Comparative study between the effect of dexmedetomidine and lidocaine infusion in lumbar fixation on hemodynamics, fentanyl requirements, and postoperative analgesia

Spinal surgery is associated with high incidence of severe postoperative pain difficult to easy control. Appropriate treatment modalities decreased the postoperative morbidity, increased patient satisfaction, allowed early mobility, and decreased hospital costs. Lidocaine was used as intravenous additives to control intraoperative pain and decrease postoperative pain. As lidocaine, dexmedetomidine infusion associated with lower postoperative pain scores decreased the opioid consumption and its related adverse events. The aim of this double blind randomized prospective comparative study was to compare the efficacy of intraoperative dexmedetomidine versus lidocaine infusion on hemodynamics, fentanyl requirements, and postoperative analgesia among 66 patients subjected to lumbar fixation surgery and randomized into group D which received dexmedetomidine 1 μg/kg infusion over 10 min as a loading dose then 0.3–0.5 μg/kg/h after induction of anesthesia as maintenance dose and group X which received lidocaine 0.3–0.5 mg/kg/h after induction of anesthesia. At 10, 15, 30, and 60 min, the mean arterial blood pressure and heart rate significantly decreased in group D compared to group X, and there was significantly higher total dose of intraoperative analgesic for fentanyl in group X than group D. There was significantly higher numeric rating scale in group X compared to group D at 2, 4, 6, 9, 12, 18, and 24 h postoperative with significant early request of the first analgesia, higher incidence of analgesic needs, and higher dose of postoperative analgesia paracetamol, voltaren, or pethidine in group X compared to group D. The intraoperative use of dexmedetomidine IV infusion was an alternative mode to decrease the demands of analgesia following spine surgery.


Background
Postoperative pain is one of the most common complications after surgery and associated with higher incidence of nausea and vomiting, increased risk of thromboembolic manifestation, and postoperative cognitive dysfunction. Opioid medications were used commonly to control postoperative pain, but it was associated with higher risk of side effects mainly nausea and constipation (Hurley and Wu 2010).
Dexmedetomidine was a selective alpha 2 agonist as clonidine, but it has a greater affinity to the alpha 2 receptor with hypnotic properties similar to natural sleep and effectively attenuates the stress response to the surgical intervention with minimal or no respiratory depression complication. Also, maintained hemodynamic stability through its function on the central and peripheral alpha 2 receptors leads to reduction of heart rate and the systemic vascular resistance (Bos et al. 2017).
Perioperative lidocaine infusion is commonly used as analgesic adjunct in enhanced recovery protocols for patients undergoing lumbar fixation surgeries and open and laparoscopic colorectal surgeries to control the intraoperative and postoperative pain scores, decrease opioid consumption, and shorten length of hospital stay and increase patients comfort (Terkawi et al. 2016).
Intravenous lidocaine infusion blockade of the neuronal transmission at the site of injury. Also, it has significant anti-inflammatory properties, reducing the release of cytokines; reduced cytokine-induced cellular damage mediated through mitochondrial adenosine triphosphate (ATP)gated potassium channels by reducing neutrophil activation decreases intraoperative consumption of inhalational anesthetics and opioids which associated with early return of bowel function (Hollmann and Durieux 2000).
The aim of this study was to compare the efficacy of intraoperative dexmedetomidine versus lidocaine infusion on hemodynamics, fentanyl requirements, and postoperative analgesia.

