Fentanyl versus Dexmedetomidine Infusion in Head and Neck Free Flap Surgery for Comparison of Hemodynamic Parameters and Anaesthetic Requirements: A Randomised Controlled Trial

Abstract

Background: This prospective, double-blinded, randomized study aimed to compare the efficacy of dexmedetomidine and fentanyl infusions in maintaining hemodynamics during head and neck free flap surgery, as well as their impact on the relative amount of blood loss. Methods: Twenty patients with American Society of Anesthesiologists physical status I and II scheduled for elective head and neck free flap surgery were enrolled. The patients were randomly assigned to receive either dexmedetomidine (1 µg/kg over 10 min at anesthesia induction, followed by 0.2 to 0.75 µg/kg per hour infusion during maintenance) or fentanyl (1 to 2 µg/kg per hour infusion during maintenance). Intraoperative hemodynamic parameters, blood loss, blood transfusion requirements, surgeon satisfaction, adverse drug effects, and free flap survival up to 7 days were recorded. Results: The dexmedetomidine group achieved a mean arterial pressure (MAP) value between 60 and 70 mmHg at multiple time points (15 min, 3rd, 4th, 5th, and 6th hours), while the fentanyl group did not reach this range at any time point. The intergroup statistical analysis revealed a significant difference only at the 5th hour with (95% CI: -16.17 to -0.62) and P = 0.036. Additionally, the dexmedetomidine group exhibited lower heart rates (< 70/min) at several time points (15 min, 2nd, 3rd, 4th, 5th, and 6th hours) compared to the fentanyl group. The intergroup comparison indicated a statistically significant difference only at the 3rd hour with (95% CI: -20.94 to -0.45) and P = 0.042. Conclusion: Dexmedetomidine can be a useful adjuvant of GA for inducing controlled hypotension and decreasing bleeding in free flap surgery of the head and neck region without any detrimental effect on the free flap survival.

Introduction

Free fibular flap (FFF), regarded as the “gold standard” for mandibular reconstruction was first introduced by Hidalgo in 1989 [1–3]. Despite the inherent advantages of the procedure, surgery is often prolonged and may result in extensive blood and fluid losses. The resulting hypovolaemic vasoconstriction if not corrected, compromises the blood flow to the flap and result in flap failure [4]. Conversely, liberal fluid administration leads to detrimental edema formation within the flap [5, 6].

Hypo-perfusion and flap failure remain major concerns despite the improvements in surgical techniques. In the hands of experienced surgeons, the incidence of free flap loss is reported to be less than 5% [7–9]. Vessel thrombosis is an ominous sign, which may lead to FFF failure. Anaesthetic management is of prime importance in free vascularized tissue transfer by maintaining optimum circulation through alterations in central hemodynamics and regional blood flow and preventing hypovolemia, hypoxia, hypocarbia and hypothermia all of which adversely affect circulation in the implanted flap. Even with good fluid management, blood flow to a flap may decrease by 50% for 6–12 h postoperatively [10]. Vasopressors have been seen to provide overall improved hemodynamic stability and help in limiting fluid administration [11].

Hypotensive anesthesia has been reported to be effective in reducing blood loss, improving the quality of surgical field and reduce the length of hospital stay in orthognatic surgeries [12, 13]. But literature on the use of controlled hypotension in free flap surgery is lacking.

Dexmedetomidine and fentanyl have been studied for providing deliberate hypotension during cochlear implant surgery in pediatric patients and in patients undergoing arthroscopic shoulder surgery [14, 15]. Dexmedetomidine has been shown to maintain hemodynamics in the post operative period without any increase in free flap failure rate [16].

Our search did not reveal any studies comparing fentanyl versus dexmedetomidine, in inducing controlled hypotension and optimizing the intra-operative hemodynamic conditions in head and neck free flap surgeries.

Purpose

To compare the efficacy of fentanyl and dexmedetomidine infusions in maintaining hemodynamics by inducing controlled hypotension in free flap surgery and its effect on relative amount of blood loss and free flap survival.

