drug or alcohol addiction, and neurological or psychiatric illness (other than mild medication-controlled depression). Surgery Following administration of general anesthetic by endotracheal intubation, patients were administered a total of 10 mL 0.75 % ropivacaine to the port sites prior to incision. Both operations were carried out as overnight stay procedures. At the end of both procedures, all ports were left in an open mode to allow full evacuation of CO2 and were removed individually as each wound is closed Method of administration using the aerosolizer The 10-mm umbilical (LC) or epigastric (LNF) port was sited first, and prior to dissection, the AeroSurgeÒ device
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sulfate). A standardized anti-emetic was also administered intraoperatively, ondansetron (4 mg IV, Ondran). Postoperative analgesia and anti-emetics Patients were prescribed postoperative analgesia as required in keeping with the WHO analgesic ladder. Morphine was permitted in the recovery room if pain scores greater than four were reported. On the ward, non-opiate and opiate analgesia were administered as required. The time, dose, and route of administration of each medication were recorded. Randomization and blinding
Fig. 1 The AeroSurge Ò device. The novel AeroSurge Ò device comprised of an AC/DC adapter which connects to the AeroSurgical controller unit, both of which lie outside the sterile field. A detachable cable is covered in a disposable sterile sheath and connected to the aerosolizer chamber which contains 10 mL of 1 % ropivacaine (TG) or 10 mL normal saline (CG) in liquid form. The modified trocar is placed in the 10-mm port, and CO2 is pumped through the aerosolizer chamber converting the liquid ropivacaine to a nebulized form
(consisting of the prototype-modified trocar and aerosolizer unit, Fig. 1) was assembled, loaded with 5 mL of 1 % ropivacaine or saline, placed in the port, and connected to the insufflator and power supply under aseptic technique. The AeroSurgeÒ controller unit was switched on at the same time as insufflation began with CO2 at 1 L/min at a maximum pressure limit of 15 mmHg. A total of 5 min were required for delivery of 5 mL ropivacaine. An additional 5 min to allow absorption of the ropivacaine mist was permitted before desufflation, and immediate re-sufflation was performed to enable clearance of the aerosolized solution, which otherwise clouded the operative field. The volume of solution, if any, left in the trocar was measured. Anesthetic protocol All patients received a standardized intraoperative anesthetic regimen with no pre-medication. Patients received 100 lg fentanyl (SublimazeÒ) 2 min prior to induction. Anesthesia was induced with 2–3 mg/kg propofol (PropovenÒ) titrated to effect. Muscle relaxation was then achieved with 0.6 mg/kg rocuronium (EsmeronÒ). Anesthesia was maintained with Sevoflurane (SevoraneÒ) in 50 % O2 in air. Intraoperative analgesia was provided at the start of the procedure with paracetamol 1 g intravenously and 0.075 mg/kg morphine IV (Morphine
The randomization sequence was conducted using computer-generated random numbers by a third party not involved in the study. Patients were randomly assigned to receive either 5 mL of nebulized 1 % ropivacaine (1 % NaropinÒ, AstraZeneca, equivalent to 50 mg ropivacaine) or 5 mL of nebulized 0.9 % normal saline. Randomization was stratified according to procedure type (i.e., LNF or LC). The treatment allocation for each patient was kept in a sealed envelope labeled with the study number. At the time of induction of anesthesia, the anesthetic assistant opened the next sequential envelope and prepared the treatment allocation in syringe in a concealed preparation room. The anesthetic assistant then loaded the aerosolizer unit with the appropriate solution. The envelope, which included the label from the used medication vial and patient demographics, was re-sealed. Only the anesthetic assistant was aware of patient allocation and was not involved at any other step in patient management, patient data recording, analysis, or write-up. The patients, all investigators, surgeons, anesthesiologists, nurses, and other medical staff responsible for the care of the patients were blinded to the study allocation. Outcome measures Outcome measures were the presence of pain (yes or no) and pain scores assessed using the verbal rating score (VRS). Blinded recovery and ward staff nurses collected data using a specifically devised data collection form. General abdominal pain and shoulder tip pain both at rest and on movement (coughing) were recorded at 10-min intervals in the recovery room, at 2, 4, 6, 12, and 24 h postoperatively on the ward and finally on discharge. Study endpoints The primary endpoint for this study was to determine the efficacy of aerosolized ropivacaine in the reduction of
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Fig. 2 CONSORT flow diagram. PCA Patient-controlled analgesia
postoperative shoulder tip pain following LNF or LC at 6 h postoperatively. Shoulder tip pain at 6 h postoperatively was selected as the primary end point to reflect the pharmacokinetic profile of ropivacaine. The secondary study endpoints were shoulder and abdominal pain within the first 24 h postoperatively, length of recovery room stay, length of hospital stay, and postoperative analgesia use.
using v2 test for nominal or ordinal data; Student’s t test or Analysis of Variance (ANOVA) and Mann–Whitney U or Kruskal–Wallis test were used for parametric and nonparametric continuous data, respectively. A p value of less than 0.05 was considered statistically significant for all tests.
Statistical analysis
Results
Statistical analysis was carried out using SPSSÒ version 20 (Chicago, IL, USA) software. Distribution of continuous data was determined using the Kolmogorov–Smirnov Z test. Univariate comparison of variables was assessed
Patient characteristics
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Between May 2011 and August 2012, 113 patients were screened and assessed for eligibility. Ninety-nine patients
World J Surg Table 1 Patient and procedural characteristics Treatment arm n = 40
Control arm n = 47
p value
Agea
45.9 ± 12.0
43.6 ± 14.3
0.426
Gender (M:F)
19:21
17:30
0.285
23 (57.5)
28 (59.6)
Surgery typeb
0.845
LNF LC
17 (42.5)
19 (40.4)
Length of procedure (min)c
35 (21–71)
35 (15–85)
0.714
83.9 ± 10.3 171.7 ± 10.0
82.7 ± 15.6 168.6 ± 9.1
0.151 0.674
a
Weight (kg) Height (cm)a BMI (kg/m2)a
27.2 ± 3.7
28.5 ± 5.0
0.187
Volume delivered (mL)
4.93 ± 0.232
4.96 ± 0.139
0.737
n Indicates number of patients, LNF laparoscopic Nissen fundoplication, LC laparoscopic cholecystectomy, BMI body mass index a
mean ± standard deviation
b
number (%)
c
median (range) in minutes for combination of both LNF and LC groups
Table 2 Incidence of postoperative shoulder tip pain Shoulder tip pain
Treatment arm
Control arm
p value
Theater recovery
21/40 (52.5 %)
33/46 (71.7 %)
0.066
Ward
28/40 (70.0 %)
33/45 (73.3 %)
0.733
Theater recovery
20/38 (52.6 %)
30/45 (66.7 %)
0.193
Ward
29/38 (76.3 %)
33/43 (76.7 %)
0.964
Theater recovery
19/23 (82.6 %)
22/27 (81.5 %)
0.918
Ward
18/23 (78.3 %)
23/26 (88.5 %)
0.335
On movement Theater recovery
17/22 (77.3 %)
21/27 (77.8 %)
0.966
Ward
18/22 (81.8 %)
23/25 (92.0 %)
0.297
At rest
On movement
Primary endpoint: shoulder tip pain at 6 h postoperatively There was no difference overall between TG and CG in shoulder tip pain at 6 h postoperatively. Secondary endpoints Overall incidence of shoulder tip pain
LNF subgroup At rest
LC subgroup
Incidence of shoulder tip pain at rest and on movement is summarized in Table 2. There was a reduction of shoulder tip pain at rest in the recovery room in TG, but this did not reach significance (52.5 vs. 71.7 %, p = 0.066). The reduction of shoulder tip pain at rest in the recovery room was significant in the LC cohort (11.8 vs. 57.9 %, p = 0.004).
