Effect of Dexmedetomidine Administation on Analgesic, Respiration and Inammatory Responses in Patients Undergoing Percutaneous Endoscopic Lumbar Discectomy: A Prospective Observational Study

pulse was measured by The visual and the plasma levels of interleukin-6 (IL-6), (TNF-α), (MDA) and glutathione peroxidase (GSH-PX) also recorded to evaluate


Abstract
Background Local anesthesia has been recommended for percutaneous endoscopic lumbar discectomy (PELD) in recent years; however, the e cacy, including oxidative stress, in ammatory reactions and ventilation effects, when intravenous dexmedetomidine (DEX) is administered during PELD has not been thoroughly described.

Methods
Sixty patients undergoing PELD were randomly allocated to either an intravenous DEX sedation group (Group A) or a normal saline group (Group B). Respiratory data, including minute ventilation (MV), tidal volume (TV), and respiratory rate (RR), were recorded using a respiratory volume monitor (RVM), and pulse oxygen saturation (SpO 2 ) was measured by pulse oximetry. The visual analog score (VAS) and the plasma levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) were also recorded to evaluate oxidative stress and in ammatory reactions.

Results
There were no signi cant differences in RR, MV, TV and SpO 2 between the two groups at any time point (p>0.05). Group B exhibited lower serum levels of GSH-PX (p<0.0001) and higher serum levels of MDA (p<0.0001) than Group A at the end of surgery. Twenty-four hours after surgery, Group B exhibited higher serum levels of IL-6 (p=0.0033), TNF-α(p=0.0002), and MDA (p<0.0001) and lower serum levels of GSH-PX (p<0.0001) than Group A. In addition, Group B exhibited lower VAS (p<0.0001) than Group A.
Conclusions DEX administration using an RVM not only provides convenient analgesia and ventilation but also alleviates oxidative stress and in ammatory reactions in patients undergoing PELD .
Trial registration ChiCTR2100044715(http://www.chictr.org.cn/index.aspx) Background As a standard full-endoscopic surgical strategy for the treatment of lumbar disc herniation, percutaneous endoscopic lumbar discectomy (PELD) has become an alternative minimally invasive procedure to open lumbar microdiscectomy [1][2][3]. In PELD, patients are placed in the prone position, and the loose herniated nucleus pulposus is clipped out under endoscopic guidance with continuous irrigation. Local anesthetic in ltration (LAI) is recommended for PELD by most surgeons because it can detect nerve root injuries in time; however, under LAI, some patients cannot tolerate the pain caused by the instrument insertion, resulting in operative anxiety, pain-induced stress and in ammatory reactions. Then, opioids are added to prevent these conditions from occurring; this creates a challenge for anesthesiologists to assess the airway of patients in the prone position, so the implications of LAI in PELD remain contentious [4].
Dexmedetomidine (DEX), a new-generation, highly selective α 2 adrenergic receptor agonist, is widely used in spine surgery due to its e cacy to achieve equilibrium between an effective analgesia and sedation regimen, and its minimal effect on the respiratory system [5][6][7]. However, the e cacy of DEX administation combined with LAI during PELD has not been thoroughly described.
Oxidative stress and in ammatory reactions are two major risk factors among the serious complications impacting patient outcomes and recovery [8]. Perioperative arrangements, such as alleviating oxidative stress and in ammatory reactions, can contribute to lowering the occurrence of organ dysfunction. To better implement the concept of enhanced recovery after surgery (ERAS), it is particularly important to optimize the anesthesia method. Therefore, this study investigated the effect of respiration, oxidative stress, and in ammatory reactions to determine the superiority of intravenous DEX.

Study Design, Settings, and Patients
This prospective, randomized trial was approved by the Medical Ethics Committee of the First This study included adult patients with American Society of Anesthesiologists physical status (ASA) I/II who were scheduled to undergo elective PELD from June 2018 to March 2021. Patients with contraindications to LAI, allergies to any of the drugs planned to be administered, infection at the puncture site, or who had previous spine surgery, severe spinal stenosis, morbid cardiovascular impairments including preexisting heart block or compromised left ventricular function (de ned as an ejection fraction <45%) were excluded from the study. Surgeons and anesthesiologists were aware of the study being conducted but were blind to participant allocation.