Methods
This is a double blind randomized prospective comparative study conducted from October 2018 to September 2019 on 66 adult patients from 40 to 60 years, from both sex, American Society of Anesthesiologist (ASA) physical status 1-2, within average body weight, undergoing primary lumbar fixation surgery with 3 h duration of surgery, randomized into 2 equal groups, each consisting of 33 patients, namely, group D in which patients received dexmedetomidine 1 μg/kg infusion over 10 min as a loading dose then 0.3-0.5 μg/kg/h after induction of anesthesia as maintenance dose and group X which included patients who received lidocaine 0.3-0.5 mg/kg/h after induction of anesthesia till the end of the operation after approval of the Ethical Committee and written informed consent from all participants were obtained.
Exclusion criteria included patients with history of allergy to dexmedetomidine and lidocaine, presence of significant dysfunction (cardiovascular, neurological, respiratory, hepatic and/or renal problems) (ASA 3-4), patients with any abnormal vital signs especially hypotension and/or bradycardia, polytrauma patients, patients who refused to participate, addict patient, and pregnant female.
All patients were subjected to history taking, clinical examination, and routine investigations according to their medical history performed.
Four syringes were prepared and coded by a clinical pharmacist and statistician; 2 of them for loading dose one contains 100 μg of dexmedetomidine diluted in 50 cc normal saline infusion, and the other contains 50 cc normal saline. The last 2 syringes were for maintenance; one of them contains 200 μg of dexmedetomidine diluted in 50 cc normal saline (the concentration were 4 μg /ml), and the other contains 200 mg of lidocaine diluted in 50 cc normal saline (the concentration was 4 mg/ml) infusion. Participating patients were randomly allocated to the different groups using computer-generated software, results concealed in opaque, sealed envelopes.
Patients were kept fasted, as per the American Society of Anesthesiologists physical status guidelines. All patients were premedicated with midazolam 1-2 mg i.v. at the preparation room before admitted to operation room. Upon arrival to the operating room, standard monitoring equipment was attached [an electrocardiogram leads II and V5, a pulse oximeter and entropy electrodes, and a noninvasive blood pressure monitor]. Baseline vital parameters, such as heart rate (HR) and mean arterial blood pressure (MAP), were noted prior to induction of anesthesia.
Begin giving loading dose dexmedetomidine 1 μg/kg infusion over 10 min in group D. Then, anesthesia was induced by administration of 2 mg/kg intravenous propofol and 2 μg/kg fentanyl. Endotracheal intubation was facilitated by intravenously injecting 0.5 mg/kg atracurium. Anesthesia was maintained using oxygen [O 2 ], with isoflurane (1.2-1.5%), and capnogram was attached. Then, top up doses atracurium guided by nerve stimulator (train of four (TOF) 0.15-0.25 indicates adequate surgical relaxation) to maintain neuromuscular relaxation. Lungs were mechanically ventilated to keep the end tidal carbon dioxide (ETCO 2 ) within 35-40 mmHg.
After intubation, patients who were in group D received dexmedetomidine 0.3-0.5 μg/kg/h as maintenance dose. And group X received lidocaine 0.3-0.5 mg/ kg/h after induction of anesthesia until the end of the operation. Give fentanyl 0.5-1 μg/kg if HR increased or mean blood pressure increase > 20% of baseline after exclusion of other causes of tachycardia (bleeding, dehydration, awareness).
At the end of surgery, inhalational anesthesia was discontinued at beginning of skin closure, and infusion was stopped at the end of operation. Patients were turned to the supine position, and the neuromuscular block was reversed using neostigmine [0.05 mg/kg] and atropine [0.001 mg/kg]. The endotracheal tube was removed when the patients met the criteria of extubation (return of gag reflex, facial grimace, and purposeful motor movements) and were transferred to the post-anesthesia care unit. Patients were then discharged from the postanesthesia care unit (PACU) when an Aldrete score > 9 was achieved.
The outcomes included assessment of the vital signs, blood pressure and heart rate, 5 min and 10 min, after beginning infusion then every 30 min intraoperative. Assessment of pain was by the Numeric Rating Scale (NRS-11) that is an 11-point scale for patient selfreporting of pain (Frattali 1999) immediately postoperative, then at 1st 24 h, every 2 h in the 1st 6 h, every 3 h in the 2nd 6 h, and every 6 h in the remaining 12 h; number of patients required postoperative rescue analgesia, first time of rescue analgesia, and total consumption of rescue analgesia either intraoperative or postoperative were documented. Patient with mild pain received paracetamol (15 mg/kg), patient with moderate pain received NSAID, and patient with severe pain received pethidine (50 mg IV). And assessment of the sedation level post-operative was carried out by modified Ramsay Sedation Scores (RSS).
Incidence of bradycardia, hypotension, and vomiting was recorded and treated probably. Infusion was stopped if HR < 50 and give atropine (0.01 mg/kg) repeated if needed or hypotension by decreasing mean blood pressure > 30% of baseline and give ephedrine (5 mg IV bolus) and repeated if needed. Patient with nausea and vomiting received 1-2 mg granisetron.