At rest Theater recovery Ward
2/17 (11.8 %)
11/19 (57.9 %)
0.004
10/17 (58.8 %)
10/19 (52.6 %)
0.709
3/16 (18.8 %)
9/18 (50.0 %)
0.057
11/16 (68.8 %)
10/18 (55.6 %)
0.429
On movement Theater recovery Ward
were recruited and randomized. Twelve patients were excluded from the final analysis (Fig. 2). Eighty-seven were included in the final analysis, 40 in the TG and 47 in the control group (CG). There were no significant differences between the two groups (Table 1). Patients in the LNF group had simple gastro-esophageal reflux disease (GERD) with no cases of a sliding hiatus hernia.
Pain scores in the recovery room There was no significant difference between the study groups in abdominal and shoulder tip pain in the recovery room. Subgroup analysis of the LC cohort revealed a significant reduction of shoulder tip pain at rest at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively) (Fig. 3). Pain scores on the ward There was no significant difference between the study groups in abdominal and shoulder tip pain on the ward. Subgroup analysis of the LNF cohort revealed a significant
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reduction of abdominal pain at rest at 6 h (p = 0.009) (Fig. 4). Length of recovery room and hospital stay There was no statistical difference in the length of stay in the recovery room and hospital between the two study groups (Table 3). Postoperative analgesia use There was no statistical difference in analgesia use in the recovery room (Table 4). There was a significant reduction in the proportion of patients in the treatment arm requiring diclofenac in the first 24 h postoperatively (p = 0.013). Fig. 3 Shoulder tip pain in patients who underwent laparoscopic cholecystectomy. Significant reduction of shoulder tip pain at rest at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively) in the treatment arm
Adverse events There was no adverse event reported with the use of aerosolized intraperitoneal ropivacaine. There were no major surgical complications.
Discussion
Fig. 4 Abdominal pain at rest in patients who underwent laparoscopic Nissen fundoplication 6 h postoperatively. Significant reduction of abdominal pain at rest at 6 h (p = 0.009) in the treatment arm
The aim of this study was to assess aerosolized ropivacaine in the management of postoperative shoulder tip pain following LNF and LC. In clinical practice, subjectively reported pain scores are the driving force influencing analgesia administration and ultimately duration of inpatient stay. There was no difference between TG and CG in shoulder tip at the primary endpoint, 6 h postoperatively. In the LC group, AILA reduced shoulder tip pain significantly at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively). Although relatively short lived, this reduction is still of clinical importance. The recovery room setting is where the majority of postoperative opiates are administered. Reduced pain scores would reduce the need for postoperative intravenous
Table 3 Length of stay in recovery room and overall Length of stay
Intervention group
Control group
p value
Theater recovery (min)
61.5 (25.0–234.0)
65.0 (31.0–214.0)
0.993
Hospital stay (h)
24.5 (16.5–68.0)
26.5 (17.0–120.0)
0.306
LNF subgroup Theater recovery (min)
65.0 (34.0–234.0)
67.0 (31.0–214.0)
0.909
Hospital stay (h)
24.0 (17.0–63.0)
34.3 (17.5–120.0)
0.109
Theater recovery (min)
60.0 (25.5–135.0)
60.0 (40.0–160.0)
0.876
Hospital stay (h)
25.0 (16.5–68.0)
25.3 (17.0–95.0)
0.851
LC subgroup
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World J Surg Table 4 Analgesic use in the recovery room and on the ward (within first 24 h) Recovery room Treatment arm 6 (0–20)
Control arm
p value
Morphine (mg)
Median (range)
8 (0–20)
0.499
Additional opioidsa
Number (%)
2/40 (5.0 %)
6/47 (12.8 %)
0.279
Diclofenacb
Number (%)
1/40 (2.5 %)
3/47 (6.4 %)
0.621
Paracetamol (g)c
Number (%)
36/40 (90 %)
42/47 (89 %)
0.356
Diclofenac (mg)d
Number (%)
2/40 (5 %)
Tramadol (mg)e
Number (%)
18/40 (45 %)
On the ward (within 24 h)
a
11/47 (23.4 %)
0.013
24/47 (51 %)
0.355
Fentanyl 100 lg; Ketamine Hydrochloride 10 mg; Oxycodone Hydrochloride 10 mg or Tramadol Hydrochloride 100 mg
b
100 mg per rectally or 75 mg intravenously
c
Paracetamol 1 g intravenously or orally
d
Diclofenac 100 mg per rectally or 75 mg orally
e
Tramadol 100 mg intravenously or orally
opioids, therefore avoiding their adverse side-effect profile and thus making these cases more amenable to day-case surgery. In addition, AILA reduced the incidence of shoulder tip pain in the LC group (11.8 vs. 57.9 %, p = 0.004). Despite no other significant difference in pain scores between the TG and CG, the CG had persistently elevated pain scores at each measured time point. Previous studies have reported the incidence of shoulder tip pain following laparoscopy to be between 35 and 72 % [7, 14, 15]. In our study, the overall incidence of shoulder tip pain at 6 h postoperatively was 37.9 %, with an incidence of 54.9 % in the LC group and 13.9 % in the LNF group. The study was carried out by a single surgeon at a single institution with a standardized protocol for peri-operative care, creating a homogenous platform of treatment to accurately assess the intervention (AILA). In addition, analgesia consumption in recovery and on the ward was recorded as part of the analysis of this study. To our knowledge, few, if any, other studies with this information have been performed. Elective LNF and LC were chosen for our study. Laparoscopic Nissen fundoplication is a clean upper GI procedure where the potential variables encountered intraoperatively are minimized. Intuitively, this would allow for greater reliability as to whether pre-emptive localized intraperitoneal local anesthetic (ropivacaine) would work or not. Laparoscopic cholecystectomy is one of the most common intraperitoneal procedures performed in general surgery notwithstanding greater intraoperative variability than Nissen fundoplication. Aerosolized ropivacaine significantly reduced only shoulder tip pain in the LC group and only abdominal pain in the LNF group. Different pain mechanisms for each of these common procedures may be the reason. Alternatively, the differing responses to aerosolized local anesthetic may have been
due to fundamental differences in these procedures, such as differences in the trocar positions for each procedure and the potential for pneumomediastinum following LNF. Pain following laparoscopy is common. There are two mechanisms of insult; Firstly, direct trauma to the abdominal wall (somatic irritation) during port placement and second, visceral irritation during surgical dissection and stretching of the diaphragmatic peritoneum on creation of the pneumoperitoneum. Intraperitoneal anesthetic delivery methods studied to date include diaphragmatic irrigation and instillation [7, 9]. Studies evaluating intraperitoneal local anesthetic instillation as a method of reducing postoperative pain have reported conflicting results. A recent study by Kahokehr et al. reported that instillation and infusion of ropivacaine provided reduced postoperative pain and less opioid analgesic requirements when compared to the placebo group following colonic resection [9]. However, a study by Stuhldreher et al. concluded that intraperitoneal local anesthetic instillation did not improve postoperative pain scores or opioid requirements in patients undergoing laparoscopic colorectal procedures [16]. Indeed, other previous studies reported little additional benefit to intraperitoneal bupivacaine on pain scores beyond 2 h postoperatively [17], or indeed no benefit at all [18]. Systematic reviews have pooled the results of trials investigating the role for intraperitoneal instillation of local anesthetic. One such review was unable to provide a conclusive answer to support or discourage its use [19]. Meanwhile, a second review conferred ‘limited support’ to the use of intraperitoneal local anesthetic during LC [20]. These conflicting results could well be due to lack of consistency in delivery methods and unequal distribution of the local anesthetic agent on the peritoneal surface. Nonetheless, the lack of reproducible evidence to support instillation as an