Study Protocol
Patients were assigned randomly to receive either intravenous DEX sedation throughout the surgery (Group A) or the same volume of normal saline intravenously (Group B) using a computer-generated table of random numbers. The patient's group allocation was concealed using a sequentially numbered, sealed opaque envelope, which was opened only by a separate investigator who prepared the anesthetic solution before the surgery. The operations were performed by a single experienced surgeon (blinded to the study protocol) using the same technique. Intravenous access was secured before the patient's arrival in the operating room.
In the operating room, standard monitoring was applied. DEX was diluted with normal saline to obtain a concentration of 4 µg·mL -1 , patients received 1 µg·kg -1 of intravenous DEX for 10 min as a loading dose, followed by continuous infusion at a rate of 0.5 µg·kg -1 ·h -1 throughout the surgery (Group A), and patients in Group B received the same volume of normal saline. After the infusion of the loading dose, all patients received LAI in the surgical site using 10 ml of 1% lidocaine (Suicheng Industrial, China) and 10 ml of 0.75% ropivacaine (Qilu Industrial, China) by the same surgeon. Intravenous DEX or normal saline administration was stopped at the start of skin closure.
An administration-approved, noninvasive, bioimpedance-based respiratory volume monitor (RVM; ExSpiron, Respiratory Motion, Inc., Waltham, MA) was used to provide real-time respiratory data, including minute ventilation (MV), tidal volume (TV), and respiratory rate (RR). The predicted MV (MV PRED ) for nonintubated patients, representing the expected MV during quiet respiration in the awake period, was calculated based on body surface area (BSA) and patient sex. The RVM collected bioimpedance traces via an electrode padset placed in the recommended positions: at the sternal notch, xiphoid, and right midaxillary line at the level of the xiphoid. The electrode padset was applied in a fashion similar to that of standard electrocardiogram electrodes.
Intraoperative hypotension (de ned as a >20% decrease in systolic pressure from baseline) was treated with 5-10 mg of intravenous ephedrine; bradycardia (de ned as a heart rate <45 beats min -1 ) was treated with 0.5 mg of intravenous atropine; and respiratory depression (an MV less than 40% of the MV PRED, sustained for a period of 1 minute or longer) was treated with endotracheal intubation for respiratory support.

Measurement Values
Data were recorded as the primary outcomes, including the SpO 2 , MV, VT, and RR at the following time points: T 0 , baseline; T 1 , 10 min after the start of intravenous DEX; T 2 , before the skin incision; T 3 , after the skin incision; T 4 , 30 min after surgery; T 5 , at the end of surgery; and T 6 , 24 hours after surgery. Venous blood samples were taken at T 0 , T 5 and T 6 to detect serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF-α) by enzyme-linked immunosorbent assay (ELISA), and malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) by colorimetric methods. The patients were asked to assess their level of pain during the procedure using a visual analog scale (VAS), which ranged from 0 (no pain) to 10 (worst possible pain), from T 2 to T 5.

Statistical Analyses
Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). Data are expressed as the mean ± standard deviation or the median (interquartile range). Data were analyzed using repeated-measures analysis of variance (ANOVA), and intergroup differences at the same time point were analyzed using a two-sample t test. A p< 0.05 was considered to indicate a statistically signi cant difference.

Results
Initially, a total of 65 patients were enrolled, and 5 patients were excluded after applying the exclusion criteria: 2 patients refused to provide informed consent, and 3 patients had severe hypertension or diabetes. A total of 60 subjects were divided by simple randomization to complete the study and were analyzed (Figure 1). There were no signi cant differences between the two groups in baseline characteristics (Table 1).

Respiratory Variations
To assess the effects of procedural sedation using intravenous DEX on the patients' respiratory drive when patients were placed in the prone position, the respiratory parameters (MV, TV, RR and SpO 2 ) measured during PELD were analyzed. Figure 2

Comparison of VAS
There was no signi cant difference in the VAS at T 0 between the 2 groups (p>0.05); however, compared with Group B, there were signi cantly lower VAS from T2-T5 in Group A (p<0.0001) (

Serum concentrations of GSH-PX, MDA, IL-6 and TNF-α
There was no signi cant difference in T 0 (the baseline in ammatory reactions and oxidative stress) between the 2 groups (p > 0.05). Compared with T 0 , the levels of GSH-PX, MDA, IL-6 and TNF-α in both groups increased at T 5 and T 6 (p<0.05). Compared with Group B, the levels of GSH-PX in Group A were signi cantly higher at T 5 and T 6 (p < 0.001) and serum levels of MDA were lower at T 5 and T 6 (p < 0.001).
No patients required endotracheal intubation for respiratory support, and no cases of MV less than 40% of the MV PRED that were sustained for a period of 1 minute or longer.

