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Background: Current continuous kidney replacement therapy (CKRT) protocols ignore physiological renal compensation for hypercapnia. This study aimed to explore feasibility, safety, and clinical benefits of pCO2-adapted CKRT for hypercapnic acute respiratory distress syndrome (ARDS) patients with indication for CKRT., Methods: We enrolled mechanically ventilated hypercapnic ARDS patients (pCO2 > 7.33 kPa) receiving regional citrate anticoagulation (RCA) based CKRT in a prospective, randomized-controlled pilot-study across five intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Patients were randomly assigned 1:1 to the control group with bicarbonate targeted to 24 mmol/l or pCO 2 -adapted-CKRT with target bicarbonate corresponding to physiological renal compensation. Study duration was six days. Primary outcome was bicarbonate after 72 h. Secondary endpoints included safety and clinical endpoints. Endpoints were assessed in all patients receiving treatment., Results: From September 2021 to May 2023 40 patients (80% male) were enrolled. 19 patients were randomized to the control group, 21 patients were randomized to pCO 2 -adapted-CKRT. Five patients were excluded before receiving treatment: three in the control group (consent withdrawal, lack of inclusion criteria fulfillment (n = 2)) and two in the intervention group (lack of inclusion criteria fulfillment, sudden unexpected death) and were therefore not included in the analysis. Median plasma bicarbonate 72 h after randomization was significantly higher in the intervention group (30.70 mmol/l (IQR 29.48; 31.93)) than in the control group (26.40 mmol/l (IQR 25.63; 26.88); p < 0.0001). More patients in the intervention group received lung protective ventilation defined as tidal volume < 8 ml/kg predicted body weight. Thirty-day mortality was 10/16 (63%) in the control group vs. 8/19 (42%) in the intervention group (p = 0.26)., Conclusion: Tailoring CKRT to physiological renal compensation of respiratory acidosis appears feasible and safe with the potential to improve patient care in hypercapnic ARDS., Trial Registration: The trial was registered in the German Clinical Trials Register (DRKS00026177) on September 9, 2021 and is now closed., (© 2024. The Author(s).)

Aims: Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO 2 inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO 2 postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI., Methods: Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO 2 for various time-courses (one/two/three cycles of 10-min inhalation/10-min break) at Days 3-7, 3-14 or 7-18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP-43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno-associated virus were applied to investigate the molecular mechanisms., Results: DCPC significantly promoted recovery of motor function in a concentration and time-course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO 3 . DCPC also increased puncta density of GAP-43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation-related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC., Conclusions: We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Carboxytherapy is defined as intradermal and/or subcutaneous microinjections of sterile purified carbon dioxide into different parts of the body for therapeutic aims. The vasodilatation effect and intradermal collagen reorganization associated with carboxytherapy have advantages for aesthetic dermatology and cosmetology., Objective: In the current article, we have reviewed some of the most important indications of this modality in dermatology and aesthetic dermatology., Method: Our review is a narrative one which has gathered some of the most important indications of carboxytherapy in dermatology and cosmetology., Results: Carboxytherapy has successfully been applied for some dermatologic and cosmetic conditions among which skin aging, cellulite, localized fat deposits, striae distensae, infraorbital hyperpigmentation, scar, lymphedema, androgenetic alopecia, alopecia areata, psoriasis, morphea, and vitiligo are the most important., Conclusion: Carboxytherapy can be considered as a safe, minimally-invasive modality used for rejuvenation, restoration, and recondition of the skin., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Fractional carbon dioxide (CO 2 ) laser resurfacing is used successfully for facial rejuvenation. Post procedure skincare is a variable that influences downtime caused by pain/tenderness, erythema, crusting, and bruising., Aims: The primary objective of this pilot study was to demonstrate the benefits of human platelet