Preemptive Analgesia by Intraperitoneal Instillation of Ropivacaine in Laparoscopic Cholecystectomy.

BACKGROUND: Preemptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery as it reduces immediate postoperative pain as well as chronic pain. AIM: To study the efficacy of preemptive analgesia with intraperitoneal instillation of ropivacaine in laparoscopic cholecystectomy (LC).
MATERIALS AND METHODS: This prospective randomized double-blind study was conducted on patients undergoing LC. Hundred patients were randomly divided into two groups of fifty each. In Group A, patients received 3 mg/kg of ropivacaine intraperitoneal instillation in 100 ml normal saline (NS) before creation of pneumoperitoneum and in Group B patients received 3 mg/kg of ropivacaine intraperitoneal instillation in 100 ml NS after completion of surgery. Postoperative visual analog scale score for abdominal and shoulder tip pain alongwith requirement of rescue analgesic were recorded for 24 h.
RESULTS: Significantly lower visual analog scores for pain were observed in Group A versus Group B. Group A reported significantly lower pain at 0 h (P < 0.001), 1 h (P = 0.003), 3 h (P = 0.006), 6 h (P = 0.003), and 12 h (P = 0.001) postoperatively, but the difference was not statistically significant after 12 h. The mean time of first rescue analgesic was 472.8 ± 26.32 min in Group A, as compared with 189 ± 11.87 min in Group B. A significantly lower analgesic requirement was observed in Group A versus Group B throughout the entire study period (P < 0.05).
CONCLUSION: The preemptive analgesia with intraperitoneal instillation of ropivacaine before creation of pneumoperitoneum is much more effective for postoperative pain relief in comparison to intraperitoneal instillation of ropivacaine after completion of surgery.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Laparoscopic cholecystectomy (LC) is an established, universally accepted procedure for cholelithiasis treatment as it causes less patient discomfort when compared to open cholecystectomy. Although LC results in less pain than open cholecystectomy, but still it is not a pain free procedure.[12] Postoperative pain remains a major concern in patients undergoing LC. Pain following LC is multifactorial. Pain is differentiated into three components - visceral, abdominal wall, and referred pain to shoulder.[3]

Preemptive analgesia is the one of the most important methods to reduce the pain after LC. Due to the “protective” effect on the nociceptive system, preemptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery as it reduces immediate postoperative pain and also prevents the development of chronic pain by decreasing the altered central sensory processing.[4]

Intraperitoneal local anesthetics are now widely used, as they provide the benefit of analgesia without systemic side effects that may result from use of enterally and parenterally administered drugs.[4] Timing of intraperitoneal instillation of local anesthetic is very important. Barczynski et al. evaluated the optimal timing of bupivacaine peritoneal instillation and concluded that peritoneal instillation was much more effective for pain relief if used before creation of pneumoperitoneum.[5] Maestroni et al. also studied preemptive analgesia in LC where both local anesthetic and normal saline (NS) were administered before creation of pneumoperitoneum and suggested only application before creation of pneumoperitoneum may preempt every neuronal central sensitization.[6] However, Zmora et al. and Elfberg and Sjövall-Mjöberg evaluated the effect of intraperitoneal bupivacaine on pain following LC and concluded that intraperitoneal bupivacaine does not attenuate pain following LC.[78]

The results of various studies have been conflicting with majority demonstrating benefit of pain reduction after intraperitoneal instillation of local anesthetics in the initial postoperative period, whereas there are some suggesting that it does not attenuate pain following LC.

Therefore, the aim of this study was to evaluate preemptive effect of ropivacaine in LC by comparing postoperative abdominal pain, shoulder pain and requirement of rescue analgesic after intraperitoneal instillation of 3 mg/kg ropivacaine in 100 ml NS before creation of pneumoperitoneum versus intraperitoneal instillation of 3 mg/kg ropivacaine in 100 ml NS after completion of surgery.