Objectives

The primary objective was to compare the hemodynamic parameters viz., mean arterial pressure (MAP) and heart rate (HR) during infusion of fentanyl versus dexmedetomidine for intraoperative controlled hypotension.

The secondary objectives were to compare the amount of blood loss; the need for transfusion for surgery; to compare the amount of additional analgesic requirement; effect on free flap survival; surgeon’s satisfaction and note any adverse effects viz., postoperative nausea and vomiting (PONV), hypotension, bradycardia, respiratory depression and pruritus.

Materials and Methods

The study was conducted in the operation theatre and the investigators were from the Department of Anaesthesiology, Pain Medicine and Critical Care and the Department of Otorhinolaryngology, All India Institute of Medical Sciences, New Delhi, India. The study was started after obtaining approval from the Institutional Ethical Committee (IECPG-476/29.11.2017) and registering with Clinical Trials Registry of India (CTRI no. 2018/04/013490). Written informed consent was taken from the consenting participants who were scheduled to undergo mandibular resection with radical neck dissection followed by fibular graft. All aspects of the study protocol complied with the Declaration of Helsinki (2013).

Ours was a prospective, randomized, double blinded, controlled trial. We included patients within the age group of 18–60 years belonging to ASAPS I&II, who were scheduled to undergo elective head and neck free flap surgery. Our exclusion criteria were patients having cardiovascular disease such as hypertension, ischemic heart disease and heart failure or having hepato-renal insufficiency. Patients with positive history of hypersensitivity to any of the studied drugs and those who refused to be a part of the study were also excluded.

Sample Size

We did an extensive review of literature on the topic using keywords (hypotensive anaesthesia, free flap surgery) but could not find any literature on controlled hypotension using the study drugs in free flap surgery. Hence, as per feasibility and availability of patients at our hospital, we decided to recruit patients over a period of 1.5years (1st January 2018–1st July 2019). Searching previous records, we estimated approximately around 25–30 patients over the study period. Anticipating possible dropouts and exclusions, we kept our study sample at 20 i.e. 10 in each group.

Procedure

All patients underwent detailed systemic examination and airway assessment. Past medical records and routine investigations were reviewed. Adequate fasting was maintained by nil per oral 6 h for light meal and 2 h for clear fluids. After explaining the study protocol, informed and written consent was obtained. Patients were pre-medicated with oral ranitidine150 mg and oral alprazolam 0.25 mg at night before and in the morning of the surgery. Baseline parameters viz., electrocardiograph (ECG), HR, non-invasive blood pressure (NIBP), oxygen saturation (SpO₂) and respiratory rate (RR) were recorded before beginning of anaesthetic induction.

For induction both groups received intravenous (IV) propofol 2-3 mg/kg, IV fentanyl 2mcg/kg and IV vecuronium 0.1 mg/kg along with isoflurane of MAC 0.7 to 0.8. The airway was secured by an appropriate size nasotracheal tube. A radial arterial line for invasive blood pressure (IBP) monitoring was secured after nasotracheal intubation.

The selected patients for the study were randomly divided into two groups using a computer generated random number sequence. Sequentially marked opaque and sealed envelopes did concealment allocation. An anaesthesiologist who was not involved in the study opened the envelope and prepared the study drugs as per the instructions in the note. The patients were randomly allocated in one of the two groups:

Group F- Fentanyl infusion @ 1mcg/kg/hr (Patients received normal saline infusion for the first 10 min).

Group D- Dexmedetomidine infusion loading dose @ 1mcg/kg over 10 min followed by 0.5mcg/kg/hr.