extract (HPE) (plated)™ CALM Serum, a new topical cosmetic product, following fractionated CO 2 ablative laser resurfacing treatment to the entire face versus standard of care., Methods: In a single-center, randomized, evaluator-blinded pilot study, a total of 18 subjects were randomized into two groups, CO 2 facial resurfacing followed by post-procedural standard of care (Stratacel silicone gel) or CO 2 facial resurfacing with the addition of HPE renewosomes in the CALM Serum., Results: CALM Serum demonstrated statistically significant less crusting at Day 10 compared to the control group (p = 0.0193) with less downtime in the first 14 days (p = 0.03). Subjects treated with CALM Serum had statistically significant brighter appearing skin at 14 days (p = 0.007) and more youthful looking skin on Days 14 and 30 (p = 0.003 and 0.04, respectively)., Conclusions: This study demonstrates that Renewosome™ technology provides statistically significant post-laser clinical recovery over silicone gel for reducing crusting, and downtime. Subjects reported less diary days of symptoms of pain/tenderness, redness, crusting/flaking, bruising, and itching in the first 14 days compared to the control group. CALM also demonstrated statistically significant improvements in brighter and more youthful appearing skin. CALM is safe and well tolerated., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Pressurized metered-dose inhalers (pMDIs) exert an environmental impact resulting from CO2 emissions. Therapeutic alternatives with less environmental impact are widely used. Nevertheless, the choice of device and appropriate therapy should meet the clinical needs and the characteristics of the patient., Objective: The primary objective was to estimate the impact of pMDIs prescribed for any indication on annual CO2 emissions in Spain.The secondary objective was to evaluate the potential impact of switching pMDIs to dry-powder inhalers (DPIs) in patients with asthma., Methods: A systematic review of the evidence published during 2010-2021 was carried out. Average annual CO2 emissions of DPIs and pMDIs were calculated in 2 scenarios: the current situation and a hypothetical situation involving a switch from all pMDIs to DPIs. The impact of the switch on clinical outcomes was also evaluated., Results: The total value of CO2-eq/year due to DPIs and pMDIs accounted for 0.0056% and 0.0909%, respectively, of total emissions in Spain. In the event of switching pMDIs to DPIs, except those used for rescue medication, the percentages were 0.0076% and 0.0579%. The evaluation of efficacy, handling, satisfaction, safety, and use of health care resources was not conclusive., Conclusions: Current CO2 emissions by pMDIs account for a small percentage of the total CO2 footprint in Spain. Nevertheless, there is a need for research into new and more sustainable devices. Suitability and patient clinical criteria such as age and inspiratory flow should be prioritized when prescribing an inhaler.

Background and Objectives : For many years, fully ablative laser treatments, particularly those performed with a carbon dioxide (CO 2 ) laser, were regarded as the gold standard for resurfacing. This study's goal is to assess the depth that can be reached by a new CO 2 scanner system, through a skin model with greater dermal thickness, to use in the treatment of deep scarring. Materials and Methods : Male human skin tissue was laser-treated using a CO 2 fractional laser and a new scanning system, and all samples were fixed in 10% neutral buffered formalin, dehydrated using a series of crescent alcohol, embedded in paraffin, sectioned in series (4-5 µm thick), stained with haematoxylin and eosin (H&E), and then analysed under an optical microscope. Results : From the epidermis through the underlying papillary and reticular dermis to various depths of the dermis, microablation columns of damage and coagulated microcolumns of collagen were observed. The reticular dermis was fully penetrated up to 6 mm at higher energy levels (210 mJ/DOT), resulting in deeper tissue injury. Although the laser might penetrate further, the skin stops there, leaving just the fat and muscular tissue. Conclusions : The deep layers of the dermis can be penetrated by the CO 2 laser system throughout the entire dermal thickness when using the new scanning system, suggesting that this laser's potential impact, at the selected settings, covers all skin targets required to perform superficial or deep treatments on any dermatological issue. Finally, patients who have problems, such as morbid scar-deep complications, which affect their quality of life, are more likely to profit from this innovative technique.

