A Comparative Evaluation of Intravenous Dexmedetomidine and Fentanyl in Breast Cancer Surgery: A Prospective, Randomized, and Controlled Trial.

BACKGROUND AND AIM: Recent studies have advised narcotic less anaestheic techniques for breast cancer surgeries due to altered immune system by use of opioids. So we planned this study to compare the efficacy of dexmedtomidine with fentanyl in breast cancer surgery in terms of haemodynamic stability, anaesthetic sparing effects, recovery profile and postoperative analgesia.
MATERIAL AND METHODS: In this randomized prospective controlled trial, a total of 60 female patients were randomly assigned into two groups. Patients in group F (n = 30) received a loading dose of fentanyl 2 μg/kg with maintenance dose of 0.5 μg/kg/h and in group D (n = 30) received dexmedetomidine 1 μg/kg as loading dose with maintenance dose of 0.25 μg/kg/h till the end of surgery. Hemodynamic parameters, desflurane requirement, recovery profile and postoperative analgesia were monitored and compared in both the groups.
RESULTS: Mean HR was less in group D compared to group F intraoperatively, before and after extubation with a significant p value. The mean MAP was also lower in group D compared to group F at all the time points. MAC requirements were found lower in group D compared to group F with a significant P < 0.001. Cognitive recovery in the form of time to respond to verbal commands, time to extubation, time to orientation was early in dexmedetomidine group.
CONCLUSION: Dexmedtomidine can be used as suitable alternative to fentanyl in breast cancer surgeries due to better hemodynamic stability, anaesthetic sparing effects and better recovery profile.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Breast cancer is the most common cancer in women, affecting one in eight women in the United States during their lifetime that requires frequent surgery.[1] It is increasingly recognized that anesthetic technique and other perioperative factors can affect the long-term outcome after cancer surgery. Anesthetic technique and drug choice can interact with the cellular immune system and affect long-term outcome.[2]

Nearly 40% of postoperative breast surgery patients experience significant acute postoperative pain, with a pain score above 5, using numeric rating scale (NRS) reflecting the inadequacy of conventional pain management.[3] Opioid analgesics continue to play an important role in the acute treatment of moderate to severe pain in the early postoperative period. However, newer nonopioid drugs such as dexmedetomidine are increasingly being used as adjuvant during perioperative period to facilitate the recovery process after surgery because of their anesthetic and analgesic-sparing effects, their ability to reduce postoperative dynamic pain and having no opioid-related side-effects (gastrointestinal and bladder dysfunction, respiratory depression).[4]

Recent studies have evaluated that opioid administration both perioperative and chronic, has been shown to suppress cell mediated and humoral immunity.[5] Opioids use can cause an overall increase in proliferation and migration of cell lines of adenocarcinoma of breast but yet no such association has been seen with dexmedetomidine.[6] Hence, these days narcotic less anesthetic techniques are being advocated for breast cancer surgeries.

Comparison of dexmedetomidine and fentanyl has been successfully used in various surgical settings, but a comprehensive comparison of intraoperative use of dexmedetomidine and fentanyl anesthesia in patients undergoing breast cancer surgery has not been done yet. The study was conducted with the aim to assess the efficacy of dexmedetomidine as a suitable alternative to opioids (fentanyl) in breast cancer surgery patients in regard to its, hemodynamic stability, inhalational agent requirements, postoperative analgesic requirements, and recovery profile. We hypothesized that use of intravenous (IV) dexmedtomidine can replace fentanyl (opioids) in breast cancer surgeries.

MATERIALS AND METHODS

After obtaining approval from the Institutional Ethical Committee and informed consent, a total of sixty female patients of physical status American Society of Anesthesiologists (ASA) Class I and II with age group between 18 and 75 years scheduled for breast cancer surgeries (breast conservative surgeries, mastectomies without flap reconstruction, modified radical mastectomies with or without axillary dissection) were enrolled in the study. Patients with any known allergy to study drugs, on chronic analgesic medication, opioids or substance abuse, ASA Class III or IV, obesity (body mass index [BMI] >30 kg/m2), neurological or psychiatric disease, cardiorespiratory disease, renal disease, hepatic disease, and refusal were excluded from the study.

The study was designed as a prospective, randomized, and double-blind controlled trial. The patients, investigators as well as attending anesthesiologist were blinded to randomization schedule. The drug was prepared by the anesthetist who was not part of the study. Total volume of both the drugs prepared was 50 ml each. Drugs were prepared such that concentration of fentanyl was 8 μg/ml and dexmedetomidine was 4 μg/ml.