MATERIALS AND METHODS

This prospective randomized, double-blind study was conducted after approval from hospital ethical committee in 100 patients of age group 20 to 60 years of American Society of Anesthesiologist physical Status I and II, scheduled for LC under general anesthesia. Patients who refused to participate in study, in whom surgery converted to open cholecystectomy, history of hypersensitivity to ropivacaine, acute cholecystitis, acute pancreatitis, pregnancy, history of peritonitis were excluded from the study. After written informed consent, patients were randomly divided using concealed opaque envelopes to one of the two groups of fifty each. In Group A, patients received intraperitoneal instillation of 3 mg/kg ropivacaine in 100 ml NS before creation of pneumoperitoneum and Group B patients received intraperitoneal instillation of 3 mg/kg ropivacaine in 100 ml NS after completion of surgery.

Detailed preanaesthetic evaluation was performed 1 day before surgery and visual analogue scale (VAS) of 0–10 was explained to all the patients.

After shifting, the patient to operation theatre, baseline heart rate, blood pressure, respiratory rate, temperature, and SpO2 were recorded and intravenous (IV) access was secured. After preoxygenation with 100% oxygen via an anatomical face mask for 3 min, all patients were induced with 0.2 mg glycopyrrolate, lignocaine 1.0 mg/kg, fentanyl 2 μg/kg and propofol 2–2.5 mg/kg. Succinylcholine 1.5 mg/kg was given to facilitate oral endotracheal intubation with appropriate size endotracheal tube. After checking and securing the endotracheal tube, anesthesia was maintained with intermittent positive pressure ventilation using closed circuit and 0.5%–2% isoflurane. Muscle relaxation was achieved with intermittent vecuronium bromide.

Drug solution was administered using veress needle before creation of pneumoperitoneum in Group A and before removal of trocars after completion of surgery in Group B by the surgeon who did not participate in the study. During surgery, all patients received an IV infusion of lactated ringers solution at a rate of 5–7 ml/kg/h patients were placed in 15°–20° reverse trendelenbergh's position with left side downward tilt. During laparoscopy, intra-abdominal pressure was limited to 10–12 mmHg. The CO2 was carefully evacuated at the end of surgery. Anesthesiologist in postanesthesia care unit was unaware of treatment to which each patient was randomized. The patients were given injection diclofenac sodium 75 mg and injection ondansetron 4 mg IV before shifting to recovery room.

All patients were assessed postoperatively in terms of following parameters:

Abdomen pain (immediately after recovery: 0 h, at 1, 3, 6, 12, 18, 24 h at rest and on deep breathing)

Shoulder tip pain (immediately after recovery: 0 h, at 1, 3, 6, 12, 18, 24 h at rest and on deep breathing)

Heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate were recorded at 0, 1, 3, 6, 12, 18 and 24 h

Time to first Analgesic requirement and number of doses of rescue analgesics

Total analgesic consumption in 24 h.

The patients with VAS score ≥4 were administered an infusion of 1 g paracetamol (IV) as rescue analgesia. Patients were administered injection ondansetron 4 mg on complaint of nausea/vomiting. Nausea and vomiting were assessed depending on the episodes, number and need for antiemetic medication and occurrence of any other adverse effects were also recorded.

RESULTS

The difference in the mean VAS score between the two groups was used to calculate the sample size. We calculated a minimum sample size of 43 patients was required in each group, assuming a Type 1 error (two-tailed) of 0.05 and a margin of error of 5%. Therefore, in this study 100 patients were randomized to two groups of 50 each.

Continuous variables were analyzed with Student's t-test and categorical variables were analyzed with the Chi-square test and Fisher exact test. Statistical significance was taken as P < 0.05. The data were analyzed using SPSS version 22 (IBM Corp, 2015, New York, USA) and Microsoft Excel 2007.