We compared the therapeutic effect of catheter direct thrombolysis (CDT) and peripheral venous thrombolysis (PVT) for patients with acute pulmonary embolism (APE). Totally, 74 patients with APE were enrolled, including 37 in the CDT group and 37 in the PVT group. The changes in clinical indicators pre and posttreatment were observed. Clinical efficacy was evaluated. Kaplan-Meier method was used to analyze the survival of patients during follow-up. In both the PVT group and CDT group, partial pressure of oxygen after treatment increased significantly than that before treatment (P < .05). However, in both groups, the levels of partial pressure of carbon dioxide, D-dimer, B-type brain natriuretic peptide, pulmonary arterial pressure, and thrombus volume after treatment were significantly decreased than those before treatment (P < .05). After treatment, patients from the CDT group had significantly lower D-dimers, partial pressure of carbon dioxide, brain natriuretic peptide, and pulmonary arterial pressure, and significantly higher partial pressure of oxygen compared to patients from the PVT group (P < .05). The total effective rate was 97.2% in the CDT group and 81.0% in the PVT group. The bleeding incidence in the CDT group was significantly lower than that in the PVT group (P < .05). The median survival time in the CDT group was significantly longer than that in the PVT group (P < .05). CDT can more effectively improve symptoms, cardiac function, and survival rate of APE patients while reducing bleeding incidence than PVT, and thus is safe and effective in treating APE., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity., Methods: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment., Results: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02)., Conclusion: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: Acne vulgaris is caused by dyslipidemia, dyskeratosis and/or abnormal bacterial growth. The obstruction of skin pores due to hyperkeratosis of the infundibulum contributes to the formation of comedones. Thus, normalizing keratinization of epidermal cells in skin pores might be useful to improve acne. Recently, it has been found that the transcutaneous application of carbon dioxide (CO 2 ) regulates imbalances of the desquamatory process. In this study, we evaluated the efficacy of a skin lotion containing CO 2 on mild acne., Methods: Twenty-four healthy Japanese males (20-29 years old) with mild acne attended this evaluation. The subjects were divided into 2 groups, one group used a skin lotion containing CO 2 and the other group used a skin lotion without CO 2 . Following facial washing, each subject topically applied the skin lotion with or without CO 2 twice a day for 4 weeks. Prior to the start of the evaluation (week 0) and following 2 and 4 weeks of treatment, acne symptoms were assessed by a dermatologist and by instrumental measurements., Results: Topical application of the skin lotion with CO 2 for 4 weeks significantly improved acne symptoms, which was recognized by the subjects. However, treatment with the skin lotion without CO 2 did not improve acne symptoms. This improvement of acne symptoms by CO 2 was not accompanied by changes in sebum levels, skin surface pH, skin capacitance, or porphyrin levels., Conclusion: The transcutaneous application of a lotion with CO 2 improves acne symptoms by normalizing keratinization without affecting skin surface conditions., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

To compare the therapeutic effect of fractional carbon dioxide (CO 2 ) laser + topical triamcinolone (TA) with intralesional TA on keloids. Twenty-two participants were randomised into two groups: group A, treated with fractional CO 2 laser + topical TA, and group B, treated with intralesional TA. The interventions were performed at every 4-week interval until the keloids were resolved or at the completion of 1 year. At each session, the scar volume, Vancouver Scar Scale (VSS) were assessed. Recurrence was observed for 1 year. The mean scar volumes and VSS scores were not significantly different between the two groups. After 1 year, the scar volume change in group B was greater than group A (86.5% vs 59.1%, P-value = .016). The mean VSS scores were significantly decreased in group A (8.0 ± 1.5 to 4.8 ± 1.6, P-value <.001) and group B (8.4 ± 0.8 to 4.8 ± 1.6, P-value <.001). The keloids were completely resolved in 63.6% and 72.7% of the patients, and recurrence was observed in 9.1% and 18.2% of the patients in groups A and B, respectively. The combination of fractional CO 2 laser with topical TA was an alternative option for the treatment of keloids., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone., Methods: Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of 'dose-limiting toxicity' (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO 2 , respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing., Discussion: Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen's use in alcoholism and guidelines for the management of opiate dependence., Trial Registration: Clinicaltrials.gov NCT05161351. Registered on 16 December 2021., (© 2022. The Author(s).)

