TITLE: Evaluation of Preoperative Flupirtine in Ambulatory Functional Endoscopic Sinus Surgery: A Prospective, Double-Blind, Randomized Controlled Trial

  ABSTRACT.BACKGROUND:
Functional endoscopic sinus surgery (FESS) is the mainstay therapeutic management for nasal pathologies. We evaluated flupirtine, a centrally acting analgesic, for producing perfect perioperative conditions in FESS for adults in a day-care setting.

ABSTRACT.MATERIALS AND METHODS:
Sixty-two patients (25–40 years) scheduled for FESS under general anesthesia were randomly divided into Group F (n = 31) receiving preoperative flupirtine (100 mg) and Group C (n = 31) receiving identical-looking placebo capsule per oral 60 min before induction of anesthesia. Perioperative Nasal bleeding and surgeon's satisfaction score during operation; amount and number of patients receiving fentanyl, propofol, and esmolol infusion for analgesia; maintenance of desired bispectral index (BIS) and deliberate hypotension, respectively. Postanesthesia Care Unit (PACU) and hospital stay, hemodynamic parameters, and side effects were all recorded for each patient.

ABSTRACT.RESULTS:
Significantly, less number of patients and less dosage of esmolol were required (P = 0.0040 and 0.0001, respectively) in Group F as compared to that in Group C. Again, number of patients requiring fentanyl and dosage of the same drug was significantly lower in Group F. Dose of propofol for the maintenance of BIS was significantly lower in Group F. However, the duration of controlled hypotension was almost similar in both groups. Group F patients suffered significantly less nasal bleeding and surgeon's satisfaction score was also high in this group. Discharge time from PACU and hospital was similar between two groups without any appreciable side effects.

ABSTRACT.CONCLUSION:
Flupirtine as a premedication found to be providing more favorable perioperative hemodynamic conditions, analgesia and thus allowing less nasal bleeding as well as more surgeons' satisfaction score.

BODY.I:
Nasal sinus pathologies are managed initially with conservative manner. Functional endoscopic sinus surgery (FESS) is the mainstay surgical management of these pathologies when conservative measures fail.[1] This technique has dramatically improved the surgical dissection with the use of enhanced illumination and visualization. FESS is usually done for the treatment of patients with acute as well as chronic sinonasal disease who do not respond to the conventional medical treatment. Good visibility during FESS is necessary because of nasal tiny anatomical structures, which are full of vessels and limit the nasal endoscopic access. In such situation, even a minor bleeding can lead the surgical procedure left unfinished.  Perioperative bleeding is a major hurdle leading to impaired visibility, prolonged surgical duration, and reduced quality of intervention during FESS under general anesthesia.[2] Various methods such as preoperative adrenaline packing, intraoperative adrenaline infiltration, patient's head elevation, and/or hypotensive anesthesia have been adopted to provide an optimal field.  Local measures such as adrenaline packing of nasal cavity and injected vasoconstrictors are not without side effects. Similarly, poorly controlled induced hypotension; can lead to critical fall in perfusion pressure in vital organs which has its own drawbacks.[3] The use of precisely dosed modern intravenous anesthetic agents, together with proper patient positioning,[4] allows us to manage hemodynamic parameters during surgery and thus to easily control hemodynamics.[5] For achieving favorable operative conditions, many drugs such as remifentanil,[5] propofol, sevoflurane, desflurane,[6] desmopressin,[7] dexmedetomidine, clonidine,[8] and gabapentin[9] have already been used with varied success rate.  Perioperative bleeding and postoperative pain are major complications of FESS, which frequently hampers implementation of the surgery on an ambulatory care basis.[101112] Flupirtine maleate, a triaminopyridine derivative, is a nonopiate, not a nonsteroidal anti-inflammatory drug, centrally acting analgesic, with N-methyl-D-aspartate receptor antagonistic properties.[13] It is the first representative of an entirely different class of analgesics which are known as "selective neuronal potassium channel openers (SNEPCOs)" and acts by centrally (both spinal and supraspinal) inhibiting exaggerated neuronal action potential generation and controls neuronal excitability.[14] Flupirtine is a potent analgesic and muscle relaxant and also has anticonvulsant and antioxidant properties.[1415] The drug contributes to these therapeutic benefits without respiratory depression, tolerance, and dependence that are typical of opioids and has much better gastric and renal tolerability profile than nonsteroidal anti-inflammatory drugs.[16]  No published clinical study has evaluated the efficacy of preoperatively administered single oral dose of flupirtine maleate for maintaining the intraoperative stable hemodynamics and operative conditions and providing perioperative analgesia in ambulatory FESS.