There was no significant difference between groups with respect to age, sex, weight, body mass index, and duration of surgery [Table 1]. The difference in intraoperative heart rate, SpO2, EtCO2, mean systolic blood pressure, mean diastolic pressure, mean arterial pressure of both the groups at all the times was statistically nonsignificant (P > 0.05). As shown in the Tables 2 and 3, the mean postoperative VAS score for abdomen and shoulder pain was significantly (P < 0.05) lower in Group A than in Group B till 12 h postoperatively, but this difference became nonsignificant after 12 h postoperatively.

Table 1

Demographic profile

Table 2

Visual analogue scale score for pain abdomen at rest

Table 3

Visual analogue scale score for shoulder pain at rest

The latency time from the end of operation to first analgesic requirement was significantly longer in Group A than in Group B. The mean time to first rescue analgesic was 472 ± 26.32 min in Group A and 189 ± 11.87 min in Group B (P < 0.001). The number of rescue analgesic requested was significantly lower in Group A than Group B and the difference was highly significant

(P < 0.001). The mean paracetamol consumption for 24 h was also significantly lower in Group A than in Group B. (P < 0.001) [Table 4].

Table 4

Requirement of analgesia

DISCUSSION

As pain after LC is multifactorial, a multimodal approach to postoperative pain management has been suggested. Recently, the use of intraperitoneal instillation of local anesthetic is emerging as a promising modality for postoperative pain management in these patients.

Various local anesthetics such as lignocaine, bupivacaine, ropivacaine, and levobupivacaine have been evaluated in many trials.[910] Several factors are important for intraperitoneal instillation of drug to decrease postoperative pain, which include choice of drug, concentration of drug, volume of drug, and timing of drug administration.[1112]

We used ropivacaine for intraperitoneal instillation because of its low toxicity and longer duration of action. Ropivacaine is a long-acting amide type local anesthetic used as regional anesthetic. It is a pure S(−) enantiomer, developed for the purpose of reducing potential cardiac toxicity and improving relative sensory and motor block profiles. When ropivacaine is given intraperitoneally it starts acting within 10–20 min, and duration of action lasts for 4–6 h.[13] Kucuk et al. have found that intraperitoneal instillation of 150 mg of ropivacaine was significantly more effective than either 100 mg bupivacaine or 100 mg ropivacaine for preventing postoperative pain.[14]

Another important aspect is the appropriate volume of the medium used for instillation. It should be large enough to reach the entire subdiaphragmatic region. Some studies have shown that better abdominal and shoulder tip pain control was observed when larger volume of local anesthetic solution was used for instillation rather than smaller volume.[511]

Timing of intraperitoneal instillation of local anesthetic is also very important. In our study, mean postoperative VAS scores for pain abdomen at rest were significantly lower in Group A than Group B in the first 12 h thereby indicating that the patients receiving intraperitoneal ropivacaine before creation of pnemoperitoneum had lesser pain in the first 12 h during the postoperative period. The VAS scores were less up to 24 h but difference was nonsignificant after 12 h postoperative period. The results are comparable with studies conducted by Barczynski et al.[5] and Maestroni et al.[6]

However, Lee et al. found that preemptive intraperitoneal bupivacaine had no significant effect on pain abdomen and shoulder pain.[11] This lack of efficacy might be due to small dosage of intraperitoneal bupivacaine used (0.25% 40 ml) for coverage of the intraabdominal organ surface.

The shoulder tip pain was also significantly less in Group A as compared to Group B up to 12 h. The exact mechanism of shoulder tip pain is yet to be clarified. The proposed mechanisms include phrenic nerve neuropraxia of short duration due to stretching of the subdiaphragmatic fibers by an increased concavity of the diaphragm induced by pneumoperitoneum with CO2 insufflated into the abdominal cavity. The preemptive analgesia with intraperitoneal instillation of ropivacaine before pneumoperitoneum could cause the inhibitory effect on development of posttraumatic hyperalgesia resulting in reduced shoulder pain. The results are similar to Barczynski et al.[5] who observed that none of the patients reported shoulder tip pain who received intraperitoneal instillation of bupivacaine preemptively.