To explore the curative effect of antibiotic combined with mucosolvan perfusion under fiber bronchoscope in treatment of pneumonia after severe cerebral hemorrhage. The clinical data of 120 patients with pneumonia after severe cerebral hemorrhage admitted to our hospital from January 2017 to December 2019 were collected. All patients were divided into the lavage group and perfusion group by random number method, with 60 patients in each group. Patients in the lavage group received antibiotics combined with mucosolvan lavage therapy under fiber bronchoscope, while patients in the perfusion group received antibiotics combined with mucosolvan perfusion therapy under fiber bronchoscope. Clinical pulmonary infection score (CPIS), arterial blood gas index, clinical symptom improvement, and hospitalization costs were compared between the two groups before and after treatment. CPIS scores were improved after treatment in both groups (P < .05), and CPIS scores of patients in the perfusion group were lower than those in the lavage group at 3, 5, and 7 days after treatment (P < .05). The blood oxygen saturation and partial arterial oxygen pressure of the perfusion group were all higher than those of the lavage group (P < .05), while the partial carbon dioxide pressure was lower than that of the lavage group (P < .05). In the perfusion group, the duration of cough, adequacy of fever, disappearance of rhonchus in the lungs, and the length of hospital stay were less than those in the lavage group (P < .05). The hospitalization costs of perfusion group were lower than that of lavage group (P < .05). The combination of antibiotics and mucosolvan infusion therapy under fiber bronchoscope can effectively improve the clinical efficacy, reduce the hospitalization cost, and improve the prognosis of patients with pneumonia after severe cerebral hemorrhage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To investigate the effect on meibomian gland function of super pulse carbon dioxide (CO 2 ) laser excision in the treatment of eyelid tumors at palpebral margin., Methods: 36 patients with 36 eyelid tumor size ≤ 1 cm and within 1 mm to palpebral margin were recruited in this study. Of which, 16 cases with tumors in the upper eyelid and 20 cases in the lower eyelid were involved. The eyelid tumors of all the patients were treated by super pulse CO 2 laser with its power density varied between 0.6 and 21.1 W/mm 2 and in repeat mode. The laser spot size ranged from 120 to 200  μ m. Ocular surface parameters including tear film break-up time (BUT) and meibograde, meibum expressibility, and meibum quality were evaluated at pretherapy, 1 week, 1 month, and 3 months posttherapy in all 36 patients., Result: All the patients were satisfied with the therapy. No infective complications and recurrence occurred in any of the 36 patients at the following period. The eyelid wound recovered well with nearly normal appearing after 2 to 3 weeks. The morphology of limbi palpebralis, BUT, meibograde, meibum expressibility, and meibum quality of all the 36 patients showed no significant difference before and after the therapy., Conclusions: Super pulse CO 2 laser had no effect on meibomian gland function and morphology in the excision of tumors at palpebral margins, which was an efficacy and well-tolerated therapy with lower complications and recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Songjiao Zhao et al.)

