Peritoneal Irrigation of Fentanyl Added to Levo-Bupivacaine Versus Patient Controlled Intravenous Analgesia (PCIA) in Patients Undergoing Major Abdominal Cancer Surgeries

Surgical interventions still the main line of treatment for upper abdominal malignancies, and according to recent statics, millions of surgical interventions were performed every year. These surgeries are classified as high-risk patients [1]. Major surgeries carried out in upper abdomen -like these selected for the studyare usually associated with intense pain that, if not properly treated, may cause deep physiological and hormonal alterations in the body .Some of the main complications of untreated postoperative pain are cardiocirculatory and respiratory complications [2,3]. So effective postoperative pain control has many benefits such as; encourages early ambulation, reducing the risk of thrombosis, decreases cardiopulmonary complications and increases health-related quality of Abstract Background: Major abdominal surgeries still the main line of treatment for upper abdominal malignancies and these surgeries induce severe postoperative pain with different types either somatic or visceral. If such pain not controlled, may cause various organ dysfunctions and prolong both hospital and ICU stay. So, an appropriate pain therapy to those patients with least complications must be applicated.


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life [4]. Opioids analgesics used to be considered the gold standard analgesic for major surgery, but unfortunately, intravenous opioids administration have many side effects, as nausea and vomiting, pruritus, gastrointestinal symptoms and respiratory depression [5].
Neuro-axial blocks as (TEA) are recently used as a good postoperative analgesic strategy because it is very effective but still invasive method and relatively needs experience [6][7]. Local anesthetic (LA) drugs are well recognized and represent one of the most important classes of drug in perioperative care. Local anesthetic agents do not have the adverse effects of systemically administered opioids and act directly on the tissue to which they are applied on as peritoneal cavity [8]. PCA if used intravenously carries many advantages over conventional pain management because the therapy is individualized to the patient and patients are the best to assess their pain and they can get medication as and when required by pressing a button of PCA pump. Thus, it reduces overdose and also reduces nursing aid [9]. The aim of this study was to compare analgesic efficacy of intraperitoneal irrigation of fentanyl added to levo-bupivacaine with patient controlled intravenous analgesia in patients undergoing major abdominal cancer surgeries.

Patients and Methods
This study was designed as a prospective randomized clinical trial after approval of local ethics committee of the South Egypt Cancer Institute, Assiut University, Assiut, Egypt. One hundred twenty patients (ASA II-III) were scheduled for elective major abdominal cancer surgery from June 2018 till March 2018 and after written informed consent from every patient. Exclusion criteria were as following: allergy to local anesthetic solutions or opioids and patient whose ability to use PCA pump or who cannot be taught how to evaluate their own pain intensity. One day before surgery, preoperative data were collected as; demographic data, medical history, physical examination and routine laboratory investigations. The night before surgery, all patients were taught how to evaluate their own pain intensity using the Numerical rating Scale (NRS), scored from 0-10 (where 0= no pain and 10=worst pain imaginable).and how to use the PCA device (Abbott   irrigation of Levo-bupivacaine 25% plus fentanyl 200mic in 50ml volume just before peritoneal closure after good surgical heamostasis. All patients received intra operative ketorolac 30mg, Paracetamol 1gm and, fentanyl was given for rescue analgesia which was adjusted as following; 1mic / kg. The analgesic regimen was adjusted to achieve a stable MAP and HR within 10% of baseline.

Standard General Anesthesia
After pre-oxygenation for 3 minutes, intravenous anesthesia (propofol 1.5mg/kg) induced with fentanyl 1-2μg/kg administered over min. Tracheal intubation was performed after adequate neuromuscular blockade with cisatracurium 0.5mg/kg. Anesthesia was maintained by sevoflurane 1-1.5 MAC, cisatracurium 0.03mg/ kg given when indicated. Patients were mechanically ventilated to maintain ETCO2 between 35-40mmHg. The inspired oxygen fraction (FIO2) was 0.5 using oxygen-and-air mixtures. At the end of surgery neuromuscular block was antagonized in all patients with neostigmine 0.05mg/kg and atropine 0.02mg/kg and trachea was extubated in the operating room. Tracheal extubation will be performed when patients meet the following criteria: hemodynamic stability, adequate muscle strength, full consciousness, and adequate ventilation breathing rate: 10 to 30 breaths/min, PaO 2 / IFO 2 ≥80/0.4, PaCO 2 , 30 to 45mmHg). Intra operative data such as HR, MAP, and operative duration were recorded for analysis. At the end of surgery, abdominal drains were closed by clamp for 30 minutes in groups II and III.
Post-operative, all patients were admitted for 48 hours to surgical ICU to received post-operative ketorolac 30mg/12 hours, Paracetamol 1gm/8 hours and, fentanyl was given for rescue analgesia via PCA which was adjusted as following; 20 mic with lockout interval of 15 min with no background infusion. The analgesic regimen was adjusted to achieve a NRS scores less than 3.
The following were recorded a) HR, MAP and were recorded everyone hour in ICU. b) NRS-every 4 hours for 2 days-for pain measurement. And total fentanyl consumption was calculated. were recorded postoperatively.

