European Journal of Cardiovascular Medicine

Oral cavity cancers are one of the most common cancers in India.1 Oral cancer is a multifactorial disease which occurs by a combination of causal and predisposing genetic factors and which at a given moment and under favourable conditions may take effect in predisposed people.2

The mainstay of cancer therapy for oral cancer is surgery and radiation treatment.3 Consequently, maxillofacial cancer surgery constitutes a large part of surgical oncology practice in India. Manipulation and excision of mandible, maxilla and tongue are extremely noxious stimuli and severe hypertension and tachycardia during these procedures is not unusual. Management includes deepening the plane of anaesthesia by increasing the inhalational anaesthetic concentration and addition of intravenous (IV) opioids.4,5

Traditionally, strong analgesics such as opioids have been used intraoperatively whereas non-steroidal anti-inflammatory drugs (NSAIDs) and Paracetamol are most commonly given at the end of surgery as part of multimodal approach to postoperative analgesia. NSAIDs are highly effective in controlling bone pain and have analgesic effects in various conditions especially where tissue inflammation contributes to pain. The combined utilization of these two groups of drugs results in additive or synergistic analgesia by acting through different mechanisms.6 Present study was aimed to compare the analgesic efficacy between intravenous fentanyl and intravenous fentanyl with diclofenac sodium infusion during mandibular surgeries in a tertiary care cancer centre.

Present study was prospective randomized control study, conducted in the department of anaesthesiology at Kidwai Memorial Institute of Oncology, Bangalore, India. Study duration was of 2 years (December 2018 to November 2020). Study was approved by institutional ethical committee.

Inclusion criteria

• Patients aged between 18-65 years belonging to ASA Grade l and ll, undergoing mandibular surgery and willing to participate in the present study.

Exclusion criteria

• Patient refusal.
• Patients belonging to ASA Grade III and IV.
• Patients with medical comorbidities like uncontrolled hypertension, uncontrolled diabetes mellitus and ischemic heart disease.
• Patients with allergic reaction to NSAIDs.
• Patients with bronchial asthma, history of hyperactive airway disorders.
• Patients with history of gastrointestinal ulcerations, bleeding/ coagulation disorders.
• Patients with renal and liver insufficiency.
• Patients on current anticoagulation medication.
• Patients unable to rate their pain score on VAS due to psychosis or other psychiatric disorders.

Study was explained to participants in local language & written informed consent was taken. Thorough pre anesthetic evaluation was done and age, weight was noted down. Thorough and complete airway assessment was done. Patients were premedicated with Tab Pantoprazole 40mg and Tab Alprazolam 0.5mg on the night prior to the surgery. Patients were kept nil by mouth 6 hours prior to the surgery.

All patients were randomly allocated to one of the two groups, based on computer generated table of random numbers.

Group l (123 patients): received 100ml normal saline after induction of anesthesia.

Group ll (123 patients): received Inj. Diclofenac sodium 1 mg/kg in 100ml normal saline after induction of anaesthesia.

On arrival in the operating room, routine monitors like ECG, NIBP and pulse oximetry (SpO₂) were applied and baseline reading of parameters like heart rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and oxygen saturation noted. An intravenous line was secured with intravenous cannula of 18 gauge. Intravenous fluid in the form of Ringer lactate was started. All patients received premedication with injection Midazolam 0.02mg/kg and Ondansetron 0.08mg/kg body weight intravenously 5 minutes prior to induction. Patients were pre oxygenated with 100% oxygen for 3 minutes before induction. Anesthesia was induced with injection fentanyl 2ug/kg followed by injection Propofol 2mg/kg body weight. Muscle relaxation was achieved with injection Vecuronium 0.1mg/kg to facilitate nasal endotracheal intubation. Patients were intubated nasally with appropriate cuffed endotracheal tube and bilateral air entry was confirmed by auscultation. Endotracheal tube was secured and connected to mechanical ventilator. Anaesthesia was maintained with oxygen, nitrous oxide mixture 50:50 and isoflurane 1.5% dialed concentration for first 15 minutes which was reduced to 0.8% thereafter and total gas flows to 1-1.5L/min. Both the groups received continuous infusion of IV fentanyl at 1mcg/kg/hour as the standard analgesic which was started immediately after intubation and continued throughout the surgery and was stopped at the time of skin closure.