Discussion
This study demonstrated that the effect of DEX administation in non-intubated, spontaneously breathing patients undergoing PELD was safe and effective, although the patients were prone-positioned. Meanwhile, intravenous DEX could alleviate oxidative stress response and in ammatory reactions,which is of great signi cance for the concept of ERAS.
A novel RVM has been developed to continuously measure and display the MV, TV, and RR to monitor ventilation clinically, and a previous study demonstrated the accuracy of the RVM when compared with ventilators, as well as the accuracy of the RVM when compared to spirometry measurements [9]. DEX is excellent at preserving airway patency and preventing respiratory compromise, but the result was based on SpO 2 instead of MV, emphasizing the need for continuous ventilation monitoring in nonintubated patients [10]. Respiratory parameters were quanti ed during the administration of midazolam and propofol and the postoperative administration of opioids, but there was a lack of data during the administration of intravenous DEX [11][12][13]. In our study, we found that compared with T 0 , the MV, TV, and RR values of the two groups largerly declined from T 1 to T 4 , which may be related to the prone position resulting in chest and abdominal organ compression, impaired diaphragmatic activity and reduced ventilation. Ventilation parameters, including the MV, TV and RR, presented a downward trend but were accompanied by a normal range of SpO 2, and we noted that the remarkable improvement in SpO 2 lacked clinical signi cance.
Respiratory depression was de ned as an MV below 40% of the MV PRED for 1 minute or more, the criteria for a low MV (below 40% of the MV PRED ) were originally based on the Acute Respiratory Distress Syndrome Network protocol [14], and previous studies have demonstrated that real-time MV measurements can be used to risk-stratify patients in the post-anesthesia care unit (PACU), where patients with an MV less than 80% of their predicted MV prior to opioid administration had reductions to a critical level of less than 40% of the predicted MV after opioid administration [12,15]. Similarly, we propose that it is feasible to identify the risk, and there were no patients with an MV less than 40% of their MV PRED that was sustained for a period of 1 minute or longer in this study, which reveals that intravenous DEX is less likely to result in respiratory depression when patients are in the prone position.
To the best of our knowledge, this is the rst ventilation monitoring study using an RVM to assess the respiratory status of patients receiving intravenous DEX. The advantage of using an RVM is that respiratory data can be monitored stably and reliably without patient discomfort, regardless of their body movements or position.
DEX has been recently used for procedural sedation, and the bene ts and risks during PELD remain undetermined. Epidural anesthesia (a low concentration of ropivacaine) and LAI, instead of general anesthesia, were recommended by most surgeons for PELD because the surgeon can still obtain feedback from the patient to avoid nerve injury [16]. Our study demonstrated that no signi cant difference was found in neurological complications between the two groups, which con rms the safety of DEX. DEX exerts its hypnotic action through the selective activation of central pre-and postsynaptic alpha-2 adrenergic receptors in the locus coeruleus. Akeju et al. assumed that the altered arousal states induced with the administration of DEX neurophysiologically approximate natural sleep, and he termed this "biomimetic sleep" [17]. The pharmacological effect that produces biomimetic sleep makes it suitable for surgeons to obtain feedback from the patient to avoid nerve injury. As the result shown above, the administation of DEX did not increase the risk of cerebrospinal uid leakage, nerve root injury, intraspinal hematoma, postoperative neuritis or other related complications.
In addition, stress, such as from surgical procedures and intraoperative pain, can cause the release of a large number of in ammatory factors, such as TNF-α and IL-6, further activating neutrophils and monocytes, which can indirectly lead to neurological dysfunction [8]. The level of in ammatory factors in the internal environment can directly re ect the stress state of the organism. When the level of oxidative stress in the body is signi cantly increased, the body will release a large amount of antioxidant enzymes such as MDA, GSH-PX and catalase. These antioxidant enzymes can resist oxidative stress and prevent the body from being damaged by oxidative stress. This study shows that DEX can markedly attenuated the increases in IL-6, TNF-α and MDA, meanwhile, DEX signifcantly increase the production of GSH-PX. The signi cant reduction in the VAS in Group A reveals that DEX could provide ideal analgesia during PELD so as to attenuate in ammatory response and pain-induced oxidative stress. DEX can activate the alpha-2 adrenergic receptor and consequently activate cholinergic transmitters to alleviate the in ammatory response; moreover, DEX can reduce the levels of in ammatory factors by inhibiting the activation of the NF-κB/Toll-like receptor signaling pathway, and perioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. [18,19] Conclusion DEX administration prevented the incidence of respiratory depression in the patients who underwent PELD, without serious side effects. It also providse ideal analgesia so as to alleviate oxidative stress and in ammatory reactions. Therefore, we recommend the use DEX in patients undergoing PELD.

Declarations
Funding Bureau of science and Technology of Ganzhou Municipality(GZ2020ZSF010) as well as the First a liated hospital of Gannan Medical University(YJYB202007) Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate Initially, a total of 65 patients were enrolled, and 5 patients were excluded after applying the exclusion criteria: 2 patients refused to provide informed consent, and 3 patients had severe hypertension or diabetes. A total of 60 subjects were divided by simple randomization to complete the study and were analyzed Figure 2 summarizes the recorded trends in MV, TV, RR and SpO 2, and the variables for MV, TV, RR and SpO 2 showed signi cant differences over time between the groups (p<0.001). There were no signi cant differences between the two groups in MV, TV, RR or SpO 2 at any time point (p>0.9999).

Figure 3
There was no signi cant difference in T 0 (the baseline in ammatory reactions and oxidative stress) between the 2 groups (p > 0.05). Compared with T 0 , the levels of GSH-PX, MDA, IL-6 and TNF-α in both groups increased at T 5 and T 6 (p<0.05). Compared with Group B, the levels of GSH-PX in Group A were signi cantly higher at T 5 and T 6 (p < 0.001) and serum levels of MDA were lower at T 5 and T 6 (p < 0.001).
In addition, Group A exhibited lower serum levels of IL-6 (p=0.0033) and TNF-α(p=0.0002) at T 6 than Group B