On the day of surgery in operation-theater after confirming preanesthetic checkup with fasting status and explaining NRS, routine monitors such as an electrocardiogram (ECG), pulse oximetry (SpO2), and noninvasive blood pressure (NIBP) were attached. The Bispectral Index (BIS) electrodes were also attached for BIS monitoring during study. An 18-gauge IV cannula was secured and IV fluid was started. The patients were randomly allocated using random table assignment to one of the following groups:

Group F - Patient received a loading dose of IV fentanyl 2 μg/kg over 10 min period before induction of anesthesia and 0.5 μg/kg/h by continuous infusion during operative period

Group D - Patient received a loading dose of IV dexmedetomidine 1 μg/kg over 10 min before induction of anesthesia and 0.25 μg/kg/h by continuous infusion during operative period.

During the period of loading dose of the study drug, hemodynamic parameters at 0, 5, and 10 min (from the start of infusion) were noted. Supplemental oxygen through nasal prong was supplied during the loading dose period.

After loading dose of study drugs, induction of anesthesia was carried out with injection propofol 2 mg/kg in both the groups. Time taken to reach BIS of 50 was noted. Tracheal intubation was carried out using appropriate size of cuffed endotracheal tube with neuromuscular blockade using injection atracurium in doses of 0.5 mg/kg. Hemodynamic parameters such as heart rate (HR), SpO2, and mean arterial pressure (MAP) were noted during induction and intubation and thereafter every 5 min till extubation. The maintenance of anesthesia was done with nitrous oxide 60% and oxygen 40% with desflurane maintaining BIS of 45–55. End-tidal desflurane concentration (EtDes) and minimum alveolar concentration (MAC) of desflurane were monitored and recorded every 5 min. Additional doses of injection atracurium 0.1 mg/kg boluses were given as per requirement. IV diclofenac 1 mg/kg was given to all patients intraoperatively. IV paracetamol 1 g was given at the time of skin suturing.

After completion of surgery, the infusion of fentanyl/dexmedetomidine was stopped along with desflurane and nitrous oxide. Patient was reversed using mixture of neostigmine 0.05 mg/kg and glycopyrolate 0.01 mg/kg and trachea was extubated once the extubation criteria were met.

Following time points (starting from the time of initiation of reversal and discontinuation of desflurane) were noted (1) time to respond to verbal commands, (2) time to extubation, and (3) time for orientation (to time, place, and person).

After extubation, all the patients were shifted to postanesthesia care unit (PACU). NIBP, ECG, and SpO2 monitoring were continued. In PACU pain was assessed using NRS immediately after orientation, at 1, 6, 12, 18, and 24 h. If score was >3/10, rescue analgesia in the form of tramadol 1 mg/kg IV was instituted and injection pethidine 10 mg IV bolus up to 50 mg was given as the second rescue analgesia. Requirements of tramadol and pethidine (if any) were also noted in the postoperative period.

Patients were assessed in the PACU with Modified Aldorete Postanesthesia Recovery Scoring System and were discharged from PACU when score of 10 was achieved.[7] Time to discharge from PACU was noted. Any untoward events in the form of nausea/vomiting/sedation/shivering/bradycardia, etc., in PACU were noted and managed accordingly.

Statistical consideration

Statistical testing was carried out using IBM SPSS Statistics for Windows, Version 16.0 (Armonk, NY, USA: IBM Corp). Sample size was calculated after consideration to detect an intergroup difference of at least 10% in blood pressure and HR with a power of 0.80 and α of 0.05. Data were expressed as mean values ± standard deviation. The patient characteristics (nonparametric data) was analyzed using the “Chi-square tests or Fisher's exact test as appropriate” and the inter group comparison of the parametric data were done using the Student's t-test. The value of P < 0.05 was considered statistically significant.

RESULTS

A total of 64 patients were enrolled in the study but four patients were excluded due to nonfulfillment of inclusion criteria. Hence, 60 patients were randomized in two groups (each group n = 30) and all the patients completed the study. Both the groups were comparable regarding demographic details (age, weight, height, and BMI) and duration of surgery [Table 1].

Table 1

Demographic profile and Clinical details

The mean time taken to reach BIS of 50 was 44.67 s in Group D and 53.63 s in Group F with a P = 0.003, which was statistically significant. At different time points, the mean HR values were compared in both the groups and were found comparable except intraoperatively (P = 0.042), before (P = 0.016) and after extubation (P < 0.001) where mean HR was less in Group D compared to Group F [Figure 1].