Statistical Analysis
The required sample size was calculated using Epi Info software

Results
Regarding demographic data there was no between all three groups ( Table 1-3). There was a significant decrease in pain sensation in all groups during first day postoperative in group II and much more in group III (P. value 0.000*) ( Table 4) and postoperative analgesic consumption much more decreased in group III in comparison to other groups (P. value 0.000*) ( Table 5)  Between three groups no significance regarding patient's characteristics. Data expressed as (Mean±SD) and number / percentage (%).
Between three groups no significance regarding MAP. Data expressed as (Mean±SD) and number / percentage (%).
Between three groups no significance regarding MAP. Data expressed as (Mean±SD) and number / percentage (%).
Between three groups there was significant difference regarding VAS scores being decreased in group II-and much more decreased in group III in comparison to group I (P value 0.000*).  P. value < 0.05 considered statistically significant.
Between three groups there was significant difference regarding post-operative morphine consumption decreased in group II-and much more decreased in group III in comparison to group I (P value 0.000*) Data expressed as (Mean±SD) and number / percentage (%).
Between three groups there was significant difference regarding sedation scores that increased in group I in comparison to other two groups. (P value 0.000*) Data expressed as (Mean±SD) and number / percentage (%).
Between three groups there was significant difference regarding post-operative MAP being decreased in early post-operative period in group II and III (P value 0.002*). Data expressed as (Mean±SD) and number / percentage (%).
Between three groups there was significant difference regarding post operative HR being decreased in early post-operative period in group II and III (P value 0.001*).
59 Figure 3: Side effects of analgesics studied.
Between three groups there was significant difference regarding side effects that noticed in group III mainly. (P value 0.005*).

Discussion
In this randomized clinical trial, we compared intraperitoneal irrigation of local anesthetic agent levo-bupivacaine group (II) and with opioid agent fentanyl (III) versus IV PCA to reduce pain after major abdominal cancer surgeries. The results were decreased postoperative pain scores in all groups but more in group III and this reflected on decrease opioids consumption post operatively.
A lot of authors find that postoperative pain is inadequately treated in approximately one half of all surgical procedures [9].
And all clinical trials confirm that a high-quality postoperative pain management improves recovery and also reduces the risk of postoperative acute adverse effects such as pulmonary dysfunction and chronic adverse effect as (delayed recovery, hospital discharge and chronic pain) [10]. Therefore, a multimodal approach, using local anesthetics with other drugs as opioids may help to improving the quality of analgesia, recovery and reduce opioid dose requirement and side effects [11]. A lot of previous clinical trial studied intraperitoneal LA as a methods of analgesic administration to control pain following different abdominal surgeries, for example Choi et al. [12] who concluded in their meta-analysis that intraperitoneal LA in patients undergoing laparoscopic cholecystectomy (LC) exhibited beneficial effects on post-operative abdominal, visceral, and shoulder pain in a resting state. Also, intraperitoneal LA has previously been shown to be of benefit in patients undergoing open hysterectomy [13], laparoscopic gynecological procedures [14], and laparoscopic cholecystectomy [15]. Also, Bucciero et al. [16] who found that intraperitoneal Ropivacaine was associated with reduced shoulder pain and unassisted walking after LC. Incisional component of pain in abdominal surgeries is the predominant component [17].
A LA used at this site effectively relieves pain [18]. Currently, there is no clear-cut consensus as to what the best mode of its use is.
However, our usage of levo-bupivacaine in peritoneal irrigation yielded excellent results in terms of significantly reduced pain and requirement of post-operative analgesics in all groups [19].
We chose levo-bupivacaine in our study because of its better pharmacokinetic and less toxic profiles especially cardiac toxicity [20,21]. However, few clinical trials have compared between LAs in terms of their practical potency as Papagiannopoulou et al. [22] who compared the analgesic efficacy of ropivacaine and levo-bupivacaine, and concluded that local tissue infiltration with levobupivacaine was more effective than ropivacaine in reducing the post-operative pain associated with abdominal surgeries. The intraperitoneal route of administration of local anesthetic (LA) is simple, does not involve additional central neuroaxial block and is suited to the practice of ambulatory anesthesia [23]. We can explain the analgesic effects of intraperitoneal Las; LAs block visceral afferent signaling, and potentially modify visceral nociception by blocking sodium channels [24]. Ahn et al. [25] who reported that, use of intraperitoneal LA i.e., at the time induction of anesthesia was better than its use at the end of procedure. As regard Postoperative nausea, vomiting and respiratory depression, were comparable in all groups but sedation in patients of the group III were significantly more sedated than other two groups at immediate postoperative time but no significant differences between both groups after that.
The total dose of post-operative fentanyl was significantly lower in group III in comparison to other two groups.

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We can get benefits from application of opioids with LAs to have synergism in efficacy because opioids can inhibit pain transmission from afferent nerves to the central nervous system through interaction with pre-and postsynaptic opioid receptors in the peripheral nerves [26]. Confirming our point of view regarding concept of synergism, a study of patients undergoing thoracic surgery, despite the infusion of bupivacaine alone via a thoracic epidural, 30%of patient's required opioid supplementation for inadequate analgesia and 80% had significant hypotension [27].
PCA in this study was used intravenously with the following advantages over conventional pain management are that the therapy is individualized to the patient. Patients are the best to assess their pain and they can get medication as and when required by pressing a button of PCA pump. Thus, it reduces overdose and reduces nursing aid [28]. At the end of the 24h postoperatively there was no significant difference in NRS between all groups. Side effects like delayed respiratory depression, nausea and vomiting were caused by the presence of drug either in systemic circulation [29]. Comparing between opioids that was added either morphine or fentanyl, our choice was fentanyl, and this is based on the higher lipophilicity of fentanyl that makes it shorter duration of action, lower incidence of side effects, and reduced risk of respiratory depression [30].

Conclusion
This study concluded that intraperitoneal irrigation of Levobupivacaine in patients undergoing major abdominal cancer surgeries was safe and effective in pain relief and adding fentanyl in a dose of 200 mic increased the analgesic efficacy with comparable side effects when compared to IV PCA. We can consider intraperitoneal irrigation is a safe, easy and effective method for control of pain following major abdominal cancer surgeries when TEA or PCA is not applicable.