Addition of dexmedetomidine, tramadol and neostigmine to lidocaine 1.5% increasing the duration of postoperative analgesia in the lower abdominal pain surgery among children: A double-blinded randomized clinical study Tara Hasani Goudarzi, Alireza Kamali, Bijan Yazdi, Gholamreza Nouri Broujerdi Medical Gas Research 2019 9(3):110-114 Pain is a common complication after surgery. Insufficient control of postoperative pain has adverse effects on the physiological, metabolic and psychological state of the child. The use of local analgesics and anesthetics alone cannot produce complete anesthesia and intraoperative comfort. The addition of adjuvant drugs is commonly used to improve the quality of the block. Therefore, adding new supplements may increase the duration of analgesia. The aim of this study was to compare the addition of dexmedetomidine, tramadol and neostigmine to lidocaine 1.5% in increasing the duration of postoperative analgesia in the lower abdominal pain surgery in children aged 2–8 years. This double-blind randomized clinical trial was conducted on children candidate for lower abdominal surgery. The 96 patients were randomly divided into 3 groups including dexmedetomidine, neostigmine, and tramadol. For all children, 3 mg of midazolam was administered orally before entering the operating room. The patients underwent general anesthesia with 2 μg/kg fentanyl, 0.03 mg/kg midazolam, 0.5 mg/kg atracurium and 5–6 mg/kg thiopental. After determining the hiatus membrane, 2 mL syringes containing air and distilled water (each of which 1 mL) slowly entered the space. After eliminating caudal resistance, 1.5% lidocaine was injected at dose of 0.5 mL/kg. A total of 96 patients were enrolled in this study. The results revealed that pain scores in the dexmedetomidine group in recovery, 2, 6 and 12 hours after surgery were less than the other two groups. Furthermore, the tramadol group showed a lower score in comparison with the neostigmine group and the duration of analgesia in the dexmedetomidine group was more than the other two groups. In addition, the mean of analgesic at 24 hours after operation in the dexmedetomidine group was lower as compared to the other two groups, indicating the effect of dexmedetomidine as an adjuvant in increasing the duration of analgesia and reducing postoperative pain in patients along with lidocaine 1.5%. All three drugs (neostigmine, tramadol and dexmedetomidine drugs), along with other local anesthetic, increased the duration of analgesia and decreased postoperative pain in children. The effect of dexmedetomidine was greater than the other two drugs. The study was approved by the Ethics Committee of Arak University of Medical Sciences, Iran (approved No. IR.ARAKMU.REC.1396.112) on October 28, 2017, and registered at Iranian Registry of Clinical Trials (registration No. IRCT20141209020258N83) on August 29, 2018.

“Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients Ji-Bing Chen, Xiao-Feng Kong, You-Yong Lv, Shu-Cun Qin, Xue-Jun Sun, Feng Mu, Tian-Yu Lu, Ke-Cheng Xu Medical Gas Research 2019 9(3):115-121 Advanced cancer treatment is a huge challenge and new ideas and strategies are required. Hydrogen exerts antioxidant and anti-inflammatory effects that may be exploited to control cancer, the occurrence and progression of which is closely related to peroxidation and inflammation. We conducted a prospective follow-up study of 82 patients with stage III and IV cancer treated with hydrogen inhalation using the “real world evidence” method. After 3–46 months of follow-up, 12 patients died in stage IV. After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain. Furthermore, 41.5% of patients had improved physical status, with the best effect achieved in lung cancer patients and the poorest in patients with pancreatic and gynecologic cancers. Of the 58 cases with one or more abnormal tumor markers elevated, the markers were decreased at 13–45 days (median 23 days) after hydrogen inhalation in 36.2%. The greatest marker decrease was in achieved lung cancer and the lowest in pancreatic and hepatic malignancies. Of the 80 cases with tumors visible in imaging, the total disease control rate was 57.5%, with complete and partial remission appearing at 21–80 days (median 55 days) after hydrogen inhalation. The disease control rate was significantly higher in stage III patients than in stage IV patients (83.0% and 47.7%, respectively), with the lowest disease control rate in pancreatic cancer patients. No hematological toxicity was observed although minor adverse reactions that resolved spontaneously were seen in individual cases. In patients with advanced cancer, inhaled hydrogen can improve patients’ quality-of-life and control cancer progression. Hydrogen inhalation is a simple, low-cost treatment with few adverse reactions that warrants further investigation as a strategy for clinical rehabilitation of patients with advanced cancer. The study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval number: Fuda20181207).