Monitoring of HR, SBP, DBP, MAP and SpO₂ was done intraoperatively and was recorded every 5 minutes for the first half an hour, followed by every 15 minutes till the end of surgery. During surgery, Heart rate and Blood Pressure above 20% of baseline values were considered as signs of inadequate analgesia and were treated with an additional bolus dose of IV fentanyl 1mcg/kg. Isoflurane and nitrous oxide was discontinued once the last suture was applied. 100% oxygen was administered thereafter. After completion of surgery, residual neuromuscular blockade was reversed with a combination of injection Neostigmine 0.05mg/kg and injection Glycopyrrolate 0.008mg/kg. After adequate motor recovery and response to oral commands, patients were shifted with nasal endotracheal tube on T-piece with O₂ at 4-6L/min to post anesthesia care unit as per institutional protocol. Monitoring of vital parameters like Heart rate, SBP, DBP, MAP, SpO₂ and Visual Analogue Score (VAS) was done and was recorded at 0 hour, every 2 hours till 8 hours and every 4 hours till 24 hours in postoperative period. The time of first demand for analgesic after admission to PACU was noted. Inj. Fentanyl 1mcg/kg body weight bolus dose was given as a rescue analgesic when VAS was 4 or above.

Intraoperative analgesia was assessed by measuring heart rate, systolic blood pressure, diastolic blood pressure and mean arterial blood pressure before induction, every 5 minutes for the first half an hour and every 15 minutes thereafter till the end of surgery. Postoperatively, the mean duration of analgesia was determined by monitoring vital parameters like heart rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and VAS scores for up to 24 hours post-surgery. Any adverse effects associated with the drugs like bradycardia, hypotension, respiratory depression, nausea, vomiting and bleeding were also noted postoperatively.

Data was entered into Microsoft excel data sheet and was analyzed using SPSS 22 version software. Categorical data was represented in the form of frequencies and proportions. Chi-square test was used as test of significance for qualitative data. Continuous data was represented as mean and standard deviation. Independent t test or Mann Whitney U test was used as test of significance to identify the mean difference between two quantitative variables and qualitative variables respectively.

The patients in both the groups were comparable with respect to demographic characteristics and ASA physical status.

Table 1: General characteristics

Mean duration of surgery in minutes was studied between two groups and it was found that the duration in Group 1 was 169.94±27.33mins and in Group 2 was 172.03±27.11mins. There was no significant difference in mean duration of surgery between the two groups.

Total analgesic dose was studied in two groups and the mean analgesic dose was compared between them. Mean total analgesic dose, in Group 1 was 57.00±42.85, median dose was 50 mcg. Median total analgesic dose in Group 2 was 0 mcg. Since, the data is skewed there is no significant difference between two groups.

Duration of analgesia in minutes was studied in both the groups and mean duration of analgesia was compared between them. Mean duration of analgesia of Group 1 was 1,398.78±226.73 mins and in Group 2 was 1,440.00 mins. There was a significant difference in mean duration of analgesia between the two groups with p=0.048 with the mean duration of analgesia being significantly higher in group 2 when compared to group 1.

Table 2: Anaesthesia characteristics comparison between two groups

Mean heart rate was compared between two groups in the intraoperative period for every 5 minutes in the first 30 minutes and every 15 minutes till the end of surgery. It was significantly higher in group 1 when compared to group 2 at 105 and 240 minutes with p values being 0.041 and 0.028 respectively. Mean heart rate was compared between the 2 groups in the postoperative period every 2 hours for the first 8 hours and every 4 hours thereafter and there was no significant difference.

Table 3: Mean heart rate comparison between two groups at different intervals of time

Mean SBP was compared between the two groups in the intraoperative period for every 5 minutes in the first 30 minutes and every 15 minutes till the end of surgery. It was significantly higher in group 2 at 5 and 20 minutes with p values being 0.007 and 0.019 respectively when compared to group 1 and it was within 20% of the baseline values. Hence, no intervention was required.

Mean SBP was compared between the 2 groups in the postoperative period every 2 hours for the first 8 hours and every 4 hours thereafter and there was no significant difference between the two groups.