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appropriate method of local anesthetic delivery means that no definitive conclusion can be reached and it is not yet incorporated into routine clinical practice. Aerosolized or nebulized delivery methods are thought to be more advantageous, as they are associated with less hypothermic effects and provide homogenous peritoneal distribution by coating the entire peritoneal cavity [12]. There are only four other reports in the literature evaluating the aerosolization or nebulization method of delivery [10, 11, 21, 22]. Zimmer et al. reported no difference in pain scores between the control and intervention groups following bupivacaine administration using the InsuflowÒ device [22]. However, unlike the AeroSurgeÒ, this device utilizes a hot evaporation technique in which the solvent is delivered to the patient, in the absence of the solvent. Alkhamesi et al. showed that aerosolized bupivacaine using the AeronebÒ device significantly reduced postoperative pain following LC (n = 60, 2 patient groups) [11]. Bucciero et al. analyzed aerosolized intraperitoneal ropivacaine delivery using the AeronebÒ device during LC (n = 80, 4 patient groups of n = 20) and reported no difference in pain scores or morphine consumption between groups, but a reduction in shoulder pain and walking time [10]. Ingelmo et al. utilized the Aeroneb ProÒ to deliver ropivacaine to patients undergoing LC (n = 90, 3 patient groups of n = 30) and reported a significant reduction of postoperative pain scores, shoulder pain scores, morphine requirements, and time to unassisted walking [21]. These studies, in combination with the present study, reveal that despite being in its infancy, aerosolized intraperitoneal local anesthetic has potential in the management of postlaparoscopic pain. Ropivacaine was the local anesthetic agent of choice for this study. It is a long-acting amide local anesthetic agent that is less lipophilic than bupivacaine and, as such, confers decreased potential for central nervous system toxicity and cardiotoxicity [23, 24]. In addition, the pharmacokinetic profile following intraperitoneal nebulization of ropivacaine is similar to extravascular administration [25, 26]. The maximum safe dose is 3–4 mk/kg, with a mean toxic plasma concentration of 4.3 mg/L (range 3.4 to 5.3 mg/L) [24]. The total cumulative dose administered in this study was 125 mg ropivacaine, comprised of 5 mL of aerosolized 1 % ropivacaine and 10 mL of 7.5 % ropivacaine infiltrated at the port sites. Pain response to ropivacaine in this study was probably underpowered as the commercially available strongest concentration was 1 %. Our previous pharmacokinetic patient safety study of this dose would suggest that a substantially more concentrated formula of ropivacaine could be used for greater efficacy without the risk of adverse systemic effects, as the total systemic ropivacaine level achieved with this dose is over 60 % below the threshold for toxicity [27].
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Pre-emptive versus postoperative local anesthetic delivery has been evaluated by Palmes et al. in patients undergoing laparoscopic hernia repair and Nissen fundoplication and reported that pre-emptive intraperitoneal local anesthetic delivery significantly reduced postoperative analgesic consumption and pain intensity following Nissen fundoplication [28]. This emphasizes the importance of ropivacaine delivery in advance of surgical dissection, as performed in this study, and likely relates to the mechanism by which local anesthetics reduce postoperative pain. These agents inhibit nociception by modifying nerve membrane-associated proteins and impeding the release and action of agents, such as prostaglandins, that sensitize the nociceptors and contribute to inflammation [29]. This study demonstrates that aerosolized intraperitoneal local anesthetic using the novel AeroSurgeÒ device has potential in post-laparoscopic pain management. It did not confer statistically significant pain score outcomes between study groups at the primary endpoint. While the results of subgroup analysis need to be interpreted with caution, pain scores at various distinct time points were improved in the treatment arm in the subgroup analysis. Studies evaluating higher total ropivacaine dose delivery in a more homogenous patient cohort (i.e., single procedure) are needed to assess this promising approach to further enhance recovery making these procedures more amenable to day-case laparoscopic surgery. Acknowledgments The authors would like to thank the patients for their participation and the theater, recovery, and ward nursing staff of the Galway Clinic, Ireland for their assistance in conducting this study. Conflict of Interest
None.
Disclosure AeroSurgical Ò provided the device for this study. None of the authors (AMD, KHC, MK, PMA, BK, BH, AA, MK, and OMA) have or had any financial relationships with AztraZeneca, the pharmaceutical company or AeroSurgicalÒ, the device company. There are no financial ties or conflicts of interest to disclose.
References 1. Ekstein P, Szold A, Sagie B, Werbin N, Klausner JM, Weinbroum AA (2006) Laparoscopic surgery may be associated with severe pain and high analgesia requirements in the immediate postoperative period. Ann Surg 243(1):41–46 2. Maestroni U, Sortini D, Devito C, Brunaldi FPMK, Anania G, Pavanelli L, Pasqualucci A, Donini A (2002) A new method of preemptive analgesia in laparoscopic cholecystectomy. Surg Endosc 16(9):1336–1340 (Epub 2002 May 1337) 3. Ji W, Ding K, Li LT, Wang D, Li N, Li JS (2010) Outpatient versus inpatient laparoscopic cholecystectomy: a single center clinical analysis. Hepatobiliary Pancreat Dis Int 9(1):60–64 4. Berggren U, Gordh T, Grama D, Haglund U, Rastad J, Arvidsson D (1994) Laparoscopic versus open cholecystectomy: hospitalization,
World J Surg
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