Inhalation of high-concentration hydrogen gas attenuates cognitive deficits in a rat model of asphyxia induced-cardiac arrest Lei Huang, Richard L Applegate II, Patricia M Applegate, Lei Gong, Umut Ocak, Warren Boling, John H Zhang Medical Gas Research 2019 9(3):122-126 Cognitive deficits are a devastating neurological outcome seen in survivors of cardiac arrest. We previously reported water electrolysis derived 67% hydrogen gas inhalation has some beneficial effects on short-term outcomes in a rat model of global brain hypoxia-ischemia induced by asphyxia cardiac arrest. In the present study, we further investigated its protective effects in long-term spatial learning memory function using the same animal model. Water electrolysis derived 67% hydrogen gas was either administered 1 hour prior to cardiac arrest for 1 hour and at 1-hour post-resuscitation for 1 hour (pre- & post-treatment) or at 1-hour post-resuscitation for 2 hours (post-treatment). T-maze and Morris water maze were used for hippocampal memory function evaluation at 7 and 14 days post-resuscitation, respectively. Neuronal degeneration within hippocampal Cornu Ammonis 1 (CA1) regions was examined by Fluoro-Jade staining ex vivo. Hippocampal deficits were detected at 7 and 18 days post-resuscitation, with increased neuronal degeneration within hippocampal CA1 regions. Both hydrogen gas treatment regimens significantly improved spatial learning function and attenuated neuronal degeneration within hippocampal CA1 regions at 18 days post-resuscitation. Our findings suggest that water electrolysis derived 67% hydrogen gas may be an effective therapeutic approach for improving cognitive outcomes associated with global brain hypoxia-ischemia following cardiac arrest. The study was approved by the Animal Health and Safety Committees of Loma Linda University, USA (approval number: IACUC #8170006) on March 2, 2017.

Hydrogen inhibits microglial activation and regulates microglial phenotype in a mouse middle cerebral artery occlusion model Jun-Long Huang, Wen-Wu Liu, Anatol Manaenko, Xue-Jun Sun, Qi-Yong Mei, Qin Hu Medical Gas Research 2019 9(3):127-132 Microglia participate in bi-directional control of brain repair after stroke. Previous studies have demonstrated that hydrogen protects brain after ischemia/reperfusion (I/R) by inhibiting inflammation, but the specific mechanism of anti-inflammatory effect of hydrogen is poorly understood. The goal of our study is to investigate whether inhalation of high concentration hydrogen (HCH) is able to attenuate I/R-induced microglia activation. Eighty C57B/L male mice were divided into four groups: sham, I/R, I/R + HCH and I/R + N2/O2 groups. Assessment of animals happened in “blind” matter. I/R was induced by occlusion of middle cerebral artery for one hour). After one hour, filament was withdrawn, which induced reperfusion. Hydrogen treated I/R animals inhaled mix of 66.7% H2 balanced with O2 for 90 minutes, starting immediately after initiation of reperfusion. Control animals (N2/O2) inhaled mix in which hydrogen was replaced with N2 for the same time (90 minutes). The brain injury, such as brain infarction and development of brain edema, as well as neurobehavioral deficits were determined 23 hours after reperfusion. Effect of HCH on microglia activation in the ischemic penumbra was investigated by immunostaining also 23 hours after reperfusion. mRNA expression of inflammation related genes was detected by PCR. Our results showed that HCH attenuated brain injury and consequently reduced neurological dysfunction after I/R. Furthermore, we demonstrated that HCH directed microglia polarization towards anti-inflammatory M2 polarization. This study indicates hydrogen may exert neuroprotective effects by inhibiting the microglial activation and regulating microglial polarization. This study was conducted in agreement with the Animal Care and Use Committee (IACUC) and Institutional Animal Care guidelines regulation (Shanghai Jiao Tong University, China (approval No. A2015-011) in November 2015.

