Perioperative Hypotension in Patients Undergoing Orthopedic Upper Extremity Surgery with Dexmedetomidine Sedation: A Retrospective Study.

(1) Background: limited data exist regarding the occurrence of hypotension associated with dexmedetomidine use and its risk factors in the context of intraoperative sedation for patients receiving peripheral nerve blocks. (2) Method: This single-center retrospective study assessed the incidence of hypotension in patients undergoing orthopedic upper extremity surgery with brachial plexus blockade. Patients were classified into three groups: group N (non-sedated), group M (midazolam), and group D (dexmedetomidine), based on their primary intraoperative sedative use. The primary outcome was the incidence of perioperative hypotension, defined as systolic blood pressure (SBP) < 90 mmHg or mean blood pressure (MBP) < 60 mmHg, at a minimum of two recorded time points during the intraoperative period and post-anesthesia care unit stay. Multivariable logistic models for the occurrence of hypotension were constructed for the entire cohort and group D. (3) Results: A total of 2152 cases (group N = 445, group M = 678, group D = 1029) were included in the analysis. The odds ratio for the occurrence of hypotension in group D was 5.68 (95% CI, 2.86 to 11.28) compared with group N. Concurrent use of a beta blocker, longer duration of surgery, and lower preoperative SBP and higher preoperative heart rate were identified as significant risk factors. (4) Conclusions: the increased risk of hypotension and the associated factors should be taken into account before using dexmedetomidine in these cases.

Optimal view detection for ultrasound-guided supraclavicular block using deep learning approaches.

Successful ultrasound-guided supraclavicular block (SCB) requires the understanding of sonoanatomy and identification of the optimal view. Segmentation using a convolutional neural network (CNN) is limited in clearly determining the optimal view. The present study describes the development of a computer-aided diagnosis (CADx) system using a CNN that can determine the optimal view for complete SCB in real time. The aim of this study was the development of computer-aided diagnosis system that aid non-expert to determine the optimal view for complete supraclavicular block in real time. Ultrasound videos were retrospectively collected from 881 patients to develop the CADx system (600 to the training and validation set and 281 to the test set). The CADx system included classification and segmentation approaches, with Residual neural network (ResNet) and U-Net, respectively, applied as backbone networks. In the classification approach, an ablation study was performed to determine the optimal architecture and improve the performance of the model. In the segmentation approach, a cascade structure, in which U-Net is connected to ResNet, was implemented. The performance of the two approaches was evaluated based on a confusion matrix. Using the classification approach, ResNet34 and gated recurrent units with augmentation showed the highest performance, with average accuracy 0.901, precision 0.613, recall 0.757, f1-score 0.677 and AUROC 0.936. Using the segmentation approach, U-Net combined with ResNet34 and augmentation showed poorer performance than the classification approach. The CADx system described in this study showed high performance in determining the optimal view for SCB. This system could be expanded to include many anatomical regions and may have potential to aid clinicians in real-time settings.Trial registration The protocol was registered with the Clinical Trial Registry of Korea (KCT0005822, https://cris.nih.go.kr ).

Comparative effects of desflurane and sevoflurane on intraoperative peripheral perfusion index: a retrospective, propensity score matched, cohort study.

Desflurane is known to have a larger vasodilatory effect than that of sevoflurane. However, its generalizability and effect size in actual clinical practice are yet to be proven. Patients aged ≥ 18 years who underwent noncardiac surgery under general anesthesia using inhalation anesthetics (desflurane or sevoflurane) were matched 1:1 by propensity score. The mean intraoperative perfusion index (PI) of each patient were compared between the two groups. Propensity score matching of 1680 patients in the study cohort identified 230 pairs of patients. PI was significantly higher in the desflurane group (median of paired difference, 0.45; 95% CI 0.16 to 0.74, p = 0.002). PI durations below 1.0 and 1.5 were significantly longer in the sevoflurane group. Mean arterial pressure (MAP) and durations of low MAP did not differ significantly between the two groups. Generalized linear mixed models revealed that the use of sevoflurane, mean MAP, mean heart rate, age, and duration of anesthesia had significant negative effects (lower PI), whereas mean age-adjusted minimum alveolar concentration of inhalation agent had a positive effect on PI (higher value). Intraoperative PI was significantly higher in patients administered desflurane than sevoflurane. However, the impact of the choice between desflurane and sevoflurane on intraoperative PI in this clinical setting was minimal.