sick leave, analgesia and trauma responses. Br J Surg 81(9):1362–1365 Sarac AM, Aktan AO, Baykan N, Yegen C, Yalin R (1996) The effect and timing of local anesthesia in laparoscopic cholecystectomy. Surg Laparosc Endosc 6(5):362–366 Liu YY, Yeh CN, Lee HL, Wang SY, Tsai CY, Lin CC, Chao TC, Yeh TS, Jan YY (2009) Local anesthesia with ropivacaine for patients undergoing laparoscopic cholecystectomy. World J Gastroenterol 15(19):2376–2380 Cunniffe MG, McAnena OJ, Dar MA, Calleary J, Flynn N (1998) A prospective randomized trial of intraoperative bupivacaine irrigation for management of shoulder-tip pain following laparoscopy. Am J Surg 176(3):258–261 Ahmed BH, Ahmed A, Tan D, Awad ZT, Al-Aali AY, Kilkenny J 3rd, Orlando FA, Al-Chalabi A, Crass R, Alrawi SJ (2008) Post-laparoscopic cholecystectomy pain: effects of intraperitoneal local anesthetics on pain control–a randomized prospective double-blinded placebo-controlled trial. Am Surg 74(3):201–209 Kahokehr A, Sammour T, Shoshtari KZ, Taylor M, Hill AG (2011) Intraperitoneal local anesthetic improves recovery after colon resection: a double-blinded randomized controlled trial. Ann Surg 254(1):28–38 Bucciero M, Ingelmo PM, Fumagalli R, Noll E, Garbagnati A, Somaini M, Joshi GP, Vitale G, Giardini V, Diemunsch P (2011) Intraperitoneal ropivacaine nebulization for pain management after laparoscopic cholecystectomy: a comparison with intraperitoneal instillation. Anesth Analg 113(5):1266–1271 Alkhamesi NA, Peck DH, Lomax D, Darzi AW (2007) Intraperitoneal aerosolization of bupivacaine reduces postoperative pain in laparoscopic surgery: a randomized prospective controlled double-blinded clinical trial. Surg Endosc 21(4):602–606 Epub 2006 Dec 2016 Greib N, Schlotterbeck H, Dow WA, Joshi GP, Geny B, Diemunsch PA (2008) An evaluation of gas humidifying devices as a means of intraperitoneal local anesthetic administration for laparoscopic surgery. Anesth Analg 107(2):549–551 Betton D, Greib N, Schlotterbeck H, Joshi GP, Ubeaud-Sequier G, Diemunsch P (2010) The pharmacokinetics of ropivacaine after intraperitoneal administration: instillation versus nebulization. Anesth Analg 111(5):1140–1145 Dobbs FF, Kumar V, Alexander JI, Hull MG (1987) Pain after laparoscopy related to posture and ring versus clip sterilization. Br J Obstet Gynaecol 94(3):262–266 Tsai HW, Wang PH, Yen MS, Chao KC, Hsu TF, Chen YJ (2013) Prevention of postlaparoscopic shoulder and upper abdominal pain: a randomized controlled trial. Obstet Gynecol 121(3): 526–531. doi:10.1097/AOG.0b013e318283fcca Stuhldreher JM, Adamina M, Konopacka A, Brady K, Delaney CP (2012) Effect of local anesthetics on postoperative pain and opioid consumption in laparoscopic colorectal surgery. Surg Endosc 26(6):1617–1623. doi:10.1007/s00464-011-2079-1 (Epub 02011 Dec 00417)
17. Hernandez-Palazon J, Tortosa JA, de la Rosa VN, Gimenez-Viudes J, Ramirez G, Robles R (2003) Intraperitoneal application of bupivacaine plus morphine for pain relief after laparoscopic cholecystectomy. Eur J Anaesthesiol 20(11):891–896 18. Rademaker BM, Kalkman CJ, Odoom JA, de Wit L, Ringers J (1994) Intraperitoneal local anaesthetics after laparoscopic cholecystectomy: effects on postoperative pain, metabolic responses and lung function. Br J Anaesth 72(3):263–266 19. Bisgaard T (2006) Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 104(4):835–846 20. Boddy AP, Mehta S, Rhodes M (2006) The effect of intraperitoneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis. Anesth Analg 103(3):682–688 21. Ingelmo PM, Bucciero M, Somaini M, Sahillioglu E, Garbagnati A, Charton A, Rossini V, Sacchi V, Scardilli M, Lometti A, Joshi GP, Fumagalli R, Diemunsch P (2013) Intraperitoneal nebulization of ropivacaine for pain control after laparoscopic cholecystectomy: a double-blind, randomized, placebo-controlled trial. Br J Anaesth 110(5):800–806. doi:10.1093/bja/aes495 22. Zimmer PW, McCann MJ, O’Brien MM (2010) Bupivacaine use in the Insuflow device during laparoscopic cholecystectomy: results of a prospective randomized double-blind controlled trial. Surg Endosc 24(7):1524–1527. doi:10.1007/s00464-009-0804-9 23. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E (2002) Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology 96(6):1427–1434 24. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N (1997) Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 78(5):507–514 25. Rowland M, Tozer T (1995) Extravascular dose. In: Balado D (ed) Clinical pharmacokinetics: concepts and application, 3rd edn. Lippincott Williams and Wilkins, Baltimore, pp 34–50 26. Labaille T, Mazoit JX, Paqueron X, Franco D, Benhamou D (2002) The clinical efficacy and pharmacokinetics of intraperitoneal ropivacaine for laparoscopic cholecystectomy. Anesth Analg 94(1):100–105 table of contents 27. McDermott AM, Chang KH, Mieske K, Abeidi A, Harte BH, Kerin MJ, McAnena OJ (2014) Total systemic ropivacaine concentrations following aerosolized intraperitoneal delivery using the AeroSurge. J clin Anesth. doi:10.1016/j.jclinane.2013.07.013 28. Palmes D, Rottgermann S, Classen C, Haier J, Horstmann R (2007) Randomized clinical trial of the influence of intraperitoneal local anaesthesia on pain after laparoscopic surgery. Br J Surg 94(7):824–832 29. Louizos AA, Hadzilia SJ, Leandros E, Kouroukli IK, Georgiou LG, Bramis JP (2005) Postoperative pain relief after laparoscopic cholecystectomy: a placebo-controlled double-blind randomized trial of preincisional infiltration and intraperitoneal instillation of levobupivacaine 0.25 %. Surg Endosc 19(11):1503–1506 (Epub 2005 Oct 1503)
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ORIGINAL SCIENTIFIC REPORT
Aerosolized Intraperitoneal Local Anesthetic for Laparoscopic Surgery: A Randomized, Double-Blinded, Placebo-Controlled Trial Ailbhe M. McDermott • Kah Hoong Chang • Kelly Mieske • Peter F. McAnena Brian Kinirons • Abdelaly Abeidi • Brian H. Harte • Michael J. Kerin • Oliver J. McAnena
•
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background Postoperative pain remains a significant challenge following laparoscopy. Aerosolized intraperitoneal local anesthetic (AILA) is a novel method to deliver local anesthetic. The aim was to evaluate aerosolized ropivacaine in pain management following laparoscopic Nissen fundoplication (LNF) and cholecystectomy (LC). Methods This prospective randomized double-blinded placebo-controlled trial enrolled consecutive patients undergoing LNF and LC. The treatment group (TG) received intraperitoneal ropivacaine (5 mL 1 %NaropinÒ) at CO2 insufflation via the AeroSurgeÒ aerosolizer device through the camera port. The control group (CG) received 5 mL of saline in the same manner. Postoperative shoulder tip pain at rest 6 h postoperatively was the primary study endpoint, with secondary endpoints of shoulder and abdominal pain within the first 24 h, recovery room stay, hospital stay, and postoperative analgesia use. Pain scores were collected using the Verbal Rating Score. Results Eighty-seven patients were included in the final analysis (TG n = 40, CG n = 47). There was no significant difference between CG and TG at the primary endpoint. In the LC group, AILA significantly reduced shoulder tip pain at rest at 10 (p = 0.030) and 30 min (p = 0.040) and shoulder tip pain on movement at 10 (p = 0.030) and 30 min (p = 0.037). In the LNF group, AILA significantly reduced postoperative abdominal pain at rest at 6 h (p = 0.009). AILA reduced overall incidence of shoulder tip pain in the LC group (11.8 vs. 57.9 %, p = 0.004). Conclusion This study did not demonstrate a significant difference between TG and CG in the primary endpoint, pain at 6 h postoperatively.