The bolus dose in both the groups were loaded in 10 ml syringe and infused over 10 min. Dexmedetomidine 200mcg was diluted with normal saline up to 50 ml giving a concentration of 4mcg/ml. Fentanyl 400mcg was diluted with normal saline up to 50 ml making it 8mcg/ml solution. Each unit change in the infusion rate changed the amount of both the drugs in equivalent amounts thus making the anaesthetist operating the infusion pump blinded to the drug being used. The infusion rate was stepped up and down for maintaining the MAP between 60-70mmHg. Dexmedetomidine infusion was titrated between 0.2 and 0.75 mcg/kg/hr and the fentanyl infusion between 1-2mcg/kg/hr. If required, additional fentanyl was given maximum up to a dose of 1mcg/kg/hr boluses in both the groups.

The vital parameters viz., systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, HR, SPO2, EtCO2 (End tidal CO₂) and surface temperature were monitored every 15 min for the first hour and then every 1 h till the end of the surgery. Whenever HR rose above 20% of baseline, rescue analgesic IV fentanyl (0.5mcg/kg) was given. Any decrease in heart rate (bradycardia) < 50 /min was treated by IV atropine 0.6 mg bolus. Similarly, MAP was maintained within the range by increasing or decreasing the infusion of dexmedetomidine and fentanyl within the prescribed limits. In case of the MAP being less than 60 mm of Hg, rescue bolus of IV ephedrine 6 mg was given. At the end of surgery, reversal of neuromuscular blockade was done by IV neostigmine 50 µg/kg and glycopyrolate 10 µg/kg. As per the surgical protocol the patients were kept intubated overnight in the post anaesthesia care unit and received infusion of IV morphine @1 mg/hr. Extubation of the trachea was done on postoperative day 1 after satisfactory surgical site inspection.

Intraoperative blood loss was measured from the suction container and soaked gauze pieces. A postoperative blood sample was sent for haemoglobin measurement. Each of the fully soaked gauze was taken as 50 ml blood and partially soaked as 20 ml. The need for blood transfusion, which was as per the institutional protocol for free flap surgery i.e., Hb < 10gm%, was documented. All patients had their urinary bladder catheterized and hourly urine output was monitored. Intraoperative fluid management was done as per the standard 4:2:1criteria. Additional fluid loss was replaced either with crystalloid or blood as per the requirement. The amount of additional intraoperative analgesic required was recorded. Surgeons were asked to rate their satisfaction using a three-point verbal rating scale (1 = dissatisfied, 2 = undecided or 3 = satisfied). Total duration of surgery was recorded. PONV was scored as (0 for no nausea or vomiting; 1 for nausea alone; 2 for an episode of vomiting or severe retching; 3 for two or more episodes of vomiting). Patients with a score of 2 or more were treated by IV ondansetron 0.1 mg/kg and if not controlled adequately IV metoclopramide 10 mg was given. Amount of ephedrine and atropine used was also noted. Other side effects such as hypotension, respiratory depression, and bradycardia were observed in the PACU. Survival of free flap surgery was assessed by pin prick and onset of bleeding time up to 7 days.

Statistical Analysis

The statistical analysis was carried out using Stata 12.0 (College Station, Texas, USA). Data were presented as number (%) or mean ± SD or median as appropriate. The patient’s characteristics and data were analysed with Student’s t-test and Fischer’s exact test.

The primary outcome, HR and MAP, was compared between the two groups over a period of time using GEE analysis. The secondary outcomes (amount of blood loss and need for blood transfusion, additional analgesic requirement, free flap survival, surgeon satisfaction) were analysed by Mann Whitney test and Fischer’s exact test.

The P value of < 0.05 was considered as statistically significant for this study.

Results

In this prospective, randomised, observer blinded study, 28 patients were screened for inclusion in the study. Among these, 1 patient refused to give consent, 2 patients were excluded because of logistical issues and 5 patients were excluded, as they did not meet inclusion criteria. The remaining 20 patients were randomised to either of the two groups (Fig. 1). Among 20 patients selected, 12 had squamous cell carcinoma of tongue, 3 had mandibular osteosarcoma, 1 had ameloblastoma and 4 had squamous cell carcinoma of gingiva.