Table 4: Mean SBP comparison between two groups at different intervals of time

Mean DBP was compared between the two groups in the intraoperative period for every 5 minutes in the first 30 minutes and every 15 minutes till the end of surgery. It was significantly higher in group 2 at 5, 10, 20, 30, 135 and 195 minutes with p values being 0.001, 0.015, 0.002, 0.014, 0.028 and 0.018 respectively when compared to group 1. Even though there was a significantly higher mean DBP in group 2 at 5, 10, 20, 30, 135 and 195 20mins in the intraoperative period, it was within 20% of the baseline values. Hence, no intervention was required.

Mean DBP was compared between the 2 groups in the postoperative period every 2 hours for the first 8 hours and every 4 hours thereafter and it was significantly higher at 8^th hour in group 2 with p value being 0.033 when compared to group 1. Even though there was a significantly higher mean DBP in group 2 at 8^th hour postoperatively, it was within 20% baseline values. Hence, no intervention was required.

Table 5: Mean DBP comparison between two groups at different intervals of time

Mean MAP was compared between the two groups in the intraoperative period for every 5 minutes in the first 30 minutes and every 15 minutes till the end of surgery. It was significantly higher in group 2 at 5, 20, 45 and 135 minutes with p values being 0.003, 0.003, 0.04 and 0.024 respectively when compared to group 1.

Mean MAP was compared between the 2 groups in the postoperative period every 2 hours for the first 8 hours and every 4 hours thereafter and it was significantly higher at 16^th hour in group 2 with p value being 0.02 when compared to group 1. There was a significantly higher mean MAP in group 2 at 5, 20, 45 and 135 minutes in the intraoperative period and at 16^th hour postoperatively. But it was not 20% higher than the baseline values necessitating any interventions at the above said time intervals.

Table 6: Mean MAP comparison between two groups at different intervals of time

Mean VAS was compared between the 2 groups in the postoperative period every 2 hours for the first 8 hours and every 4 hours thereafter and it was significantly higher at 8^th and 20^th hour in group 2 with p value being <0.001 and 0.002 respectively when compared to group 1. There was a statistically significant higher mean VAS in group 2 at 8^th and 20^th hour postoperatively when compared to group 1. But it was within the acceptable limits requiring no rescue analgesics.

There were no incidences of the any side effects (Bradycardia, Hypotension, Postoperative nausea and vomiting or increased bleeding) noted in either of the groups in our study.

Table 7: Mean VAS comparison between two groups at different intervals of time

The pharmacological methods employing opioids continue to be a cornerstone in management of postoperative pain control. However, the use of large dose of opioids can be associated with an increased incidence of postoperative complications like ventilatory depression, sedation, postoperative nausea and vomiting, pruritus, difficulty in voiding and ileus which in turn prolong postoperative hospital stay.⁷ Other than the common side effects of opioids, there is a potential risk of abuse which reflect the striking and generalized role endogenous opioids play in physiology.⁸ Hence, there is a need to employ alternate methods to improve analgesic efficacy and reduce the opioid consumption.

The administration of opioids and NSAIDs in conjunction is designed to reduce the side effect profiles of opioid analgesics. The NSAIDs have been shown to have an opioid sparing effect of more than 30%. Randomized or clinical controlled trials that assessed NSAIDs revealed a significant reduction in opioid consumption after major surgery.^9,10 NSAIDs like Diclofenac sodium is effective in controlling bone pain.^11,12 There is no study done only in Mandibular surgeries using intravenous diclofenac sodium as an adjunct to centrally acting analgesic for intraoperative and postoperative analgesia.

Our study consisted of 2 groups with 123 cases each. We used intravenous diclofenac sodium 1mg/kg infusion in 100ml saline post induction in one group and 100ml normal saline in another group. Both the groups were comparable with respect to demographic data and baseline values of hemodynamic variables, thus ascertaining adequate randomization eliminating selection bias.

In our study, we compared changes in HR, SBP, DBP and MAP between the 2 groups in the intraoperative as well as in the postoperative periods and the results were analyzed. In our study, in the intraoperative period, the mean Heart rate was with statistically significant higher values in group 1 when compared to group 2 at 105mins and 240 mins with no significant difference in the postoperative period similar to the observations in the study conducted by Bhoyar K et al.,¹⁰ where mean Heart rate was comparable between 2 groups without any significant difference both in the intraoperative and postoperative periods.