BODY.M:
After obtaining Institutional Ethical Committee permission, written consent was obtained from all the patients. A total of 62 adult patients were randomly allocated to two equal groups (n = 31 in each group) using a computer-generated random number list. Between March 2009 and February 2010, patients having American Society of Anesthesiologists (ASA) Physical Status I and II, aged 25–40 years of both sexes undergoing ambulatory FESS under general anesthesia were enrolled in the study. Group F patients received single dose oral 100 mg flupirtine (Retense® [100 mg], Sun Pharma Laboratories Ltd., India) capsule and Group C patients received single dose oral placebo (Vitamin B complex) capsule 1 h before induction of general anesthesia. Intraoperative analgesia was managed with fentanyl (Verfen® [100 μmg], Verve Healthcare Ltd., India) and paracetamol (Neomol® [1000 mg], Neon Laboratories, India) was used for routine postoperative analgesia in both the groups. As both the drugs are available in different color form, we took the help of DBcaps® Capsules; two-piece gelatin capsules with a tamper evident design to ensure blinding. Drugs were swallowed with sips of water in the presence of resident doctor not taking part in the study. The anesthesiologist performing the general anesthesia was unaware of the constituent of the premedication drug and allotment of the group, and similarly, resident doctors keeping records of different parameters were also unaware of group allotment. Thus, blinding was properly maintained.  For topical vasoconstriction and local anesthesia, 1/1000 epinephrine-soaked cotton was placed in the nasal cavity for 5 min. A solution containing (2%) 20 mg/mL lignocaine hydrochloride + 0.01 mg/mL epinephrine (Xylocaine® 2% adrenaline (1:200000), Astra Zeneca Pharma India Limited, India) was applied to the nasal side of both the medial and lateral conchae at the same dose.

BODY.M.EXCLUSION CRITERIA:
Patient's refusal, any known allergy or contraindication to flupirtine, pregnancy, lactating mothers and children, hepatic, renal, or cardiopulmonary abnormality, alcoholics, diabetics were excluded. Patients having a history of significant neuropsychiatric or neuromuscular disorders were also excluded. Bilateral ethmoidal polyp, sinusitis, orbital abscess, cerebrospinal fluid (CSF) leak with or without CSF rhinorrhea, and orbital decompression surgeries, all were also excluded. Being ambulatory surgeries, patients having no assistance in home and dwelling at more than 10 km from our institution were also excluded from this study.  In preoperative assessment, patients were enquired about history of previous anesthesia and drug allergy. General and systemic examinations and assessment of the airway were done. Preoperative fasting of minimum 6 h was ensured before operation in all cases. All patients received premedication of tablet alprazolam 0.5 mg and ranitidine 150 mg orally at night before surgery.  Patients were brought to the observation room; baseline parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), Mean Arterial Pressure (MAP), and oxygen saturation (SpO2) were measured. Premedication was administered. After 1 h of premedication, the patient was shifted to the operation table and multichannel monitor was attached. HR, SBP, DBP, MBP, respiratory rate, temperature, and 12-lead electrocardiography were continuously recorded using Philips IntelliVue (MP20) monitor. Bispectral index (BIS) monitor was separately been used for checking depth of anesthesia.  Intravenous (I.V.) Ringer's lactate started with the help of 18G cannula. After 5 min preoxygenation with 100% O2, premedication was given with injection glycopyrrolate (0.02 mg) and injection fentanyl (100 μg) was given 3 min before induction. Induction was done with injection propofol (2 mg/kg). After that, atracurium (0.5 mg/kg) was given to facilitate laryngoscopy and intubation. Laryngoscopy, intubation, and cuff inflation were completed within 20 s in all cases. Muscle relaxation was maintained with intermittent intravenous atracurium (0.2 mg/kg) as and when required and controlled ventilation was maintained with 70% N2O in O2 and isoflurane up to 1–2 minimum alveolar concentration using anesthesia workstation. After completion of surgery, neuromuscular block was reversed with injection glycopyrrolate 0.01 mg/kg and injection neostigmine 0.05 mg/kg and extubated when adequate spontaneous ventilation was established and BIS ≥70. After extubation, all patients were transferred to Postanesthesia Care Unit (PACU).  When peroperative mean arterial pressure (MAP) was ≥70 mmHg, 50 μg/kg/min esmolol was applied for 4 min; again, when MAP was ≤55 mmHg, 5 mg of mephentermine was applied. When HR was ≤50, 0.6 mg I.V. atropine was applied to combat bradycardia. When BIS value increases >60, propofol infusion started at 50 μg/kg/min. The presence of hypertension or tachycardia during anesthesia, while BIS was 40–60 (i.e., within desired range), was attributed to insufficient analgesia and a bolus dose of fentanyl 1 μg/kg was given. Fentanyl was administered primarily, and if its administration did not able to control hemodynamics, then esmolol infusion started.  The time for PACU stay (admission–discharge from PACU) and hospital discharge (eye opening–discharge from hospital) and the incidence of adverse events were also recorded. Patients were considered ready for discharge from the PACU when the modified Aldrete postanesthesia score was ≥9. Patients were transferred to the ward after being discharged from PACU. For nausea and vomiting, ondansetron 0.15 mg/kg IV was administered. All the patients were operated by the same surgeon, and surgical site bleeding was rated according to a 6-point scale every 5 min by him in terms of bleeding and dryness [Table 1]. Surgeon's satisfaction was scored by the same surgeon with a 4-point scale [Table 1].   Table 1 Fentanyl and esmolol for analgesia and controlled hypotension 