Pain after LC is dynamic and exacerbated by coughing or movement (supine to sitting), or deep breathing and vomiting.[14] Pain at rest and at movement was correlated in our study and the mean postoperative VAS scores for pain abdomen and shoulder pain at deep breathing were significantly lower in Group A than Group B in the first 12 h.

The latency time from end of the operation to the first rescue analgesic requirement was significantly longer in Group A (472 ± 26.32 min) than in Group B (189 ± 11.87 min) patients. This shows that the application of peritoneal instillation with ropivacaine before the creation of pneumoperitoneum is superior to its use after the completion of surgery. The results were comparable to Barczynski et al.[5] in which latency time in patients who received intraperitoneal bupivacaine before creation of pneumoperitoneum was (426 ± 57 min), whereas it was (307 ± 39 min) in patients who received intraperitoneal instillation of bupivacaine after the completion of surgery. Longer latency time for first rescue analgesic in our study might be explained by higher dose of ropivacaine (3 mg/kg), whereas Barczynski et al. used 2 mg/kg intraperitoneal instillation of bupivacaine. Our result is also supported by Pasqualucci et al. who observed that the latency time for first analgesic was significantly more (324 ± 43.4 min) in patients who received intraperitoneal bupivacaine before creation of pneumoperitoneum in comparison to patients who received intraperitoneal bupivacaine after completion of surgery (218.4 ± 14.6 min) in postoperative period.[15]

The total analgesic requirement was also significantly less in patients who received intraperitoneal instillation of drug before creation of pneumoperitoneum (1.34 ± 0.52 g paracetamol) than patients who received after completion of surgery (2.4 ± 0.97 g paracetamol). Maestroni et al. also observed a significantly lower total pain intensity and total analgesic requirement during initial 8 h postoperatively in patients who received ropivacaine preemptively.[6] Kim et al. also concluded intraperitoneal instillation of ropivacaine at the beginning of LC combined with NS infusion is an effective method for reducing pain after LC.[16]

However, Sozbilen et al. suggested that administration of ropivacaine preoperatively and postoperatively for LC has similar effects on postoperative pain and the stress response of patients.[17]

Our findings are contradicted to Lee et al. who found that preemptive intraperitoneal bupivacaine had no significant effect on duration of first analgesic requirement and total analgesic requirements.[11] That lack of efficacy might be because of the low dosage of intraperitoneal bupivacaine used (0.25% 40 ml) for coverage of the intraabdominal organ surface. In a systematic analysis to evaluate the effect of intraperitoneal local anesthetic on pain characteristics after LC. Choi et al. concluded that intraperitoneal local anesthetics exhibited beneficial effects on postoperative abdominal, visceral and shoulder pain in a resting state.[18]

There are certain limitations of our study. Pain perception is subjective and also related to anxiety which can affect the result. The individual requirement of analgesia also varies significantly so exact interpretation is difficult. We did not measure plasma level of ropivacaine, cortisol or catecholamine levels. All the patients were admitted for at least 24 h while in some centers laparoscopy is a day care procedure.

Our study demonstrates that analgesia administered before a nociceptive stimulus reduces the degree of sensitization produced in the nervous system and intraperioneal instillation of ropivacaine before creation of pneumoperitoneum produces a significant decline in pain scores in comparison to intraperitoneal instillation of ropivacaine after completion of surgery.

CONCLUSION

Preemptive analgesia with intraperitoneal instillation of ropivacaine in saline before the creation of pneumoperitoneum has improved surgical outcome after LC in terms of significantly diminished total abdominal and shoulder tip pain, decreased analgesia request and analgesic consumption.

Because protocol used is safe and without apparent side effects, we believe that optimal timing of intraperitoneal instillation of local anesthetics in patients undergoing elective LC is before the creation of pneumoperitoneum.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.