Hemidiaphragmatic paralysis following costoclavicular versus supraclavicular brachial plexus block: a randomized controlled trial.

Costoclavicular brachial plexus block is emerging as a promising infraclavicular approach performed just below the clavicle. However, there are relatively little data regarding the hemidiaphragmatic paralysis (HDP) compared to the commonly performed supraclavicular block. We hypothesized that the incidence of HDP in costoclavicular block is lower than supraclavicular block like classical infraclavicular approach. Eighty patients were randomly assigned to ultrasound-guided supraclavicular (group S) or costoclavicular (group C) block with 25 mL of local anesthetics (1:1 mixture of 1% lidocaine and 0.75% ropivacaine). The primary outcome was the incidence of HDP, defined as less than 20% of fractional change in the diaphragm thickness on ultrasound M-mode. Also, pulmonary function test and chest radiograph were assessed before and after the surgery. The incidence of HDP was 4/35 (11.4%) in the group C and 19/40 (47.5%) in the group S (risk difference, - 36%; 95% CI - 54 to - 17%; P = 0.002). The mean (SD) change of DTF values were 30.3% (44.0) and 56.9% (39.3) in the group C and S, respectively (difference in means, - 26.6%; 95% CI - 45.8 to - 7.4%; P = 0.007). The pulmonary function was more preserved in group C than in group S. The determined diagnostic cut off value of the diaphragm elevation on chest radiograph was 29 mm. Despite the very contiguous location of the two approaches around the clavicle, costoclavicular block can significantly reduce the risk of HDP compared with supraclavicular block.

Costoclavicular brachial plexus block reduces hemidiaphragmatic paralysis more than supraclavicular brachial plexus block: retrospective, propensity score matched cohort study.

BACKGROUND: Hemidiaphragmatic paralysis, a frequent complication of the brachial plexus block performed above the clavicle, is rarely associated with an infraclavicular approach. The costoclavicular brachial plexus block is emerging as a promising infraclavicular approach. However, it may increase the risk of hemidiaphragmatic paralysis because the proximity to the phrenic nerve is greater than in the classical infraclavicular approach. METHODS: This retrospective analysis compared the incidence of hemidiaphragmatic paralysis in patients undergoing costoclavicular and supraclavicular brachial plexus blocks. Of 315 patients who underwent brachial plexus block performed by a single anesthesiologist, 118 underwent costoclavicular, and 197 underwent supraclavicular brachial plexus block. Propensity score matching selected 118 pairs of patients. The primary outcome was the incidence of hemidiaphragmatic paralysis, defined as a postoperative elevation of the hemidiaphragm > 20 mm. Factors affecting the incidence of hemidiaphragmatic paralysis were also evaluated. RESULTS: Hemidiaphragmatic paralysis was observed in three patients (2.5%) who underwent costoclavicular and 47 (39.8%) who underwent supraclavicular brachial plexus blocks (P < 0.001; odds ratio, 0.04; 95% confidence interval, 0.01-0.13). Both the brachial plexus block approach and the injected volume of local anesthetic were significantly associated with hemidiaphragmatic paralysis. CONCLUSIONS: The incidence of hemidiaphragmatic paralysis is significantly lower with costoclavicular than with supraclavicular brachial plexus block.

The mTOR Inhibitor Rapamycin Prevents General Anesthesia-Induced Changes in Synaptic Transmission and Mitochondrial Respiration in Late Postnatal Mice.

Preclinical animal studies have continuously reported the possibility of long-lasting neurotoxic effects after general anesthesia in young animals. Such studies also show that the neurological changes induced by anesthesia in young animals differ by their neurodevelopmental stage. Exposure to anesthetic agents increase dendritic spines and induce sex-dependent changes of excitatory/inhibitory synaptic transmission in late postnatal mice, a critical synaptogenic period. However, the mechanisms underlying these changes remain unclear. Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway, an important regulator of neurodevelopment, has also been shown to induce similar changes during neurodevelopment. Interestingly, previous studies show that exposure to general anesthetics during neurodevelopment can activate the mTOR signaling pathway. This study, therefore, evaluated the role of mTOR signaling after exposing postnatal day (PND) 16/17 mice to sevoflurane, a widely used inhalation agent in pediatric patients. We first confirmed that a 2-h exposure of 2.5% sevoflurane could induce widespread mTOR phosphorylation in both male and female mice. Pretreatment with the mTOR inhibitor rapamycin not only prevented anesthesia-induced mTOR phosphorylation, but also the increase in mitochondrial respiration and male-dependent enhancement of excitatory synaptic transmission. However, the changes in inhibitory synaptic transmission that appear after anesthesia in female mice were not affected by rapamycin pretreatment. Our results suggest that mTOR inhibitors may act as potential therapeutic agents for anesthesia-induced changes in the developing brain.