Figure 1

Heart rate in group F and group D.

Independent evaluation of HR in each group revealed that the decrease in HR 10 min after starting the infusion was statistically significant in both the groups with a P < 0.001. The increase in HR after intubation was found to be insignificant in both the groups (P > 0.05). No change in HR was observed after the skin incision in both the groups. The increase in HR after extubation was statistically significant in Group F (P < 0.001) but not significant in Group D (P = 0.137) as shown in Figure 2.

Figure 2

Heart rate at different time points in group F and group D.

The mean MAP was lower in Group D compared to Group F at all the different time points. This difference in MAP was statistically significant 5 min after starting the infusion, 10 min after starting the infusion, after skin incision, intraoperatively (mean), before and after extubation [Figure 3]. When each group was evaluated independently, mean MAP in both Group D and Group F was observed to decrease after infusion with respect to values before (P < 0.001). However, in fentanyl group, there was statistically significant increase in MAP after intubation and extubation with respect to previous values (P < 0.05) in comparison to Group D [Figure 4]. There was no significant difference in oxygen saturation in both the groups.

Figure 3

Mean arterial pressure in group F and group D.

Figure 4

Mean arterial pressure at different time points in group F and group D.

On comparison of EtDes in both the groups at different time points maintaining BIS of 45–55, there was statistically significant decrease in EtDes in Group D, from 15 min after the intubation till the end of surgery (P < 0.001) as shown in Figure 5. MAC requirements were compared in both the groups and found lower in Group D compared to Group F with a significant P < 0.001 [Figure 6].

Figure 5

End tidal desflurane in group F and group D.

Figure 6

Comparison of minimum alveolar concentration between group F and group D.

Regarding recovery profile, patients in Group D had significant faster cognitive recovery as compared to Group F [Table 2].

Table 2

Recovery profile of Group F and Group D

Postoperatively pain scores were comparable in both the groups at different time points. None of the patient presented with pain scores >3 at 12, 18, and 24 h after orientation in both the groups [Table 3]. The time for first rescue analgesic dosage required was 31.63 min in Group D and 26.47 min in Group F which was comparable in both the groups (P > 0.05). Eight patients in the Group F required tramadol in PACU, whereas seven patients in Group D, but there was no statistical difference between the two groups (P = 0.739). The percentage of patients requiring pethidine when pain was not controlled by tramadol (50 mg) was comparable in both the groups. Four out of eight patients receiving tramadol in Group F required pethidine, whereas three out of seven patients in Group D required pethidine.

Table 3

Pain Score >3 Postoperatively at different times

Both the groups were comparable with respect to any other adverse event in the recovery room. Only four patients in Group F experienced nausea as compared to none in Group D. The mean PACU discharge time was 58.50 ± 17.57 min in Group F and 54.00 ± 18.49 min in Group D which was statistically insignificant (P = 0.338).

DISCUSSION

The incidence of breast malignancy as well as the need of surgical treatment has increased probably due to prevention campaigns and modern diagnostic tools. General anesthesia, almost always combining IV and inhalational agents, is the technique commonly used for breast cancer surgeries. Other controversial effects of general anesthesia in oncologic patients are related with depression of the immune system.[6]

After reviewing the literature, we found that no satisfactory studies have reported any equipotent doses of fentanyl and dexmedetomidine. Fentanyl in a loading dose of 2–6 μg/kg along with any sedative-hypnotic and a muscle relaxant has been advised for induction of anesthesia followed by continuous infusion of 0.5–5 μg/kg/h for the maintenance of anesthesia and analgesia. IV infusion of dexmedetomidine is commonly initiated with a 1 μg/kg loading dose, administered over 10 min, followed by a maintenance infusion of 0.2–0.7 μg/kg/h.[8] Hence, we employed the minimum doses of fentanyl (2 μg/kg bolus dose followed by 0.5 μg/kg/h) and dexmedetomidine (1 μg/kg bolus dose followed by 0.25 μg/kg/h) in this study. The rate of two infusions were kept constant during the intraoperative period and depth of anesthesia was maintained by maintaining BIS of 50, titrating the EtDes concentrations and MAC.