Statistical analysis
Sample size was calculated using PASS® version 11 program, setting the type-1 error (α) at 0.05 and power at 80%. Results from a previous study of Talke et al. (Talke et al. 2000) reported that heart rate was slower with dexmedetomidine (73 ± 11 bpm) than control (83 ± 20 bpm). Calculation according to these values produced a minimal sample size of 33 cases per group, estimated effect size according to Cohen's d = (83 − 73)/16.140012 = 0.619578.
Our data were analyzed using the Statistical Package for Social Sciences, version 20.0 (SPSS Inc., Chicago, IL, USA). Quantitative data were expressed as mean ± standard deviation (SD). Qualitative data were expressed as frequency and percentage. Independent sample t test of significance was used when comparing between two means, and Mann-Whitney U test for non-parametric data between two-groups. Chi-square (χ 2 ) test of significance was used to compare proportions between qualitative parameters. The confidence interval was set to 95%, and the margin of error accepted was set to 5%. So, the p value ≤ 0.05 was considered significant, p value ≤ 0.001 was considered as highly significant, and p value > 0.05 was considered insignificant.

Results
One hundred patients were assessed for eligibility, 34 patients were not excluded nor met inclusion criteria, and remaining 66 patients were randomly divided to one of each group (Fig. 1). In the current study, the majority of  (Table 1).
In the current study, at 10, 15, 30, and 60 min, the mean arterial blood pressure and heart rate significantly decreased in group D compared to group X as p = 0.037, 0.029, 0.009, and 0.018, respectively for MAP and 0.041, 0.014, 0.013, and 0.026 respectively for HR (Figs. 2 and 3). Table 2 shows a highly statistically significant higher mean value of group X compared to group D according to total dose of intraoperative analgesic for fentanyl.
There was statistically significant higher mean value of numeric rating scale in group X compared to group D at 2, 4, 6, 9, 12, 18, and 24 h postoperative, as p = 0.035, 0.032, 0.020, 0.026, 0.009, 0.025, 0.024 respectively (Fig. 4). Table 3 shows statistically significant short time of mean value of group X compared to group D according to time of first analgesia (min).
Also, there was statistically significant difference between groups according to needs for analgesia as in group D; 57.6% of cases required one dose, versus (100%) in group X, with statistically significant difference between groups according to needs for analgesia (Table 4).