Effects of magnesium chloride on rocuronium-induced neuromuscular blockade and sugammadex reversal in an isolated rat phrenic nerve-hemidiaphragm preparation: An in-vitro study.

BACKGROUND: Magnesium potentiates the effects of nondepolarising muscle relaxants. However, few studies have used magnesium chloride (MgCl2). Sugammadex reverses neuromuscular block by steroidal nondepolarising muscle relaxants. OBJECTIVES: To assess the effects of MgCl2 on rocuronium-induced neuromuscular blockade and its reversal by sugammadex. DESIGN: In-vitro experimental study. SETTING: Animal laboratory, Asan Medical Center, Seoul, South Korea, from 20 March 2016 to 3 April 2016. ANIMALS: Forty male Sprague Dawley rats. INTERVENTION: Left phrenic nerve-hemidiaphragms from 40 Sprague Dawley rats were allocated randomly to four groups (1, 2, 3 and 4 mmol l MgCl2 group, n = 10 each). Rocuronium was administered cumulatively until the first twitch of train-of-four (TOF) disappeared completely. Then, equimolar sugammadex was administered. MAIN OUTCOME MEASURES: The effective concentration (EC) of rocuronium was obtained in each group. After administering sugammadex, recovery of the first twitch height and the TOF ratio were measured for 30 min. RESULTS: EC50, EC90 and EC95 significantly decreased as the concentration of MgCl2 increased (all P ≤ 0.001), except the comparison between the 3 and 4 mmol l MgCl2 groups. After administration of sugammadex, the maximal TOF ratio (%) was lower in the 4 mmol l MgCl2 group than the 1 mmol l MgCl2 group [median 91.7 interquartile range (83.4 to 95.8) vs. 98.3 interquartile range (92.2 to 103.4), P = 0.049]. The mean time (s) from sugammadex injection to achieving maximal first twitch was significantly prolonged in the 4 mmol l MgCl2 group vs. the 1 mmol l MgCl2 and 2 mmol l MgCl2 groups [1483.9 (±â€Š237.0) vs. 1039.0 (±â€Š351.8) and 926.0 (±â€Š278.1), P = 0.022 and 0.002, respectively]. CONCLUSION: Increases in MgCl2 concentration reduce the ECs of rocuronium. In addition, administering sugammadex equimolar to the administered rocuronium shows limited efficacy as MgCl2 concentration is increased. TRIAL REGISTRATION: The in-vitro study was not registered in a database.

Multiple exposures of sevoflurane during pregnancy induces memory impairment in young female offspring mice.

BACKGROUND: Earlier studies have reported conflicting results regarding long-term behavioral consequences after anesthesia during the fetal period. Previous studies also suggest several factors that may explain such conflicting data. Thus, we examined the influence of age and sex on long-term behavioral consequences after multiple sevoflurane exposures during the fetal period. METHODS: C57BL/6J pregnant mice received oxygen with or without sevoflurane for 2 hours at gestational day (GD) 14-16. Offspring mice were subjected to behavioral assays for general activity (open field test), learning, and memory (fear chamber test) at postnatal day 30-35. RESULTS: Multiple sevoflurane exposures at GD 14-16 caused significant changes during the fear chamber test in young female offspring mice. Such changes did not occur in young male offspring mice. However, general activity was not affected in both male and female mice. CONCLUSIONS: Multiple sevoflurane exposures in the second trimester of pregnancy affects learning and memory only in young female mice. Further studies focusing on diverse cognitive functions in an age-, sex-dependent manner may provide valuable insights regarding anesthesia-induced neurotoxicity.