Cutaneous neurofibromas (cNF) are one of the hallmarks of neurofibromatosis 1 (NF1). The number of cNFs varies between individuals from a few to hundreds or even thousands and increases throughout adult life. cNFs cause a significant disease burden to adult patients and constitute an unmet need for therapy, since they may cause itch and pain and, being conspicuous and unsightly, stigmatize the patient. There is a lack of reports on how the outcome of various treatment options are perceived by the patients. Here we describe a technique for cNF removal using CO 2 laser, and report how patients experience the procedure. Questionnaires were sent to patients who had had CO 2 laser surgery in the French Referral Center for Neurofibromatoses, and in the Turku University Hospital, Finland, to retrospectively evaluate the patients' global satisfaction of the procedure, treatment indications, and reasons for withdrawal from treatment, if this was the case. The number of returned questionnaires was 233/473 in France and 23/27 in Finland. The results showed that the most important indications for cNF removal were esthetic, and pain and itch caused by the tumors. In general, the procedure was well tolerated, and the degree of satisfaction was 8-10 on a scale from 0 to 10. For those 30% who discontinued the tumor removal program, the main reasons were organizational constraints, a non-satisfactory esthetic result, too many cNFs to treat, or problems with healing. Thus, the CO 2 laser method is well tolerated but does not fully answer to the needs of the patients. Since medical treatment is not yet available, we encourage the use of laser removal of cNFs as a feasible method to decrease the tumor burden of the patients., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Orbital floor fractures subsequently lead to consequences such as diplopia and enophthalmos. The graft materials used in orbital floor fractures varied from autografts to alloplastic grafts, which possess certain limitations. In the present study, a novel porcine bone matrix decellularized by supercritical CO2 (scCO2), ABCcolla® Collagen Bone Graft, was used for the reconstruction of the orbital framework. The study was approved by the institutional review board (IRB) of Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH). Ten cases underwent orbital floor reconstruction in KMUH in 2019. The orbital defects were fixed by the implantation of the ABCcolla® Collagen Bone Graft. Nine out of ten cases used 1 piece of customized ABCcolla® Collagen Bone Graft in each defect. The other case used 2 pieces of customized ABCcolla® Collagen Bone Graft in one defect area due to the curved outline of the defect. In the outpatient clinic, all 10 cases showed improvement of enophthalmos on CT (computerized tomography) at week 8 follow-up. No replacement of implants was needed during follow-ups. To conclude, ABCcolla® Collagen Bone Graft proved to be safe and effective in the reconstruction of the orbital floor with high accessibility, high stability, good biocompatibility, low infection rate and low complication rate., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Neuropsychiatric complications of surgical coronary revascularization are inconspicuous but frequent and clinically relevant. So far, attempts to reduce their occurrence, such as the introduction of off-pump coronary artery bypass (OPCAB) grafting method, have not brought the desired results. The aim of this trial was to determine whether using any of the 2 selected modifications of OPCAB could decrease the incidence of these undesired sequelae., Methods: In this single-center, assessor- and patient-blinded, superiority, randomized controlled trial, 192 patients scheduled for elective isolated OPCAB were randomized to 3 parallel arms. The control arm underwent "conventional" OPCAB with vein grafts. The first study arm underwent anaortic OPCAB (ANA) with total arterial revascularization. The second study arm underwent OPCAB with vein grafts using carbon dioxide surgical field flooding (CO 2 FF). Outcomes included the incidence of postoperative delirium (PD) and early postoperative cognitive dysfunction (ePOCD)., Results: The incidence of PD was 35.9% in the control (OPCAB) arm, 32.8% in the CO 2 FF arm, and 12.5% in the ANA arm (χ 2 [2, N = 191] = 