Safety of inhaled hydrogen gas in healthy mice Alexis R Cole, Ali Raza, Humera Ahmed, Brian D Polizzotti, Robert F Padera, Nick Andrews, John N Kheir Medical Gas Research 2019 9(3):133-138 The purpose of this work was to determine the safety of inhaled hydrogen gas in healthy animals. Female mice were exposed to medical air with or without hydrogen gas (concentration 2.4%) for 72 hours (n = 25 mice/group). Mice underwent a standardized and validated neurobehavioral examination, SmithKline Beecham, Harwell, Imperial College, Royal London Hospital, Phenotype Assessment (SHIRPA) protocol, prior to and following the exposure period. Blood was withdrawn for serologic evaluation and all major organ tissues were evaluated histologically. The average hydrogen concentration within the chamber was 2.27%. Following exposure, there was no significant change in body weight in either group. Similarly, there was no significant change in the total SHIRPA score, although hydrogen-treated mice exhibited significantly lower spontaneous locomotor activity (P < 0.0001) in a subset of the test; all other aspects of the mouse neurologic exam were normal in hydrogen-treated animals. Brain histopathology was also normal in all mice, as was the histology of all other major organs. There were no significant differences in complete blood count, serum chemistry, or arterial blood gases between control and hydrogen-treated mice (P > 0.05 for all). Hydrogen gas did not appear to cause significant adverse effects when administered to healthy mice for 72 hours, with the possible exception of decreased spontaneous locomotor activity. The study was approved by the Institutional Animal Care and Use Committee at Boston Children’s Hospital, USA (approved number 18-01-3536) on January 25, 2018.

Effect of intermittent hyperoxia on stem cell mobilization and cytokine expression Kent J MacLaughlin, Gregory P Barton, Rudolf K Braun, Marlowe W Eldridge Medical Gas Research 2019 9(3):139-144 The best known form of oxygen therapy is hyperbaric oxygen (HBO) therapy, which increases both concentration and atmospheric pressure. HBO supports tissue regeneration and is indicated in an increasing number of pathologies. Less known but still showing some promising effects is normobaric oxygen (NBO) therapy, which provides some advantages over HBO including eliminating barotrauma risk, increased ease of administration and a significant cost reduction. However, still little is known about differences and similarities in treatment effects between HBO and NBO. Therefore we tested whether NBO induces a biological response comparable to HBO with a focus on stem progenitor cell mobilization and changes in serum cytokine concentration. We randomly assigned Sprague-Dawley rats into an NBO treatment group (n = 6), and a room air control group (n = 6). The NBO treatment group was exposed to 42% oxygen for 2 hours a day for 10 days. The room air group was concurrently kept at 20.9% oxygen. The frequency and number of stem progenitor cells in peripheral blood were analyzed by flow cytometry. Plasma cytokine expression was analyzed by cytokine array enzyme linked immunosorbent assay. All analyses were performed 24 hours after the final exposure to control for transient post treatment effects. The NBO treatment group showed an increase in circulating CD133+/CD45+ stem progenitor cell frequency and number compared to the room air control group. This rise was largely caused by CD34– stem progenitor cells (CD133+/CD34–/CD45+) without changes in the CD34+ population. The plasma cytokine levels tested were mostly unchanged with the exception of tumor necrosis factor-α which showed a decrease 24 hours after the last NBO exposure. These findings support our hypothesis that NBO induces a biological response similar to HBO, affecting serum stem progenitor cell populations and tumor necrosis factor-α concentration. The study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Wisconsin, Madison, WI, USA (approval No. M005439) on June 28, 2016.

Hydrogen sulphide-releasing aspirin enhances cell capabilities of anti-oxidative lesions and anti-inflammation An-Sha Zhao, Dan Zou, Hao-Hao Wang, Xiao Han, Ping Yang, Nan Huang Medical Gas Research 2019 9(3):145-152 Hydrogen sulphide (H2S) has been considered as a toxic gas for a long time till new researches discovered the endogenous H2S effects on physiological and pathological processes. In virtue of H2S’s effects on cellular redox imbalance and aspirin’s good anticoagulation property, exogenous H2S donors, such as H2S-releasing aspirin (ACS14), have been explored to attenuate side effects of aspirin on gastrointestinal mucosal damage. However, existing researches mainly focus on the antithrombotic effects. Considering H2S role in angiogenesis and vascular-protection progress, we herein focused on if ACS14 further has the ability to attenuate oxidative lesion and inflammation in human umbilical vein endothelial cells (HUVECs) and macrophages. In this study, we synthesized ACS14 by 5-(4-methoxyphenyl)-1,2-dithiole-3-thione and o-acetylsalicylic acid (aspirin), and the obtained compounds showed the ability to release H2S. Our data illustrated that both aspirin and ACS14 had good cytocompatibility, and could support the proliferation of HUVECs. And, ACS14 was found to be able to promote 1.6 folds increase compared to aspirin. H2S released from ACS14 was detected inside cells, wherein H2S fluorescence intensity increased twofold in 5 μM and 10 μM ACS14 groups than 1 μM group. Owing to reactive oxygen species inside cells being obviously decreased in ACS14 group, the apoptosis rate of HUVEC herein was reduced as low as 1.6% from 60% of blank group. Meanwhile, the tumour necrosis factor alpha release in macrophage was also declined by 15% in ACS14 groups than the others. Basically, the ACS14 we obtained had the cyto-protective and anti-inflammatory capabilities. Potential applications for vascular intima repair in atherosclerosis are further expected.