Sevoflurane Exposure during the Critical Period Affects Synaptic Transmission and Mitochondrial Respiration but Not Long-term Behavior in Mice.

BACKGROUND: Anesthesia during the synaptogenic period induces dendritic spine formation, which may affect neurodevelopment. The authors, therefore, evaluated whether changes in synaptic transmission after dendritic spine formation induced by sevoflurane were associated with long-term behavioral changes. The effects of sevoflurane on mitochondrial function were also assessed to further understand the mechanism behind spinogenesis. METHODS: Postnatal day 16 to 17 mice were exposed to sevoflurane (2.5% for 2 h), and synaptic transmission was measured in the medial prefrontal cortex 6 h or 5 days later. The expression of postsynaptic proteins and mitochondrial function were measured after anesthesia. Long-term behavioral changes were assessed in adult mice. RESULTS: Sevoflurane increased the expression of excitatory postsynaptic proteins in male and female mice (n = 3 to 5 per group). Sevoflurane exposure in male mice transiently increased miniature excitatory postsynaptic current frequency (control: 8.53 ± 2.87; sevoflurane: 11.09 ± 2.58) but decreased miniature inhibitory postsynaptic current frequency (control: 10.18 ± 4.66; sevoflurane: 6.88 ± 2.15). Unexpectedly, sevoflurane increased miniature inhibitory postsynaptic current frequency (control: 1.81 ± 1.11; sevoflurane: 3.56 ± 1.74) in female mice (neurons, n = 10 to 21 per group). Sevoflurane also increased mitochondrial respiration in male mice (n = 5 to 8 per group). However, such changes from anesthesia during the critical period did not induce long-term behavioral consequences. Values are presented as mean ± SD. CONCLUSIONS: Sevoflurane exposure during the critical period induces mitochondrial hyperactivity and transient imbalance of excitatory/inhibitory synaptic transmission, without long-lasting behavioral consequences. Further studies are needed to confirm sexual differences and to define the role of mitochondrial activity during anesthesia-induced spine formation.

The anti-inflammatory role of extranuclear apurinic/apyrimidinic endonuclease 1/redox effector factor-1 in reactive astrocytes.

Apurinic/apyrimidinic endonuclease 1 (APE1), a ubiquitous multipurpose protein, is also known as redox effector factor-1 (Ref-1). It is involved in DNA repair and redox signaling and, in turn, oxidative stress-induced neurodegeneration. Although previous studies have demonstrated that APE1/Ref-1 functions as a negative regulator of inflammatory response via several mechanisms in neuronal cells, little is known about the roles of APE1/Ref-1 in glial cells. In this study, we found that cytoplasmic APE1/Ref-1 expression was upregulated in reactive astrocytes of the kainic acid- or lipopolysaccharide (LPS)-injected hippocampus. Analysis of the inflammatory response induced by extranuclear APE1/Ref-1 (ΔNLS-Ref-1) in cultured primary astrocytes revealed that it markedly suppressed inducible nitric oxide synthase (iNOS) expression and tumor necrosis factor-α (TNF-α) secretion induced by LPS to a similar extent as did wild type APE1/Ref-1 (WT-Ref-1), supporting the concept an anti-inflammatory role of extranuclear APE1/Ref-1 in astrocytes. Additionally, overexpression of WT- and ΔNLS-Ref-1 suppressed the transcriptional activity of nuclear factor-κB (NF-κB), although it effectively enhanced activator protein 1 (AP-1) activity. The blunting effect of APE1/Ref-1 on LPS-induced NF-κB activation was not mediated by IκB kinase (IKK) activity. Instead, APE1/Ref-1 inhibited p300-mediated acetylation of p65 by suppressing intracellular reactive oxygen species (ROS) levels following LPS treatment. Taken together, our results showed that altered expression and/or subcellular distribution of APE1/Ref-1 in activated astrocytes regulated the neuroinflammatory response to excitotoxin and endotoxin insults used in model of neurodegenerative brain diseases.

Facilitation of AMPA receptor-mediated steady-state current by extrasynaptic NMDA receptors in supraoptic magnocellular neurosecretory cells.