Fig. 1.

Consort Flow Diagram of the present study

Demographic Data

The demographic parameters of the patients were comparable between the groups (Table 1).

Table 1.

Demographic data between two groups

Baseline Characteristics	Group D (n = 10)	Group F (n = 10)	P value
Age (years)	37.3 ± 14.04	30.6 ± 15.75	0.329
Sex
Male  Female	8(80%) 2(20%)	6(60%) 4(40%)	0.628
Weight (kg)	63.9 ± 12.4	58.5 ± 15.37	0.399
ASA
I  II	7(70%) 3(30%)	8(80%) 2(20%)	1
Duration of Surgery (hours)	7.49 ± 0.77	7.05 ± 0.724	0.206

Data are represented by mean ± SD, number (%) where applicable. *P < 0.05 is statistically significant. D = dexmedetomidine; F = fentanyl

Primary Outcome

The hemodynamic parameters, heart rate and mean arterial blood pressure, were recorded every 15 min during the first hour and thereafter every hour till the end of surgery.

MAP value between 60-70mmHg was attained at more time points (15 min, 3rd, 4th, 5th, 6th hours) in the dexmedetomidine group but wasn’t achieved at any time point in the fentanyl group (Fig. 2). Intergroup statistical comparison gave significance difference only at 5 h time point [95% CI (-16.17 to − 0.62)] (P = 0.036).

Fig. 2.

Comparison of MAP between two groups

Lower heart rates < 70/min were observed at more time points (15 min, 2nd, 3rd, 4th, 5th and 6th hours) in the dexmedetomidine group (Fig. 3). Intergroup comparison revealed statistically significant differences only at 3rd hour [95% CI (-20.94 to − 0.45)] (P = 0.042).

Fig. 3.

Comparison in HR between two groups

Secondary Outcomes

The blood loss in the dexmedetomidine group was significantly less (P = 0.023) than in the fentanyl group. More patients required blood transfusion in the fentanyl group than in the dexmedetomidine group (Table 2).

Table 2.

Secondary outcomes between two groups

Parameters	Group D (n = 10)	Group F (n = 10)	P value
Blood Loss (ml)	475 ± 111.18	710 ± 279.68	0.023*
Blood Transfused (units)
0  1  2	9(90%) 1(10%) 0(0%)	5(50%) 3(30%) 2(20%)	0.173
Fentanyl (mcg)	143 ± 43.02	287 ± 180.75	0.032*
Surgeon Satisfaction
Satisfied  Dissatisfied  Undecided	9(90%) 0(0%) 1(10%)	5(50%) 2(20%) 3(30%)	0.173

Data are represented by mean ± SD, number (%) where applicable. * P < 0.05 is statistically significant. D = dexmedetomidine; F = fentanyl

The amount of fentanyl required as rescue analgesic during intraoperative period was significantly more [95%CI (-267.94 to -21.05)] (P = 0.032) in the fentanyl group than in the dexmedetomidine group (Table 2). Free flap survival was assessed till 7 days and all the patients in both groups had 100% survival rate.

Adverse Effects

Only 1 patient in the fentanyl group reported of PONV with score 3. The amount of ephedrine used for hypotensive episodes was 12.6 ± 9.09 mg (mean ± SD) in the dexmedetomidine group and 10 ± 1.73 mg (mean ± SD) in the fentanyl group [95% CI -10.79 to 15.99] (P = 0.644). Bradycardia was noted in 5 patients with the use of dexmedetomidine during the loading period and required intervention with a single dose of IV atropine 0.6 mg. There were no hypotension, bradycardia or respiratory depression reported in any patient in the post-operative period. None of the patients in either group reported of pruritus.

Discussions

The current study aimed to compare the hemodynamic effects of fentanyl infusion versus dexmedetomidine infusion in patients undergoing head and neck free flap surgery. To the best of our knowledge there are no prior studies in the available literature that have compared the hemodynamic parameters of fentanyl and dexmedetomidine infusions specifically in the context of head and neck free flap surgery. The study design therefore aims to fill a gap in the existing literature by providing valuable insights into the hemodynamic effects of these two drugs specifically in this surgical context.