BODY.M.STATISTICAL ANALYSIS:
A crossover pilot study with 8 patients was used to determine the sample size. It was found that 20% reduction in the requirements of Esmolol (hypotensive agent) as infusion to achieve the target MAP (60–70 mmHg) with a power of 80% (α error = 0.05, β error = 0.2), the sample size calculated was 56 patients (28/group) to be able to reject the null hypothesis which will be increased to patients 62 (31/group) for possible dropouts. All the collected raw data were entered into a Microsoft Excel SpreadSheet and analyzed using standard statistical software SPSS® statistical package version 18.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were analyzed using the Chi-square test. Fisher's exact test was used in comparison of sedation, hypotension, bradycardia, vomiting, shivering, headache, and number of patients requiring propofol, fentanyl, and esmolol for maintenance of desired BIS value and hemodynamics, respectively. Normally distributed continuous variables were analyzed using the independent sample t-test, and P < 0.05 was considered statistically significant.

BODY.R:
We recruited 31 participants per group, more than the calculated sample size. There were no dropouts. 31 patients in the flupirtine Group (F) and 31 in the placebo Group (C) were eligible for effectiveness analysis.  The age, sex distribution, body weight, height, ASA status, preoperative hemoglobin, and packed cell volume, all were found to be (P > 0.05) comparable [Table 2]. Indications for FESS are given in Table 3. Duration of surgery and anesthesia was quite comparable among two groups [Table 4]. Controlled hypotension was more sustained but statistically insignificant in the Group C than F [Table 4]. Post anaesthesia care unit and hospital discharge time were also more prolonged but statistically insignificant in Group F than Group C [Table 4].   Table 2 Demographic profile and the preoperative hematologic status in both groups   Table 3 Indications of functional endoscopic sinus surgery for randomized patient groups   Table 4 Operation related timings   Number of patients treated with fentanyl and the mean dose of the drug were significantly higher (P < 0.05) in the control group than flupirtine group [Table 1]. Propofol consumption for BIS maintenance was significantly higher in placebo group [Table 1]. Again to ensure induced hypotension, dose of esmolol and the number of patients treated with it were significantly higher (P < 0.05) in Group C than F [Table 1]. Nasal bleeding score and subsequently surgeon's satisfaction score both were significantly (P < 0.05) better in flupirtine-treated group than control group [Table 5]. Side effects were all comparable between two groups (P > 0.05) [Table 6]. MAP and HR between two groups were found to be quite comparable among two groups (P > 0.05) [Figures 1 and 2]. Consort flow diagram shows the patient enrollment, allocation, follow-up, and analysis of all the patients in the study [Flowchart 1].  Table 5 Surgical bleeding score and surgeon satisfaction score   Table 6 Side effects   Figure 1Comparison of mean arterial pressure between two groups  Figure 2Comparison of mean heart rate between two groups  Flowchart 1CONSORT 2010 flow diagram