In addition to classical synaptic transmission, information is transmitted between cells via the activation of extrasynaptic receptors that generate persistent tonic current in the brain. While growing evidence supports the presence of tonic NMDA current (INMDA) generated by extrasynaptic NMDA receptors (eNMDARs), the functional significance of tonic INMDA in various brain regions remains poorly understood. Here, we demonstrate that activation of eNMDARs that generate INMDA facilitates the α-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor (AMPAR)-mediated steady-state current in supraoptic nucleus (SON) magnocellular neurosecretory cells (MNCs). In low-Mg(2+) artificial cerebrospinal fluid (aCSF), glutamate induced an inward shift in Iho lding (IGLU) at a holding potential (Vholding) of -70 mV which was partly blocked by an AMPAR antagonist, NBQX. NBQX-sensitive IGLU was observed even in normal aCSF at Vholding of -40 mV or -20 mV. IGLU was completely abolished by pretreatment with an NMDAR blocker, AP5, under all tested conditions. AMPA induced a reproducible inward shift in Iholding (IAMPA) in SON MNCs. Pretreatment with AP5 attenuated IAMPA amplitudes to ~60% of the control levels in low-Mg(2+) aCSF, but not in normal aCSF at Vholding of -70 mV. IAMPA attenuation by AP5 was also prominent in normal aCSF at depolarized holding potentials. Memantine, an eNMDAR blocker, mimicked the AP5-induced IAMPA attenuation in SON MNCs. Finally, chronic dehydration did not affect IAMPA attenuation by AP5 in the neurons. These results suggest that tonic INMDA, mediated by eNMDAR, facilitates AMPAR function, changing the postsynaptic response to its agonists in normal and osmotically challenged SON MNCs.

A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis.

BACKGROUND: Recent studies have reported that cancer surgeries involving regional anesthesia have better outcomes than those under general anesthesia. However, the effects of anesthetic technique have not been investigated in patients with bladder cancer. Therefore, this retrospective study was conducted to investigate which anesthetic technique results in a better bladder cancer prognosis. METHODS: Sixty-one of 531 patients underwent transurethral resection of a bladder tumor under general anesthesia from 2001 to 2008 in our hospital. Patients who attended five years of follow-up and who had pathological findings of urothelial carcinoma grades I-II were enrolled. Finally, 24 patients (G group) who underwent general anesthesia and 137 (R group) who underwent regional (spinal or epidural) anesthesia were compared. Five-year survival and recurrence-free time were compared using the chi-square and t-tests, respectively. A logistic regression and partial correlation analysis were performed to evaluate other factors affecting survival. RESULTS: Five-year survival was 87.5% for general anesthesia and 96.3% for regional (P = 0.099). The regression analysis showed that older age contributed to reduced survival (odds ratio = 0.85, P = 0.001). Regional anesthesia showed higher 5-year survival (coefficient = -0.167, P = 0.044) more than general anesthesia through the partial correlation analysis. CONCLUSIONS: Though partial correlation analysis show that five-year survival is higher in patients whose surgery is under regional than general anesthesia, the association was not significant in the chi-square test and logistic regression analysis. Large prospective studies are needed to determine whether the association between regional anesthesia and survival is causative.

Protease-Activated Receptor-2 Is Associated with Terminal Differentiation of Epidermis and Eccrine Sweat Glands.

BACKGROUND: Protease-activated receptor 2 (PAR-2) participates in various biological activities, including the regulation of epidermal barrier homeostasis, inflammation, pain perception, and melanosome transfer in the skin. OBJECTIVE: To evaluate the basic physiological role of PAR-2 in skin. METHODS: We investigated PAR-2 expression in human epidermis, skin tumors, and cultured epidermal cells using western blot and immunohistochemical analysis. Additionally, we examined the effect of the PAR-2 agonist, SLIGRL-NH2, on cultured keratinocytes. RESULTS: Strong PAR-2 immunoreactivity was observed in the granular layer of normal human skin and the acrosyringium of the eccrine sweat glands. In contrast, weak PAR-2 immunoreactivity was seen in the granular layer of callused skin and in the duct and gland cells of the eccrine sweat glands. Interestingly, PAR-2 immunoreactivity was very weak or absent in the tumor cells of squamous cell carcinoma (SCC) and syringoma. PAR-2 was detected in primary keratinocytes and SV-40T-transformed human epidermal keratinocytes (SV-HEKs), an immortalized keratinocyte cell line, but not in SCC12 cells. SV-HEKs that were fully differentiated following calcium treatment displayed higher PAR-2 expression than undifferentiated SV-HEKs. Treatment of cultured SV-HEKs with PAR-2 agonist increased loricrin and filaggrin expression, a terminal differentiation marker. CONCLUSION: Our data suggest that PAR-2 is associated with terminal differentiation of epidermis and eccrine sweat glands.