In this study, dexmedetomidine group showed that HR and MAP decreases after the loading dose (P < 0.001) and stabilized thereafter during the intraoperative period to within 20% of the baseline values. There was no significant increase in HR and MAP in response to intubation, skin incision and extubation in dexmedetomidine group (P > 0.05). Both these effects are presumably caused by an inhibition of central sympathetic outflow that overrides the direct effects of dexmedetomidine on the vasculature, thus attenuating the stress induced sympathoadrenal response to intubation, during skin excision, extubation and during emergence from anesthesia. The results were consistent with the study of Talke et al., where they demonstrated that dexmedetomidine attenuates increase in HR and plasma nor-epinephrine levels observed during emergence from anesthesia.[9] In fentanyl group, there was a significant increase in HR and MAP in response to intubation and extubation (P < 0.001). The findings were confirmed by various studies which concluded that dexmedetomidine is more effective in attenuating hemodynamic pressor responses to laryngoscopy, intubation, and extubation.[1011121314]

Mean intraoperative HR and MAP was lower in dexmedetomidine group compared to fentanyl group and dexmedetomidine was seen to provide better perioperative hemodynamics as in earlier studies.[1415]

This study showed that after the loading dose of the drug, the time taken for BIS awake to decrease to BIS 50 on induction with propofol was significantly reduced in dexmedetomidine group compared to fentanyl group. This may be due to sedative and hypnotic properties of dexmedetomidine as shown by Turgut et al.[16]

Anesthetic–sparing effect of dexmedetomidine was also observed by decreased EtDes concentrations and decreased MAC requirements in dexmedetomidine group in our study. A 30%–35% reduction of inhalational agent requirements were also reported in other studies.[1517]

Dexmedetomidine by its sympatholytic action decreases HR and blood pressure, thus assessing the depth of anesthesia by hemodynamic parameters would be unreliable in evaluating its effect on the depth of anesthesia. Hence, we used BIS to measure the depth of anesthesia and thereby eliminating the bias of evaluation by hemodynamic parameters as in earlier studies. Patel et al. demonstrated a 21.5% decrease in end tidal sevoflurane using dexmedetomidine as a sole analgesic using entropy for monitoring depth of anesthesia.[17] Using BIS index to assess the depth of anesthesia, Magalhães et al. showed decreased requirement of sevoflurane with continuous infusion of dexmedetomidine and fentanyl during general anesthesia, however, we found decrease in the desflurane requirements only in dexmetedomidine group.[18]

Various studies have shown a significant decrease in the use of narcotics and respiratory suppression when dexmedetomidine is used for acute pain management.[1519] The narcotic sparing effects of dexmedetomidine were evident both intraoperatively (low inhalational agent requirements) and postoperatively (lower total dose of self-administered PCA morphine). However, we did not find significant difference in quantity of rescue analgesic required in both the groups. Although, the infusions were discontinued at the end of the surgery, it is likely that analgesic sparing properties of both the drugs persisted in the recovery period as half-life of both the drugs is approximately 2–3 h. In our study, the time to first rescue analgesic dose (minutes) and postoperative pain scores were comparable in both the groups which were consistent with the study of Manaa et al., where they demonstrated that time for the first analgesic dose was significant shorter in placebo group compared with fentanyl and dexmedetomidine group, where it was similar.[20]

As for emergence characteristics our study showed an advantage with dexmedetomidine over fentanyl. The time to respond to verbal commands, time to extubation and time for orientation was lower in dexmedetomidine group and it might be because of lower volatile anesthetic agent requirement. Many studies comparing dexmedetomidine with placebo have demonstrated better recovery profile and faster recovery in dexmedetomidine group.[2122]

PACU discharge time was also similar in both the groups in our study and it was consistent with result of Turgut et al.[21] Many studies have found that intraoperative fentanyl infusion causes frequent postoperative nausea and vomiting (PONV) compared with dexmedetomidine.[2123] Although, in our study PONV was seen in four patients in fentanyl group and none in dexmedetomidine group, but this difference was not statistically significant.

CONCLUSION

So, it was found that dexmedetomidine provides better hemodynamic stability, helps attenuating pressor responses during laryngoscopy, intubation and extubation in comparison to fentanyl and has anesthetic sparing effects. Use of dexmedetomidine also allows early cognitive recovery, hastening the recovery of the patient and provides similar quality of analgesia as provided by fentanyl.

To conclude, dexmedetomidine can be used as a suitable alternative to opioids (fentanyl) for breast cancer surgeries (Breast Conservation Surgery and Modified Radical Mastectomy).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.