Trial Registration: European Medicines Agency European Clinical Trials Database, EudraCT 2009-015236-15. A. M. McDermott K. H. Chang K. Mieske P. F. McAnena M. J. Kerin O. J. McAnena (&) Discipline of Surgery, National University of Ireland, Galway, Ireland e-mail: [email protected] A. M. McDermott e-mail: [email protected]
Abbreviations AILA Aerosolized intraperitoneal local anesthetic ASA American Society of Anesthesiologists BMI Body mass index B. Kinirons B. H. Harte Department of Anesthesia, Galway University Hospital, Galway, Ireland O. J. McAnena Department of Surgery, Galway Clinic, Doughiska, Galway, Ireland
B. Kinirons A. Abeidi B. H. Harte Department of Anesthesia, Galway Clinic, Doughiska, Galway, Ireland
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CG CO2 CONSORT CNS GERD IV Kg LC LNF Mg NSAID O2 PCA TG US VRS
Control group Carbon dioxide Consolidated standards of reporting of trials Central nervous system Gastro-esophageal reflux disease Intravenous Kilogram Laparoscopic cholecystectomy Laparoscopic Nissen fundoplication Milligram Non-steroidal anti-inflammatory drug Oxygen Patient-controlled analgesia Treatment group United States Verbal rating score
Introduction Laparoscopy is a commonly performed procedure. Favor of a laparoscopic approach over an open procedure for several benign and malignant pathologies has been corroborated extensively in the literature over the past two decades. While associated with reduced postoperative pain, laparoscopy is not pain free, particularly in the immediate postoperative period [1, 2]. Postoperative abdominal and shoulder tip pain often prolongs patient hospitalization resulting in additional costs [3, 4]. Increasing understanding of the mechanisms of postlaparoscopy pain has led to the use of intraperitoneal local anesthetic agents, which provide pain relief without the side-effect profile of opioids. Studies evaluating different techniques of local anesthetic delivery including peri-portal infiltration [5, 6], diaphragmatic irrigation [7], instillation into the sub-diaphragmatic area [8], or diffuse instillation [2, 9] have shown conflicting results to date. Intraperitoneal delivery of a local anesthetic in a nebulized or aerosolized form has shown promising results thus far [10, 11]. The AeroSurgeÒ device delivers preemptive aerosolized local anesthetic (ropivacaine) at the time of peritoneal insufflation with carbon dioxide (CO2). Initial experimental studies on early designs of this aerosolization device (AeronebÒ) confirmed its superiority over evaporation devices, with over 90 % of the total volume of ropivacaine being delivered to the peritoneal cavity [12]. Animal studies have demonstrated the pharmacokinetic safety of intraperitoneal ropivacaine delivery using an early design of this device (Aeroneb ProÒ) [13]. The AeroSurgeÒ comprised of an aerosolizer chamber, and modified trocar is a novel device, capable of producing a
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faster flow rate (1 mL/min) than earlier AeronebÒ models (0.3 mL/min). The aim of this study was to evaluate aerosolized ropivacaine delivered using the AeroSurge Ò device in the management of postoperative pain following laparoscopic Nissen fundoplication (LNF) and cholecystectomy (LC).
Materials and methods This was a randomized double-blinded placebo-controlled trial, registered with the European Clinical Trials Database (EudraCT 2009-015236-15). Ethical approval was granted by the Irish Medicines Board and local research ethics committee. Written informed consent was obtained from all participants. Sample size was calculated from pain scores collected during a pilot study based on a power of 0.9 and type I error 0.05. In order to detect a 20 % reduction in the shoulder tip pain score at 6 h postoperatively in the treatment group (TG), 70 patients were required, with 35 in each arm. Additional patients were recruited to allow for mechanical device, laparoscopic equipment malfunction, or deviation from the strict study protocol. Participants Consecutive patients undergoing LNF and LC between May 2011 and August 2012 were assessed for eligibility. Inclusion criteria included: American Society of Anesthesiologist (ASA) grade I or II, between 18 and 70 years of age, free from pain preoperatively, ability to understand and comply with the protocol, and ability to provide informed consent. Exclusion criteria included: renal or hepatic impairment, pregnant or breast feeding, taking regular analgesia, prior laparoscopic surgery, allergy or suspected allergy to local anesthetic agents or opiates, drug or alcohol addiction, and neurological or psychiatric illness (other than mild medication-controlled depression). Surgery Following administration of general anesthetic by endotracheal intubation, patients were administered a total of 10 mL 0.75 % ropivacaine to the port sites prior to incision. Both operations were carried out as overnight stay procedures. At the end of both procedures, all ports were left in an open mode to allow full evacuation of CO2 and were removed individually as each wound is closed Method of administration using the aerosolizer The 10-mm umbilical (LC) or epigastric (LNF) port was sited first, and prior to dissection, the AeroSurgeÒ device
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sulfate). A standardized anti-emetic was also administered intraoperatively, ondansetron (4 mg IV, Ondran). Postoperative analgesia and anti-emetics Patients were prescribed postoperative analgesia as required in keeping with the WHO analgesic ladder. Morphine was permitted in the recovery room if pain scores greater than four were reported. On the ward, non-opiate and opiate analgesia were administered as required. The time, dose, and route of administration of each medication were recorded. Randomization and blinding
Fig. 1 The AeroSurge Ò device. The novel AeroSurge Ò device comprised of an AC/DC adapter which connects to the AeroSurgical controller unit, both of which lie outside the sterile field. A detachable cable is covered in a disposable sterile sheath and connected to the aerosolizer chamber which contains 10 mL of 1 % ropivacaine (TG) or 10 mL normal saline (CG) in liquid form. The modified trocar is placed in the 10-mm port, and CO2 is pumped through the aerosolizer chamber converting the liquid ropivacaine to a nebulized form
(consisting of the prototype-modified trocar and aerosolizer unit, Fig. 1) was assembled, loaded with 5 mL of 1 % ropivacaine or saline, placed in the port, and connected to the insufflator and power supply under aseptic technique. The AeroSurgeÒ controller unit was switched on at the same time as insufflation began with CO2 at 1 L/min at a maximum pressure limit of 15 mmHg. A total of 5 min were required for delivery of 5 mL ropivacaine. An additional 5 min to allow absorption of the ropivacaine mist was permitted before desufflation, and immediate re-sufflation was performed to enable clearance of the aerosolized solution, which otherwise clouded the operative field. The volume of solution, if any, left in the trocar was measured. Anesthetic protocol All patients received a standardized intraoperative anesthetic regimen with no pre-medication. Patients received 100 lg fentanyl (SublimazeÒ) 2 min prior to induction. Anesthesia was induced with 2–3 mg/kg propofol (PropovenÒ) titrated to effect. Muscle relaxation was then achieved with 0.6 mg/kg rocuronium (EsmeronÒ). Anesthesia was maintained with Sevoflurane (SevoraneÒ) in 50 % O2 in air. Intraoperative analgesia was provided at the start of the procedure with paracetamol 1 g intravenously and 0.075 mg/kg morphine IV (Morphine
The randomization sequence was conducted using computer-generated random numbers by a third party not involved in the study. Patients were randomly assigned to receive either 5 mL of nebulized 1 % ropivacaine (1 % NaropinÒ, AstraZeneca, equivalent to 50 mg ropivacaine) or 5 mL of nebulized 0.9 % normal saline. Randomization was stratified according to procedure type (i.e., LNF or LC). The treatment allocation for each patient was kept in a sealed envelope labeled with the study number. At the time of induction of anesthesia, the anesthetic assistant opened the next sequential envelope and prepared the treatment allocation in syringe in a concealed preparation room. The anesthetic assistant then loaded the aerosolizer unit with the appropriate solution. The envelope, which included the label from the used medication vial and patient demographics, was re-sealed. Only the anesthetic assistant was aware of patient allocation and was not involved at any other step in patient management, patient data recording, analysis, or write-up. The patients, all investigators, surgeons, anesthesiologists, nurses, and other medical staff responsible for the care of the patients were blinded to the study allocation. Outcome measures Outcome measures were the presence of pain (yes or no) and pain scores assessed using the verbal rating score (VRS). Blinded recovery and ward staff nurses collected data using a specifically devised data collection form. General abdominal pain and shoulder tip pain both at rest and on movement (coughing) were recorded at 10-min intervals in the recovery room, at 2, 4, 6, 12, and 24 h postoperatively on the ward and finally on discharge. Study endpoints The primary endpoint for this study was to determine the efficacy of aerosolized ropivacaine in the reduction of
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Fig. 2 CONSORT flow diagram. PCA Patient-controlled analgesia
postoperative shoulder tip pain following LNF or LC at 6 h postoperatively. Shoulder tip pain at 6 h postoperatively was selected as the primary end point to reflect the pharmacokinetic profile of ropivacaine. The secondary study endpoints were shoulder and abdominal pain within the first 24 h postoperatively, length of recovery room stay, length of hospital stay, and postoperative analgesia use.
using v2 test for nominal or ordinal data; Student’s t test or Analysis of Variance (ANOVA) and Mann–Whitney U or Kruskal–Wallis test were used for parametric and nonparametric continuous data, respectively. A p value of less than 0.05 was considered statistically significant for all tests.