10.17; P = .006). Post hoc tests revealed that the incidence of PD in the ANA arm differed from that in the OPCAB arm (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.09-0.68; P = .002). The incidence of ePOCD was 34.4% in the OPCAB arm, 28.1% in the CO 2 FF arm, and 9.5% in the ANA arm (χ 2  [2, N = 191] = 11.58; P = .003). Post hoc tests revealed that the incidence of ePOCD differed between the ANA and OPCAB arms (OR, 0.20; 95% CI, 0.06-0.58; P < .001)., Conclusions: Performing ANA significantly decreases the incidence of PD and ePOCD compared with "conventional" OPCAB with vein grafts, whereas CO 2 FF is inconsequential in this regard. These results, which probably reflect decreased delivery of embolic load to the brain in ANA, may have practical applicability in daily practice to improve clinical outcomes., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Chronic wounds in diabetics are difficult to treat, therefore, adjuvant therapies have been investigated. Bathing in CO 2 -rich water (spa therapy) has been known in Europe for decades for its positive effect on peripheral vascular disorders. Recently, much effort has been invested in developing optimal application methods of CO 2 . Uses include subcutaneous injections of CO 2 , bathing in CO 2 -enriched water, and transcutaneous application of CO 2 . To verify the effect of transcutaneous application of gaseous CO 2 on the healing of chronic diabetic wounds, a randomized double-blind clinical research was designed. The research included 30 and 27 wounds in the study and control groups, respectively. In addition to standard treatment, patients in the study group received 20 therapies with medical-grade CO 2 gas and the control group received the same treatment with air. Results showed significantly faster healing in the study group: 20 of the 30 wounds in the study group were healed compared with none in the control group. Mean wound surface and volume in the study group was reduced significantly (surface: 96%, P = .001, volume: 99%, P = .003) compared with a small reduction in the control group (surface: 25%, P = .383, volume: 27%, P = .178). Considering our results, transcutaneous application of gaseous CO 2 is an effective adjuvant therapy in diabetic chronic wound treatment., (© 2020 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H 2 ) or graded restoration of normocapnia with CO 2 for 4 h after asphyxia would augment the neuroprotective effect of TH in a subacute (48 h) HIE piglet model. Piglets were randomized to untreated naïve, control-normothermia, asphyxia-normothermia (20-min 4%O 2 -20%CO 2 ventilation; T core = 38.5 °C), asphyxia-hypothermia (A-HT, T core = 33.5 °C, 2-36 h post-asphyxia), A-HT + H 2 , or A-HT + CO 2 treatment groups. Asphyxia elicited severe hypoxia (pO 2 = 19 ± 5 mmHg) and mixed acidosis (pH = 6.79 ± 0.10). HIE development was confirmed by altered cerebral electrical activity and neuropathology. TH was significantly neuroprotective in the caudate nucleus but demonstrated virtually no such effect in the hippocampus. The mRNA levels of apoptosis-inducing factor and caspase-3 showed a ~10-fold increase in the A-HT group compared to naïve animals in the hippocampus but not in the caudate nucleus coinciding with the region-specific neuroprotective effect of TH. H 2 or CO 2 did not augment TH-induced neuroprotection in any brain areas; rather, CO 2 even abolished the neuroprotective effect of TH in the caudate nucleus. In conclusion, the present findings do not support the use of these medical gases to supplement TH in HIE management.

Poultry red mites (PRMs), Dermanyssus gallinae , are one of the most harmful ectoparasites of laying hens. Because of their public health impact, safe, effective methods to eradicate PRMs are greatly needed. Carbon dioxide (CO₂) was shown to eradicate phytophagous mites; however, there is no evidence that PRMs can be eradicated by CO₂. Thus, the efficacy of CO₂, applied by direct-spraying and dry ice-generated exposure, for eradicating PRMs was investigated. Both treatments eradicated > 85% of PRMs within 24 h and 100% of PRMs by 120 h of post-treatment. Therefore, these novel approaches may be useful for eradicating PRMs in clinical settings., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Korean Society of Veterinary Science.)