Controlled hypotensive anesthesia is a technique that is used to lower the MAP of a patient by 30% of the preoperative value and maintain it at that range for the desired period of time. This technique is typically used in surgeries that are associated with significant blood loss, such as middle ear/nasal surgery, neurosurgical operations, major orthopedic procedures, etc. The benefit of reduction in blood loss is both improved visualization of the surgical field and decreased need for blood transfusion [17].

The physiological principle underlying hypotensive anesthesia is derived from the fact that in the clinical setting of massive bleeding, the natural survival response of the body is to lower blood pressure in order to reduce blood loss and maintain adequate blood flow to vital organs [18]. A decrease in MAP is directly associated with decrease in the organ perfusion. Hypotensive anesthesia should be administered only when it is deemed safe and appropriate as those having pre-existing cardiovascular disease may be at increased risk of complications with its use. Intense monitoring of hemodynamics is of utmost importance to avoid unwarranted complications.

Dexmedetomidine is a highly specific alpha-2 agonist with analgesic, anesthetic-sparing, and sympatholytic properties. It works by activating postsynaptic receptors in the central nervous system, leading to a decrease in sympathetic activity, blood pressure, and heart rate [19]. Its properties have been widely utilized in clinical settings for achieving hypotensive anesthesia in orthognatic surgery, middle ear and nasal surgery [20–22]. Dexmedetomidine was reported to be effective in inducing controlled hypotension with a favourable surgical field and lowering the use of opioid consumption as reported in meta-analyses [23, 24].

Dexmedetomidine was found to be significantly more efficacious than fentanyl in inducing deliberate hypotension by decreasing HR and MAP in cochlear implant and shoulder arthoscopic surgery [14, 15]. Intraoperative infusion of dexmedetomidine was observed to have better postoperative hemodynamic stability and equivalent effect on pain control as compared to fentanyl and remifentanil infusion. The current study also demonstrated the superiority of dexmedetomidine over fentanyl in lowering the HR and MAP but the difference was not statistically significant at all time points. In both the study groups, MAP value between 60-70mmHg was attained at more time points (15 min, 3 h, 4 h and 5 h) in patients receiving dexmedetomidine but wasn’t achieved at any time point in fentanyl group.

Dexmedetomidine was found to decrease bleeding in septoplasty, tympanoplasty and in rhinoplasty when compared with medications like clonidine or with placebo [25–27]. A study conducted by Janatmakan et al. showed the mean blood loss in the dexmedetomidine group to be significantly lower than the placebo group (P < 0.001) in surgery of the spine [28].

We observed a significant decrease in intra operative blood loss in the dexmedetomidine group as compared to the fentanyl group. This can be attributed to lower MAP achieved with dexmedetomidine as compared to fentanyl. This strengthens the fact that dexmedetomidine is an efficacious agent for decreasing the surgical blood loss in free flap surgery.

In a study conducted by Jaakola et al., the analgesic effects of dexmedetomidine and fentanyl were compared in healthy volunteers [29]. The researchers administered different doses of dexmedetomidine and fentanyl (2 µg/kg) and evaluated the analgesic response. The results showed that dexmedetomidine had a moderate analgesic effect, which was most pronounced at a dose of 0.5 µg/kg. This suggests that dexmedetomidine may be a useful alternative or adjunct to opioids for pain management in certain clinical settings. In a meta analysis conducted by Liu et al., decreased intraoperative analgesic consumption as well as reduced post operative pain intensity were observed following intraoperative use of dexmedetomidine in neurosurgery [30]. Use of dexmedetomidine resulted in decreased analgesic requirement as compared to fentanyl in septoplasty and reduced the post operative pain scores following arthoscopic shoulder surgery [15, 27]. This is in agreement with the current study where the amount of fentanyl used in the intraoperative period as a rescue analgesic was significantly higher in the fentanyl group as compared to the dexmedetomidine group.