Statistical analysis
Results
Statistical analysis was carried out using SPSSÒ version 20 (Chicago, IL, USA) software. Distribution of continuous data was determined using the Kolmogorov–Smirnov Z test. Univariate comparison of variables was assessed
Patient characteristics
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Between May 2011 and August 2012, 113 patients were screened and assessed for eligibility. Ninety-nine patients
World J Surg Table 1 Patient and procedural characteristics Treatment arm n = 40
Control arm n = 47
p value
Agea
45.9 ± 12.0
43.6 ± 14.3
0.426
Gender (M:F)
19:21
17:30
0.285
23 (57.5)
28 (59.6)
Surgery typeb
0.845
LNF LC
17 (42.5)
19 (40.4)
Length of procedure (min)c
35 (21–71)
35 (15–85)
0.714
83.9 ± 10.3 171.7 ± 10.0
82.7 ± 15.6 168.6 ± 9.1
0.151 0.674
a
Weight (kg) Height (cm)a BMI (kg/m2)a
27.2 ± 3.7
28.5 ± 5.0
0.187
Volume delivered (mL)
4.93 ± 0.232
4.96 ± 0.139
0.737
n Indicates number of patients, LNF laparoscopic Nissen fundoplication, LC laparoscopic cholecystectomy, BMI body mass index a
mean ± standard deviation
b
number (%)
c
median (range) in minutes for combination of both LNF and LC groups
Table 2 Incidence of postoperative shoulder tip pain Shoulder tip pain
Treatment arm
Control arm
p value
Theater recovery
21/40 (52.5 %)
33/46 (71.7 %)
0.066
Ward
28/40 (70.0 %)
33/45 (73.3 %)
0.733
Theater recovery
20/38 (52.6 %)
30/45 (66.7 %)
0.193
Ward
29/38 (76.3 %)
33/43 (76.7 %)
0.964
Theater recovery
19/23 (82.6 %)
22/27 (81.5 %)
0.918
Ward
18/23 (78.3 %)
23/26 (88.5 %)
0.335
On movement Theater recovery
17/22 (77.3 %)
21/27 (77.8 %)
0.966
Ward
18/22 (81.8 %)
23/25 (92.0 %)
0.297
At rest
On movement
Primary endpoint: shoulder tip pain at 6 h postoperatively There was no difference overall between TG and CG in shoulder tip pain at 6 h postoperatively. Secondary endpoints Overall incidence of shoulder tip pain
LNF subgroup At rest
LC subgroup
Incidence of shoulder tip pain at rest and on movement is summarized in Table 2. There was a reduction of shoulder tip pain at rest in the recovery room in TG, but this did not reach significance (52.5 vs. 71.7 %, p = 0.066). The reduction of shoulder tip pain at rest in the recovery room was significant in the LC cohort (11.8 vs. 57.9 %, p = 0.004).
At rest Theater recovery Ward
2/17 (11.8 %)
11/19 (57.9 %)
0.004
10/17 (58.8 %)
10/19 (52.6 %)
0.709
3/16 (18.8 %)
9/18 (50.0 %)
0.057
11/16 (68.8 %)
10/18 (55.6 %)
0.429
On movement Theater recovery Ward
were recruited and randomized. Twelve patients were excluded from the final analysis (Fig. 2). Eighty-seven were included in the final analysis, 40 in the TG and 47 in the control group (CG). There were no significant differences between the two groups (Table 1). Patients in the LNF group had simple gastro-esophageal reflux disease (GERD) with no cases of a sliding hiatus hernia.
Pain scores in the recovery room There was no significant difference between the study groups in abdominal and shoulder tip pain in the recovery room. Subgroup analysis of the LC cohort revealed a significant reduction of shoulder tip pain at rest at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively) (Fig. 3). Pain scores on the ward There was no significant difference between the study groups in abdominal and shoulder tip pain on the ward. Subgroup analysis of the LNF cohort revealed a significant
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reduction of abdominal pain at rest at 6 h (p = 0.009) (Fig. 4). Length of recovery room and hospital stay There was no statistical difference in the length of stay in the recovery room and hospital between the two study groups (Table 3). Postoperative analgesia use There was no statistical difference in analgesia use in the recovery room (Table 4). There was a significant reduction in the proportion of patients in the treatment arm requiring diclofenac in the first 24 h postoperatively (p = 0.013). Fig. 3 Shoulder tip pain in patients who underwent laparoscopic cholecystectomy. Significant reduction of shoulder tip pain at rest at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively) in the treatment arm
Adverse events There was no adverse event reported with the use of aerosolized intraperitoneal ropivacaine. There were no major surgical complications.
Discussion
Fig. 4 Abdominal pain at rest in patients who underwent laparoscopic Nissen fundoplication 6 h postoperatively. Significant reduction of abdominal pain at rest at 6 h (p = 0.009) in the treatment arm
The aim of this study was to assess aerosolized ropivacaine in the management of postoperative shoulder tip pain following LNF and LC. In clinical practice, subjectively reported pain scores are the driving force influencing analgesia administration and ultimately duration of inpatient stay. There was no difference between TG and CG in shoulder tip at the primary endpoint, 6 h postoperatively. In the LC group, AILA reduced shoulder tip pain significantly at 10 and 30 min (p = 0.030 and 0.040, respectively) and shoulder tip pain on movement at 10 and 30 min (p = 0.030 and 0.037, respectively). Although relatively short lived, this reduction is still of clinical importance. The recovery room setting is where the majority of postoperative opiates are administered. Reduced pain scores would reduce the need for postoperative intravenous
Table 3 Length of stay in recovery room and overall Length of stay
Intervention group
Control group
p value
Theater recovery (min)
61.5 (25.0–234.0)
65.0 (31.0–214.0)
0.993
Hospital stay (h)
24.5 (16.5–68.0)
26.5 (17.0–120.0)
0.306
LNF subgroup Theater recovery (min)
65.0 (34.0–234.0)
67.0 (31.0–214.0)
0.909
Hospital stay (h)
24.0 (17.0–63.0)
34.3 (17.5–120.0)
0.109
Theater recovery (min)
60.0 (25.5–135.0)
60.0 (40.0–160.0)
0.876
Hospital stay (h)
25.0 (16.5–68.0)
25.3 (17.0–95.0)
0.851
LC subgroup
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World J Surg Table 4 Analgesic use in the recovery room and on the ward (within first 24 h) Recovery room Treatment arm 6 (0–20)
Control arm
p value
Morphine (mg)
Median (range)
8 (0–20)
0.499
Additional opioidsa
Number (%)
2/40 (5.0 %)
6/47 (12.8 %)
0.279
Diclofenacb
Number (%)
1/40 (2.5 %)
3/47 (6.4 %)
0.621
Paracetamol (g)c
Number (%)
36/40 (90 %)
42/47 (89 %)
0.356
Diclofenac (mg)d
Number (%)
2/40 (5 %)
Tramadol (mg)e
Number (%)
18/40 (45 %)
On the ward (within 24 h)
a
11/47 (23.4 %)
0.013
24/47 (51 %)
0.355
Fentanyl 100 lg; Ketamine Hydrochloride 10 mg; Oxycodone Hydrochloride 10 mg or Tramadol Hydrochloride 100 mg
b
100 mg per rectally or 75 mg intravenously
c
Paracetamol 1 g intravenously or orally
d
Diclofenac 100 mg per rectally or 75 mg orally
e
Tramadol 100 mg intravenously or orally
opioids, therefore avoiding their adverse side-effect profile and thus making these cases more amenable to day-case surgery. In addition, AILA reduced the incidence of shoulder tip pain in the LC group (11.8 vs. 57.9 %, p = 0.004). Despite no other significant difference in pain scores between the TG and CG, the CG had persistently elevated pain scores at each measured time point. Previous studies have reported the incidence of shoulder tip pain following laparoscopy to be between 35 and 72 % [7, 14, 15]. In our study, the overall incidence of shoulder tip pain at 6 h postoperatively was 37.9 %, with an incidence of 54.9 % in the LC group and 13.9 % in the LNF group. The study was carried out by a single surgeon at a single institution with a standardized protocol for peri-operative care, creating a homogenous platform of treatment to accurately assess the intervention (AILA). In addition, analgesia consumption in recovery and on the ward was recorded as part of the analysis of this study. To our knowledge, few, if any, other studies with this information have been performed. Elective LNF and LC were chosen for our study. Laparoscopic Nissen fundoplication is a clean upper GI procedure where the potential variables encountered intraoperatively are minimized. Intuitively, this would allow for greater reliability as to whether pre-emptive localized intraperitoneal local anesthetic (ropivacaine) would work or not. Laparoscopic cholecystectomy is one of the most common intraperitoneal procedures performed in general surgery notwithstanding greater intraoperative variability than Nissen fundoplication. Aerosolized ropivacaine significantly reduced only shoulder tip pain in the LC group and only abdominal pain in the LNF group. Different pain mechanisms for each of these common procedures may be the reason. Alternatively, the differing responses to aerosolized local anesthetic may have been