Glomus tumor causing anterior thigh pain: a case report.

Glomus tumors are a rare, benign neoplasm and 75% exist in the subungual region. Extradigital glomus tumors are much more difficult to diagnose because of their atypical location and symptoms. Furthermore, if their symptoms are similar to neuropathic pain, the patient can suffer from misdirected treatment due to misdiagnosis. It is essential to perform careful evaluation of the lesion itself in order to reduce misdiagnosis. Ultrasonography is a useful, non-invasive method that can be easily performed in the pain clinic for local evaluation and diagnosis. We report a case of misdiagnosed glomus tumor in the thigh which was properly diagnosed after ultrasonography.

Intrathecal ketamine and pregabalin at sub-effective doses synergistically reduces neuropathic pain without motor dysfunction in mice.

Peripheral or central nerve injury often leads to neuropathic pain. Although ketamine and pregabalin are first line options for the treatment of neuropathic pain, their clinical application is limited due to side effects such as sedation, dizziness and somnolence. We designed this study to determine whether the intrathecal (i.t.) co-treatment with ketamine and pregabalin at sub-effective low doses would elicit a sufficient pain relief without producing side effect in a neuropathic pain mouse model. At day 7 after chronic constriction injury (CCI) of sciatic nerve, dose dependent effects of i.t. ketamine (3, 10, 30, 100 µg) or i.t. pregabalin (10, 30, 100 µg) on mechanical allodynia and thermal hyperalgesia were measured. For combination treatment, 3 or 10 µg of ketamine and 30 µg of pregabalin were selected because these doses of drugs were not effective on neuropathic pain. Interestingly, combined i.t. treatment groups (ketamine 3 µg+pregabalin 30 µg and ketamine 10 µg+pregabalin 30 µg) produced strong analgesia on neuropathic pain although these doses of ketamine and pregabalin alone are not effective. Moreover, rota rod test revealed that normal motor function was not affected by combined treatment while i.t. ketamine at doses above 10 µg showed a significant motor dysfunction. Results of this study suggested that i.t. co-treatment with ketamine and pregabalin at sub-effect low doses may be a useful therapeutic method for the treatment of neuropathic pain patients.

Antinociceptive effect of phenyl N-tert-butylnitrone, a free radical scavenger, on the rat formalin test.

BACKGROUND: Reactive oxygen species (ROS) such as superoxide radicals, hydrogen peroxide, nitric oxide, and nitroperoxide, cause oxidative stress which interferes with normal cell functioning, resulting in cell damage. It is reported to be associated with chronic pain, especially neuropathic pain, and inflammatory pain. ROS is also closely related to central sensitization. Therefore, this study was designed to explore the effects of Phenyl N-tert-butylnitrone (PBN), an ROS scavenger, in acute, continuous, and increasing pain caused by central sensitization. METHODS: Male Sprague-Dawley rats were divided into 2 groups, an intraperitoneal group (IP) and an intrathecal group (IT), and once again divided into an experimental group and a control group. The experimental group was injected with Phenyl N-tert-butylnitrone (PBN), a free radical scavenger, either intraperitoneally or intrathecally. After inducing pain by injecting formalin into the hind paw, pain behaviors were measured. Lumbar enlargement immmunohistochemistry was performed to assess nitrotyrosine, an oxidative stress marker, to identify the degree of protein nitration. RESULTS: Both experimental groups of IP and IT showed statistically significant decreases in the number of flinches compared to the control group in phase 1 and 2. Immunohistochemical evaluation in the control group revealed an increase in nitrated proteins in the gray matter of the lumbar spinal cord, but a significant decrease in nitrated proteins in the gray matter of lumbar spinal cord of the experimental group. CONCLUSIONS: Intraperitoneal and intrathecal administration of PBN decreases analgesic behaviors, allowing us to believe that ROS is mainly responsible for acute pain and central sensitization.