There are conflicting reports on the use of dexmedetomidine versus remifentanil in tympanoplasty [21, 31]. However, remifentanil is a very expensive drug to be used for long duration procedures such as free flap surgery.

Surgical field and surgeon’s satisfaction was better with dexmedetomidine than with fentanyl in pediatric patients undergoing cochlear implantation and in shoulder arthroscopy [14, 15]. Dexmedetomidine provided a better surgical field as compared to placebo in tympanoplasty or septorhinoplasty [24]. Dexmedetomidine also provided a good surgical field in functional endoscopic surgery. In our study although the surgeon’s satisfaction was higher in the dexmedetomidine group as compared to the fentanyl group the difference was statistically insignificant.

We did not encounter any flap failures in our study subjects who were monitored till the 7th postoperative day. Dexmedetomidine has been credited for maintaining hemodynamics in the postoperative period without any increase in free flap failure [16]. Experiments on animal models have shown a positive impact of dexmedetomidine on flap survival. In the porcine model, dexmedetomidine was seen to preserve microcirculation in free flap as depicted by microdialysis and tissue oxygenation [32]. Dexmedetomidine was seen to provide a protective effect on the survival of flaps in rats by decreasing inflammatory immunoregulatory proteins and by promoting angiogenesis and blood perfusion [33].

Large volume (> 7 L) fluid resuscitation and MAP below 60mmHg was seen to have adverse outcomes in free flap surgeries [34]. Intraoperative core body temperature between 34.3 and 37.6 °C and a mean core body temperature of 36.5 °C was suggested to be protective against postoperative flap complication [35]. Although we did not take the amount of IV fluid and core body temperature as an outcome, none of our patients required a high amount of fluid beyond the calculated maintenance and replacement of loss. The surface temperature varied between 35°C and 36.4°C in our study subjects.

In our study, 5 patients in the dexmedetomidine group had bradycardia during infusion of the bolus and required atropine. The sympatholytic effect of dexmedetomidine causes increased vagal tone resulting in bradycardia.

Opioid-induced nausea and vomiting is a well-known adverse effect that has both peripheral and central components. Opioids activate mu opioid receptors in the chemoreceptor trigger zone resulting in stimulation of vomiting [36]. In the study, only one patient in the fentanyl group experienced a PONV score of 3. This indicates that the incidence of opioid-induced nausea and vomiting was low in the study population.

Limitations

With the current sample size, the power achieved was only 70% hence a larger sample size with appropriate power would give more conclusive results. We did not check serial hematocrit values which optimises blood flow to free flaps. The requirement for inhalation agents is reduced when dexmedetomidine is used concurrently. However, due to the absence of a BIS monitor and the need for blinding, we maintained a constant minimum alveolar concentration (MAC) of isoflurane. We used surface temperature instead of core body temperature, which is a more accurate measure of body temperature.

Conclusion

Dexmedetomidine can be a useful adjuvant of GA for inducing controlled hypotension and decreasing bleeding in free flap surgery of the head and neck region without any detrimental effect on the free flap survival.

Author contribution

A.B and D.G were responsible for the study design. D.G and V.R managed the inclusion of the participants. Together with A.B they conducted all measurements. A.B was responsible for data collection and analysis. D.G, V.R, P.K, R.P and C.S interpreted the data. A.B wrote the first draft of the manuscript. D.G, V.R, P.K, R.P and C.S made substantial contributions to the final version of the manuscript and all revisions. All authors read and approved the final manuscript.

Funding

None.

Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Ethical approval for this study was provided by the Institutional Ethical Committee (IECPG-476/29.11.2017) and registering with Clinical Trials Registry of India (CTRI no. 2018/04/013490). Written informed consents were obtained from all participants before inclusion.

Consent for publication

Not applicable.

Competing interest

None.