due to fundamental differences in these procedures, such as differences in the trocar positions for each procedure and the potential for pneumomediastinum following LNF. Pain following laparoscopy is common. There are two mechanisms of insult; Firstly, direct trauma to the abdominal wall (somatic irritation) during port placement and second, visceral irritation during surgical dissection and stretching of the diaphragmatic peritoneum on creation of the pneumoperitoneum. Intraperitoneal anesthetic delivery methods studied to date include diaphragmatic irrigation and instillation [7, 9]. Studies evaluating intraperitoneal local anesthetic instillation as a method of reducing postoperative pain have reported conflicting results. A recent study by Kahokehr et al. reported that instillation and infusion of ropivacaine provided reduced postoperative pain and less opioid analgesic requirements when compared to the placebo group following colonic resection [9]. However, a study by Stuhldreher et al. concluded that intraperitoneal local anesthetic instillation did not improve postoperative pain scores or opioid requirements in patients undergoing laparoscopic colorectal procedures [16]. Indeed, other previous studies reported little additional benefit to intraperitoneal bupivacaine on pain scores beyond 2 h postoperatively [17], or indeed no benefit at all [18]. Systematic reviews have pooled the results of trials investigating the role for intraperitoneal instillation of local anesthetic. One such review was unable to provide a conclusive answer to support or discourage its use [19]. Meanwhile, a second review conferred ‘limited support’ to the use of intraperitoneal local anesthetic during LC [20]. These conflicting results could well be due to lack of consistency in delivery methods and unequal distribution of the local anesthetic agent on the peritoneal surface. Nonetheless, the lack of reproducible evidence to support instillation as an
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appropriate method of local anesthetic delivery means that no definitive conclusion can be reached and it is not yet incorporated into routine clinical practice. Aerosolized or nebulized delivery methods are thought to be more advantageous, as they are associated with less hypothermic effects and provide homogenous peritoneal distribution by coating the entire peritoneal cavity [12]. There are only four other reports in the literature evaluating the aerosolization or nebulization method of delivery [10, 11, 21, 22]. Zimmer et al. reported no difference in pain scores between the control and intervention groups following bupivacaine administration using the InsuflowÒ device [22]. However, unlike the AeroSurgeÒ, this device utilizes a hot evaporation technique in which the solvent is delivered to the patient, in the absence of the solvent. Alkhamesi et al. showed that aerosolized bupivacaine using the AeronebÒ device significantly reduced postoperative pain following LC (n = 60, 2 patient groups) [11]. Bucciero et al. analyzed aerosolized intraperitoneal ropivacaine delivery using the AeronebÒ device during LC (n = 80, 4 patient groups of n = 20) and reported no difference in pain scores or morphine consumption between groups, but a reduction in shoulder pain and walking time [10]. Ingelmo et al. utilized the Aeroneb ProÒ to deliver ropivacaine to patients undergoing LC (n = 90, 3 patient groups of n = 30) and reported a significant reduction of postoperative pain scores, shoulder pain scores, morphine requirements, and time to unassisted walking [21]. These studies, in combination with the present study, reveal that despite being in its infancy, aerosolized intraperitoneal local anesthetic has potential in the management of postlaparoscopic pain. Ropivacaine was the local anesthetic agent of choice for this study. It is a long-acting amide local anesthetic agent that is less lipophilic than bupivacaine and, as such, confers decreased potential for central nervous system toxicity and cardiotoxicity [23, 24]. In addition, the pharmacokinetic profile following intraperitoneal nebulization of ropivacaine is similar to extravascular administration [25, 26]. The maximum safe dose is 3–4 mk/kg, with a mean toxic plasma concentration of 4.3 mg/L (range 3.4 to 5.3 mg/L) [24]. The total cumulative dose administered in this study was 125 mg ropivacaine, comprised of 5 mL of aerosolized 1 % ropivacaine and 10 mL of 7.5 % ropivacaine infiltrated at the port sites. Pain response to ropivacaine in this study was probably underpowered as the commercially available strongest concentration was 1 %. Our previous pharmacokinetic patient safety study of this dose would suggest that a substantially more concentrated formula of ropivacaine could be used for greater efficacy without the risk of adverse systemic effects, as the total systemic ropivacaine level achieved with this dose is over 60 % below the threshold for toxicity [27].
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Pre-emptive versus postoperative local anesthetic delivery has been evaluated by Palmes et al. in patients undergoing laparoscopic hernia repair and Nissen fundoplication and reported that pre-emptive intraperitoneal local anesthetic delivery significantly reduced postoperative analgesic consumption and pain intensity following Nissen fundoplication [28]. This emphasizes the importance of ropivacaine delivery in advance of surgical dissection, as performed in this study, and likely relates to the mechanism by which local anesthetics reduce postoperative pain. These agents inhibit nociception by modifying nerve membrane-associated proteins and impeding the release and action of agents, such as prostaglandins, that sensitize the nociceptors and contribute to inflammation [29]. This study demonstrates that aerosolized intraperitoneal local anesthetic using the novel AeroSurgeÒ device has potential in post-laparoscopic pain management. It did not confer statistically significant pain score outcomes between study groups at the primary endpoint. While the results of subgroup analysis need to be interpreted with caution, pain scores at various distinct time points were improved in the treatment arm in the subgroup analysis. Studies evaluating higher total ropivacaine dose delivery in a more homogenous patient cohort (i.e., single procedure) are needed to assess this promising approach to further enhance recovery making these procedures more amenable to day-case laparoscopic surgery. Acknowledgments The authors would like to thank the patients for their participation and the theater, recovery, and ward nursing staff of the Galway Clinic, Ireland for their assistance in conducting this study. Conflict of Interest
None.