Effects of degradation products of biomedical magnesium alloys on nitric oxide release from vascular endothelial cells Shuo Wang, Shi-Jie Zhu, Xue-Qi Zhang, Jing-An Li, Shao-Kang Guan Medical Gas Research 2019 9(3):153-159 Nitric oxide (NO) released by vascular endothelial cells (VECs), as a functional factor and signal pathway molecule, plays an important role in regulating vasodilation, inhibiting thrombosis, proliferation and inflammation. Therefore, numerous researches have reported the relationship between the NO level in VECs and the cardiovascular biomaterials’ structure/functions. In recent years, biomedical magnesium (Mg) alloys have been widely studied and rapidly developed in the cardiovascular stent field for their biodegradable absorption property. However, influence of the Mg alloys’ degradation products on VEC NO release is still unclear. In this work, Mg-Zn-Y-Nd, an Mg alloy widely applied on the biodegradable stent research, was investigated on the influence of the degradation time, the concentration and reaction time of degradation products on VEC NO release. The data showed that the degradation product concentration and the reaction time of degradation products had positive correlation with NO release, and the degradation time had negative correlation with NO release. All these influencing factors were controlled by the Mg alloy degradation behaviors. It was anticipated that it might make sense for the cardiovascular Mg alloy design aiming at VEC NO release and therapy.

Preventing explosions of hydrogen gas inhalers Ryosuke Kurokawa, Shin-ichi Hirano, Yusuke Ichikawa, Goh Matsuo, Yoshiyasu Takefuji Medical Gas Research 2019 9(3):160-162 Production and excretion of hydrogen (H2) gas in human was reported in 1969, since then it has been regarded as non-toxic molecule. For preventive and therapeutic medical uses, a possible treatment for cancer was reported and another article was published on how H2 acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. A variety of H2 gas inhalers have been available in the market for hospital and home uses. However, H2 is odorless and flammable or explosive ignited by static electricity. We have examined the safety of a variety of H2 gas concentrations from the viewpoint of flammability and explosion. We have also measured concentrations of H2 gas inhalers in the market respectively. This paper also details how to control H2 gas concentration for preventing explosions.

Clinical utility of ozone therapy in dental and oral medicine Yiji Suh, Shrey Patel, Re Kaitlyn, Jason Gandhi, Gunjan Joshi, Noel L Smith, Sardar Ali Khan Medical Gas Research 2019 9(3):163-167 Ozone is a highly reactive compound composed of three oxygen atoms that acts as an oxidant and oxidizer. It exists at the ground level as an air pollutant and a constituent of urban smog, as well as in the Earth’s upper atmosphere as a protective layer from ultraviolet rays. Healthy cells contain antioxidants such as vitamins C and E to protect against ozone oxidization. However, pathogens such as bacteria contain very trace amounts of antioxidants in their membranes, which make them susceptible to ozone and destroy the cell membrane. This review explores the history, composition, and use of ozone worldwide in dentistry. Ozone therapy has thus far been utilized with wound healing, dental caries, oral lichen planus, gingivitis and periodontitis, halitosis, osteonecrosis of the jaw, post-surgical pain, plaque and biofilms, root canals, dentin hypersensitivity, temporomandibular joint disorders, and teeth whitening. The utility of ozone will undoubtedly grow if studies continue to show positive outcomes in an increasing number of dental conditions.