BODY.D:
Ambulatory surgery has proven over the years as the best method to reduce the burden on the health-care resources as well as achievement of extreme patient satisfaction.[17] In developing countries, most of the patients avoid bearing expenses of prolonged hospital stay.[18]  In the ambulatory care scenario, nasal bleeding (28.9%) and postoperative pain (23.7%) in the immediate postoperative period are the first and next most common causes of delayed recovery and discharge after surgery and most frequent (even extending up to 8.8%) cause of unplanned admission and subsequently delayed return to work.[1920]  Maintenance of stable hemodynamics is utmost important for control of bleeding and hence improved visibility without much need for induced hypotension. Prophylactic analgesia has long been tried to control the perioperative stress response, hence stable hemodynamics and good surgical visibility leading to improved surgeon's satisfaction score.[21] In our study, we had chosen a target MAP 60–70 mmHg to provide the best surgical conditions without the risk of tissue hypoperfusion depending on a review of literature conducted by Barak et al.[22] with an MAP of 50–65 mmHg during major maxillofacial surgeries.  For the relief of pain due to surgery, traumatic injury, dental procedures, headache/migraine, and abdominal spasms, flupirtine has proved at least as effective as the opiate analgesics codeine, dihydrocodeine, and pentazocine; the nonsteroidal anti-inflammatory agents ibuprofen, diclofenac, and ketorolac; as well as dipyrone and paracetamol (acetaminophen).[23] Flupirtine maleate, a water-soluble compound, undergoes rapid gastric absorption (bioavailability 90%) after oral administration, with a peak plasma concentration of approximately 0.8–2 mg/L, achieved in about 1.6–2 h.[24] We have chosen to administer the selected dose (100 mg), 1 h before induction, with a target to maximize the analgesic effect for the duration of surgery. This methodology is further supported by observation of decreased intraoperative fentanyl requirement in our study. Further increase in oral dose increases the side effects such as drowsiness, muscle relaxation, and concentration impairment effects, least desirable during the immediate postoperative period.[25]  Unfortunately, not a single clinical trial studied the effectiveness of flupirtine maleate for maintaining the intraoperative stable hemodynamics and providing perioperative analgesia in ambulatory FESS. In this prospective, randomized, double-blinded trial, we had tried to compare the efficacy of preoperative 100 mg oral flupirtine and placebo (given 1 h before surgery) for producing stable hemodynamics as well as on visibility of surgical field, satisfaction of the surgeon, postoperative need for analgesia (fentanyl requirement), and recovery profile for the patients undergoing FESS in a day-care setting.  The demographic profile and durations of anesthesia [Tables 2 and 3] between two groups, which was statistically insignificant (P > 0.05) of our patients were quite similar to other research investigations and provided us the uniform platform to evenly compare the results obtained.[26]  Regarding PACU recovery (time to reach Aldrete score ≥9) and hospital discharge, no study had clearly mentioned these parameters. Two placebo-controlled studies had shown that higher sedation was observed in flupirtine group. Yadav et al.[26] found that sedation was (nonsignificant) greater in flupirtine (200 mg)-treated group. Similarly, Thapa et al.[27] found significant difference in sedation score in flupirtine (100 mg) group, but the awakening was same in both the groups. Here, we also have found that sedation was quite comparable in both the groups, and proportionately, slight delay was seen in PACU recovery and hospital discharge in flupirtine-treated group, but the results were statistically insignificant.  In our study, duration of controlled hypotension was slightly prolonged in Group F than C, but the difference was clinically insignificant. Similarly, Attri et al.[28] in a study on elective abdominal surgeries found that hemodynamics in flupirtine- and diclofenac-treated groups was quite comparable. However, surprisingly, in our study, mean dose of esmolol and the number of patients receiving the same were significantly high in the control group.  