Discussion
In the current study, we described the use of intraoperative dexmedetomidine versus lidocaine infusion in lumbar fixation surgery at 10, 15, 30, and 60 min; the mean arterial blood pressure and heart rate significantly decreased in group D compared to group X. This may be Fig. 3 Comparison between group D and group X according to heart rate (beat/min) explained by binding of dexmedetomidine to α2adrenoreceptors within the peripheral and central nervous systems in either pre-, post-, and extra-synaptic sites which in turn decreased the norepinephrine release also hypotension resulting from vasodilatation associated with dexamedetomedine is mediated through three α2-adrenoreceptors (α2a, α2b, and α2c) within the vascular endothelial cells respond by causing a. Also, the centrally located α2a and α2c adrenoreceptors had an important role in development of hypotension associated with dexmedetomidine. As regard to lidocaine, it has a stabilizing effect on the heart and blood pressure, possibly by direct myocardial depressant effect, a peripheral vasodilating effect, and through its anti-inflammatory activity, but this effect is less potent than dexmedetomidine (Weerink et al. 2017).
In harmony with our finding, Anis et al. found that dexmedetomidine attenuation of the HR was statistically highly significant compared with that of lidocaine (L), as the maximum increase in the mean values of the HR in group L was less than 20% from the baseline value and was not associated with a significant increase in the mean values of the MAP, and this may be explained by different surgical procedures in their study (Anis et al. 2016).
Similarly, Prasad et al., found that there was fall in HR and MAP when compared to the baseline value. Compared to group L, fall in HR and MAP was highly significant in group D (dexmedetomidine) (p = 0.000) (Prasad et al. 2015).
In contrast, among 90 female patients who underwent elective abdominal gynecological surgeries and were enrolled in the Menshawi and Fahim, the MAP and HR had no significant difference between groups D and L (Menshawi and Fahim 2019).
In the current study, the total dose of intraoperative analgesic for fentanyl was significantly higher in group X than group D. This was explained by the anesthetic and opioid-sparing effects of dexmedetomidine (Dunn et al. 2016).
Moharram and Mostafa enrolled 60 patients scheduled for elective lumbar spine instrumentation divided into (group C) who received placebo and dexmedetomidine group (group D) and found a significant reduction in intraoperative fentanyl consumption by dexmedetomidine Fig. 4 Comparison between group D and group X according to numeric rating scale Table 3 Comparison between group D and group X according to time of first analgesia (min) Also, Menshawi and Fahim found no significant difference between groups L and D in the total intraoperative fentanyl consumption (Menshawi and Fahim 2019).
In the present study, at 2, 4, 6, 9, 12, 18, and 24 h postoperative, the numeric rating scale was significantly higher in group X compared to group D mediated by dexmedetomidine binding to the central and spinal cord α2-receptors which resulted in decreased substance P and glutamate release (Weerink et al. 2017).
Similarly, Andjelković et al. found that the distribution of the average VAS differed significantly between dexmedetomidine group (DG) and lidocaine group (LG) (p = 0.028) and between control group (CG) and LG (p = 0.023) (Andjelković et al. 2018). In contrast, according to Cho et al., no significant difference was observed in VAS score among group L and group D during the first 24 h after LC (Cho et al. 2014).
In the present study, the time to first analgesic was statistically significantly delayed in group D than group X. Also, there was significantly higher incidence of requesting analgesia in group X. Similarly, Manne et al. observed an increase in the time to receive first rescue analgesia, with a decrease in total analgesic requirements in the first 24 postoperative hours among patients who received dexmedetomidine infusion (Manne et al. 2014).
In agreement with our results, according to Menshawi and Fahim, the time to the first postoperative analgesic requirement was significantly longer in group D when compared with groups L and C (Menshawi and Fahim 2019).
But in the study by Bakan et al., they found that intraoperative administration of the intravenous dexmedetomidine and lidocaine was associated with decreased postoperative opioid use in laparoscopic cholecystectomy and delayed the first rescue analgesia up to 6 h postoperatively compared with conventional opioidbased anesthesia (Bakan et al. 2015).
In this study, the required dose of postoperative analgesia paracetamol, voltaren, or pethidine in group X was significantly higher than in group D. Dexmedetomidine contains analgesic properties therefore reducing opioid requirements intraoperatively as well as postoperatively. The present study is supported by previous studies; the intravenous dexmedetomidine infusion reduced the requirement for fentanyl in the PACU (Park et al. 2012;Kaur and Singh 2011;Feld et al. 2006).
Similarly, Garg and colleagues found a 54% decrease in opioid requirement post-operatively when dexmedetomidine was used (Garg et al. 2016).
But discordances with study by Anis et al. found that the total dose of pethidine given to patients in both lidocaine and dexmedetomidine groups was less than 50 mg, and this was statistically non-significant (Anis et al. 2016).
Limitation of this study included small sample size; we did not measure the serum level of lidocaine as the loading and maintenance dose was similar to previous studies that reported no detectable side effects. Also, the effect of both drugs was not seen in hypertensive and cardiac patients as those patients were excluded from the study although they have apriority of pain control, and pain assessment was done only at rest only in this study and not during active movement.
Further studies on a larger sample size were recommended, and using different doses of both drugs may be helpful to detect an optimal dose of lidocaine and dexmedetomidine. It will be more useful to study in highrisk hypertensive and cardiac patients and to correlate between uses of either drugs and plasma catecholamine levels, which reflected the stress response, and it was necessary to evaluate postoperative pain on movement in farther studies.

Conclusion
Our results suggest the unique role of dexmedetomidine infusion added to routine general anesthesia in significantly decreased postoperative pain intensity and decreased the need for rescue analgesics than lidocaine infusion, among patients that underwent lumbar fixation surgery.