Disclosure AeroSurgical Ò provided the device for this study. None of the authors (AMD, KHC, MK, PMA, BK, BH, AA, MK, and OMA) have or had any financial relationships with AztraZeneca, the pharmaceutical company or AeroSurgicalÒ, the device company. There are no financial ties or conflicts of interest to disclose.
References 1. Ekstein P, Szold A, Sagie B, Werbin N, Klausner JM, Weinbroum AA (2006) Laparoscopic surgery may be associated with severe pain and high analgesia requirements in the immediate postoperative period. Ann Surg 243(1):41–46 2. Maestroni U, Sortini D, Devito C, Brunaldi FPMK, Anania G, Pavanelli L, Pasqualucci A, Donini A (2002) A new method of preemptive analgesia in laparoscopic cholecystectomy. Surg Endosc 16(9):1336–1340 (Epub 2002 May 1337) 3. Ji W, Ding K, Li LT, Wang D, Li N, Li JS (2010) Outpatient versus inpatient laparoscopic cholecystectomy: a single center clinical analysis. Hepatobiliary Pancreat Dis Int 9(1):60–64 4. Berggren U, Gordh T, Grama D, Haglund U, Rastad J, Arvidsson D (1994) Laparoscopic versus open cholecystectomy: hospitalization,
World J Surg
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
sick leave, analgesia and trauma responses. Br J Surg 81(9):1362–1365 Sarac AM, Aktan AO, Baykan N, Yegen C, Yalin R (1996) The effect and timing of local anesthesia in laparoscopic cholecystectomy. Surg Laparosc Endosc 6(5):362–366 Liu YY, Yeh CN, Lee HL, Wang SY, Tsai CY, Lin CC, Chao TC, Yeh TS, Jan YY (2009) Local anesthesia with ropivacaine for patients undergoing laparoscopic cholecystectomy. World J Gastroenterol 15(19):2376–2380 Cunniffe MG, McAnena OJ, Dar MA, Calleary J, Flynn N (1998) A prospective randomized trial of intraoperative bupivacaine irrigation for management of shoulder-tip pain following laparoscopy. Am J Surg 176(3):258–261 Ahmed BH, Ahmed A, Tan D, Awad ZT, Al-Aali AY, Kilkenny J 3rd, Orlando FA, Al-Chalabi A, Crass R, Alrawi SJ (2008) Post-laparoscopic cholecystectomy pain: effects of intraperitoneal local anesthetics on pain control–a randomized prospective double-blinded placebo-controlled trial. Am Surg 74(3):201–209 Kahokehr A, Sammour T, Shoshtari KZ, Taylor M, Hill AG (2011) Intraperitoneal local anesthetic improves recovery after colon resection: a double-blinded randomized controlled trial. Ann Surg 254(1):28–38 Bucciero M, Ingelmo PM, Fumagalli R, Noll E, Garbagnati A, Somaini M, Joshi GP, Vitale G, Giardini V, Diemunsch P (2011) Intraperitoneal ropivacaine nebulization for pain management after laparoscopic cholecystectomy: a comparison with intraperitoneal instillation. Anesth Analg 113(5):1266–1271 Alkhamesi NA, Peck DH, Lomax D, Darzi AW (2007) Intraperitoneal aerosolization of bupivacaine reduces postoperative pain in laparoscopic surgery: a randomized prospective controlled double-blinded clinical trial. Surg Endosc 21(4):602–606 Epub 2006 Dec 2016 Greib N, Schlotterbeck H, Dow WA, Joshi GP, Geny B, Diemunsch PA (2008) An evaluation of gas humidifying devices as a means of intraperitoneal local anesthetic administration for laparoscopic surgery. Anesth Analg 107(2):549–551 Betton D, Greib N, Schlotterbeck H, Joshi GP, Ubeaud-Sequier G, Diemunsch P (2010) The pharmacokinetics of ropivacaine after intraperitoneal administration: instillation versus nebulization. Anesth Analg 111(5):1140–1145 Dobbs FF, Kumar V, Alexander JI, Hull MG (1987) Pain after laparoscopy related to posture and ring versus clip sterilization. Br J Obstet Gynaecol 94(3):262–266 Tsai HW, Wang PH, Yen MS, Chao KC, Hsu TF, Chen YJ (2013) Prevention of postlaparoscopic shoulder and upper abdominal pain: a randomized controlled trial. Obstet Gynecol 121(3): 526–531. doi:10.1097/AOG.0b013e318283fcca Stuhldreher JM, Adamina M, Konopacka A, Brady K, Delaney CP (2012) Effect of local anesthetics on postoperative pain and opioid consumption in laparoscopic colorectal surgery. Surg Endosc 26(6):1617–1623. doi:10.1007/s00464-011-2079-1 (Epub 02011 Dec 00417)
17. Hernandez-Palazon J, Tortosa JA, de la Rosa VN, Gimenez-Viudes J, Ramirez G, Robles R (2003) Intraperitoneal application of bupivacaine plus morphine for pain relief after laparoscopic cholecystectomy. Eur J Anaesthesiol 20(11):891–896 18. Rademaker BM, Kalkman CJ, Odoom JA, de Wit L, Ringers J (1994) Intraperitoneal local anaesthetics after laparoscopic cholecystectomy: effects on postoperative pain, metabolic responses and lung function. Br J Anaesth 72(3):263–266 19. Bisgaard T (2006) Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 104(4):835–846 20. Boddy AP, Mehta S, Rhodes M (2006) The effect of intraperitoneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis. Anesth Analg 103(3):682–688 21. Ingelmo PM, Bucciero M, Somaini M, Sahillioglu E, Garbagnati A, Charton A, Rossini V, Sacchi V, Scardilli M, Lometti A, Joshi GP, Fumagalli R, Diemunsch P (2013) Intraperitoneal nebulization of ropivacaine for pain control after laparoscopic cholecystectomy: a double-blind, randomized, placebo-controlled trial. Br J Anaesth 110(5):800–806. doi:10.1093/bja/aes495 22. Zimmer PW, McCann MJ, O’Brien MM (2010) Bupivacaine use in the Insuflow device during laparoscopic cholecystectomy: results of a prospective randomized double-blind controlled trial. Surg Endosc 24(7):1524–1527. doi:10.1007/s00464-009-0804-9 23. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E (2002) Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology 96(6):1427–1434 24. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N (1997) Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 78(5):507–514 25. Rowland M, Tozer T (1995) Extravascular dose. In: Balado D (ed) Clinical pharmacokinetics: concepts and application, 3rd edn. Lippincott Williams and Wilkins, Baltimore, pp 34–50 26. Labaille T, Mazoit JX, Paqueron X, Franco D, Benhamou D (2002) The clinical efficacy and pharmacokinetics of intraperitoneal ropivacaine for laparoscopic cholecystectomy. Anesth Analg 94(1):100–105 table of contents 27. McDermott AM, Chang KH, Mieske K, Abeidi A, Harte BH, Kerin MJ, McAnena OJ (2014) Total systemic ropivacaine concentrations following aerosolized intraperitoneal delivery using the AeroSurge. J clin Anesth. doi:10.1016/j.jclinane.2013.07.013 28. Palmes D, Rottgermann S, Classen C, Haier J, Horstmann R (2007) Randomized clinical trial of the influence of intraperitoneal local anaesthesia on pain after laparoscopic surgery. Br J Surg 94(7):824–832 29. Louizos AA, Hadzilia SJ, Leandros E, Kouroukli IK, Georgiou LG, Bramis JP (2005) Postoperative pain relief after laparoscopic cholecystectomy: a placebo-controlled double-blind randomized trial of preincisional infiltration and intraperitoneal instillation of levobupivacaine 0.25 %. Surg Endosc 19(11):1503–1506 (Epub 2005 Oct 1503)
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