We have found that fentanyl requirement both in terms of number and the total dosage was significantly less in the flupirtine-treated Group (F) than placebo (C). Similarly, analgesic consumption as morphine requirement was significantly lower in flupirtine-treated group was also observed by Thapa et al.,[27] with P = 0.009, 0.004, 0.002 at 2, 4, 6 h, respectivel, y in the postoperative period. Ahuja et al. in a study on gynecological ambulatory surgeries found that requirement for rescue analgesia was reduced in flupirtine group as compared to group ibuprofen but failed to reach statistical significance.[29]  In our study, esmolol dose and the number of patients treated with it were significantly less in flupirtine-pretreated group while compared with placebo group. However, Hummel et al.[25] in a placebo-controlled trial found only 200 mg dose of flupirtine caused significant increase in SBP, but DBP and HR remain unaltered. This may be due to administration of half dose of flupirtine in our study.  Various opioid and nonopioid drugs have been used to reduce the dose of propofol for maintenance of optimal BIS value. Contreras-Domínguez and Carbonell-Bellolio in a study compared two different routes of administration of sufentanil and their effect on propofol consumption for maintenance of BIS.[30] Again, in another study, Choi et al.[31] found that intravenous administration of magnesium sulfate reduces propofol infusion requirements for maintenance of BIS. Here, in our study, we had found that flupirtine-treated group needed significantly less amount of propofol for the maintenance of BIS <60.  In our study, we have found that flupirtine had reduced intraoperative bleeding during FESS, and hence, surgeon's satisfaction score is much higher in this group. No any previous study had measured bleeding with the use of flupirtine in FESS. In a placebo-controlled study, Guven et al.[32] found that use of dexmedetomidine had improved the visibility in FESS by reducing bleeding as well as improved surgeon's satisfaction score. A similar type of study was conducted by Srivastava et al.[33] with the use of esmolol and found that it effectively reduced bleeding in FESS while compared with nitroglycerine.  Various studies indicate that flupirtine is well tolerated if administered on a short-term basis. Commonly observed side effects with continued administration include sedation, gastrointestinal upset, headache, disorientation, and hallucinations.[2425] In our study, nausea, vomiting, shivering, bradycardia, headache, hypotension, and dry mouth are the side effects and are comparable among two groups. We, in our study, found that sedation was arousable and are quite comparable among two groups. On the contrary, with similar dosing of flupirtine, Thapa et al.[27] found that easily arousable sedation was significantly higher in test group.  There were some limitations of our study that need discussion. One of the limitations is that we did not use a score for assessing the postoperative pain; however, the FESS is usually followed headache sensation rather than pain and it was managed successfully by IV fentanyl. We had not measured sedation score, visual analog scale score, and plasma catecholamine or stress hormone concentrations which may reveal relations with SNEPCOs and earlier discharge after their use. Another limitation is that we have used flupirtine based on their known optimal as well as safe premedicating dose for day-care setting without the knowledge of its exact optimal dose. However, a larger study with large sample size needs to be conducted to establish the author's point of view with solidarity.

BODY.C:
During ambulatory FESS, 100 mg oral flupirtine administered 60 min before induction of anesthesia is effective for providing stable hemodynamics and analgesia with smaller need of an additional hypotensive agent esmolol and analgesic agent fentanyl., Flupirtine maintains better depth of anesthesia, indicated by less requirement of intraoperative propofol. It also renders an excellent surgical field with higher surgeon's satisfaction score and lesser analgesic requirement without major hemodynamic alteration and side effects.

BODY.C.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

BODY.C.CONFLICTS OF INTEREST:
There are no conflicts of interest.

Question: Compared to Group C receiving identical-looking placebo what was the result of Group F receiving preoperative flupirtine on Side effects ?
Evidence: MAP and HR between two groups were found to be quite comparable among two groups (P > 0.05) [Figures 1 and 2].
Answer: no significant difference