In our study, the total requirement of mean rescue analgesic dose, in group 1 was 57.00±42.85mcg both in the intraoperative and postoperative periods whereas no additional rescue analgesic dose was required in group 2 both in the intraoperative as well as in the postoperative period. This signifies the opioid (fentanyl) sparing effect of Diclofenac sodium.

Our observations are similar to the study conducted by Bhoyar K et al.,¹⁰ who observed that Diclofenac Sodium administered at the beginning of surgery reduced Fentanyl consumption in the intraoperative period with extension of analgesia into the early postoperative period. Time to demand for first dose of analgesia in postoperative period was significantly shorter for the control group. Kiran Malhotra et al.,¹³ studied the effect of single dose of rectal Diclofenac suppository as an adjunct to tramadol for intraoperative as well as postoperative analgesia in ENT surgery. They found that more than 73% of the patients required supplemental analgesia in the control group while in the diclofenac group around 92% of the patient had adequate intraoperative analgesia and did not require any supplementation, thereby suggesting the opioid sparing action of diclofenac. These findings are similar to our study wherein patients receiving Diclofenac sodium (group 2) did not require any supplemental or rescue analgesics in the intraoperative as well as postoperative periods.

In our study, the time period between stopping the fentanyl infusion in the intraoperative period till the administration of first rescue analgesic dose in postoperative period was taken as the duration of postoperative analgesia. In our study, there was a significant difference in the mean VAS score at 8hr and 20 hrs. postoperatively with the VAS scores being higher in group 2 when compared to group 1 but were within the acceptable limits. Since the scores were less than 4, no intervention was required. It can probably be due to the duration of action of Diclofenac. The mean elimination half-life of diclofenac 50mg after IV administration is about 1 hour,¹⁴ but it has prolonged analgesic effect despite its short elimination half-life in plasma. Its uptake and retention by tissues is extensive and its analgesic efficacy may be more closely related to tissue levels than plasma levels.¹⁵

In the study by Bhoyar K et al.,¹⁰ where mean pain intensity at rest measured on VAS at arrival was found to be significantly less in the Diclofenac Group when compared to Placebo Group which correlate with the findings in our study. Also, in our study the mean duration of analgesia was significantly higher in group 2 by 41.22 minutes and Group 2 was pain free in the postoperative period and did not require any rescue analgesic dose (Inj. Fentanyl 1mcg/kg) when compared to group 1. This indicates reduction in opioid consumption in our study in group 2 indicating the opioid sparing effect of diclofenac sodium. Similar findings were noted in studies by Bone ME and Fell D¹⁶, who reported a duration of analgesia for 7.3 hours while in the study by Kiran Malhotra et al.,¹⁴ they have reported duration of analgesia extending up to a period of 14 hours.  Amir M Yassen et al.,⁹ in their study found that low dose ketorolac infusion improves postoperative analgesia combined with patient controlled fentanyl analgesia after living donor hepatectomy. VAS score was significantly lower in Ketorolac group compared to similar values in Fentanyl group starting from 6 hours until 36 hours and the daily doses of fentanyl consumption were significantly lower in Ketorolac group compared to Fentanyl group at 24 hours which are comparable to the findings of our study.

The observations of the VAS scores for postoperative analgesia between the two groups correlate with the findings of the study of Adarsh ES et al.,¹⁷ who observed that preoperative rectal Diclofenac 1mg/kg was effective from 30 minutes postoperatively and extended to cover a period of up to 6 hours evidenced by the reduction in the pain scores, in cleft lip repair. Side effects like bradycardia, hypotension, respiratory depression, nausea, vomiting, bleeding were studied in both the groups.

Limitations of the study were, study was limited to ASA 1 and 2 patients only. Patients up to 65 years of age only were included. Distinction between hemodynamic stress response and inadequate analgesia in the intraoperative period maybe difficult in major surgeries. Thus, intravenous diclofenac sodium in the dose of 1mg/kg/hr infusion after induction may be recommended for effective analgesia and better hemodynamic stability during perioperative period. More studies are required to establish the effects of intravenous diclofenac in major surgeries. The effect was in ASA grade 1 and grade 2 patients. But the effectiveness in high risk cases needs to be evaluated. Studies can be employed in trans-oral robotic assisted surgeries.

From our study, it was concluded that administration of single dose of intravenous Diclofenac Sodium post induction augments the intraoperative as well as postoperative analgesic effect of Fentanyl without any added morbidity in mandibular surgeries.

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