Background: Muscle atrophy causes difficulty in resuming daily activities after a fracture. Because transcutaneous carbon dioxide (CO 2 ) application has previously upregulated oxygen pressure in the local tissue, thereby demonstrating its potential in preventing muscle atrophy, here we investigated effects of CO 2 application on muscle atrophy after femoral shaft fracture., Methods: Thirty fracture model rats were produced and randomly divided into a no treatment (control group) and treatment (CO 2 group) groups. After treatment, the soleus muscle was dissected at post-fracture days 0, 14, and 21. Evaluations were performed by measuring muscle weight and performing histological examination and gene expression analysis., Results: Muscle weight was significantly higher in the CO 2 group than in the control group. Histological analysis revealed that the muscle fiber cross-sectional area was reduced in both groups. Nevertheless, the extent of atrophy was lesser in the CO 2 group. Muscle fibers in the control group tended to change into fast muscle fibers. Vascular staining revealed that more capillary vessels surrounded the muscle fibers in the CO 2 group than in the control group. Messenger RNA (mRNA) analysis revealed that the CO 2 group had a significantly enhanced expression of genes that were related to muscle synthesis., Conclusion: Transcutaneous CO 2 application may be a novel therapeutic strategy for preventing skeletal muscle atrophy after fracture., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

BACKGROUND Schwannoma, also called neuroma or neurolemmoma, is a tumor originating from the Schwann cells surrounding the nerves. It is an isolated benign tumor and its transformation into malignant cancer is very rare. Relatively uncommon, it is only the 5% of all the tumors of soft tissues. Its localization in the head and neck region accounts for up to 25-45% of schwannomas. In the outer ear, it commonly involves the external auditory canal, while auricle and tympanic membranes are very rare localizations of schwannomas. CASE REPORT We report a case of a 23-year-old male with a 3-year medical history of a growing neoplasm located in the left auricle concha, which was treated with a carbon dioxide laser (CO₂ laser) under local anesthesia. CONCLUSIONS Using a CO₂ laser allowed us to easily remove the tumor, reduce bleeding and surgical time, and avoid sutures and thus unsightly scars on the face. No complications and no relapse at 5 years of follow-up occurred.

Breast cancer rates are rising in low- and middle-income countries (LMICs), yet there is a lack of accessible and cost-effective treatment. As a result, the cancer burden and death rates are highest in LMICs. In an effort to meet this need, our work presents the design and feasibility of a low-cost cryoablation system using widely-available carbon dioxide as the only consumable. This system uses an 8-gauge outer-diameter needle and Joule-Thomson expansion to percutaneously necrose tissue with cryoablation. Bench top experiments characterized temperature dynamics in ultrasound gel demonstrated that isotherms greater than 2 cm were formed. Further, this system was applied to mammary tumors in an in vivo rat model and necrosis was verified by histopathology. Finally, freezing capacity under a large heat load was assessed with an in vivo porcine study, where volumes of necrosis greater than 1.5 cm in diameter confirmed by histopathology were induced in a highly perfused liver after two 7-minute freeze cycles. These results demonstrate the feasibility of a carbon-dioxide based cryoablation system for improving solid tumor treatment options in resource-constrained environments., Competing Interests: BS, SY, YH, TB, ST, EM, PA, GK, SH, and ND are inventors on a provisional patent application (U.S. 62/664,998, Carbon Dioxide-Based Percutaneous Cryosurgical System) relating to the cryotherapy system presented here and may receive royalties if the intellectual property is licensed. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors have no competing interests to declare.

Background: Laparoscopic colorectal surgery may adversely affect respiration, circulation, and acid-base balance in elderly patients, owing to the relatively long duration of CO2 absorption. We conducted this retrospective study to determine the safety and efficacy of warmed, humidified CO2 pneumoperitoneum in elderly patients undergoing laparoscopic colorectal surgery., Methods: We enrolled 245 patients between January 2016 and August 2018.The experimental group (warming and humidification group [WH]) received warmed (37°C), humidified (98%) insufflation of CO2, and the control group (cold, dry CO2/control group [CD]) received standard CO2 (19°C, 0%). All other aspects of patient care were standardized. Intraoperative hemodynamic data, arterial blood pH, and lactic acid levels were recorded. We also recorded intra-abdominal pressure, incidence of shivering 1 hour after surgery, satisfaction scores of patients and surgeons 24 hours after surgery, times to first flatus/defecation, first bowel movement, and tolerance of semiliquid food, discharge time, and incidence of vomiting, diarrhea, and surgical site infections., Results: Compared with the WH group, heart rate and mean arterial pressure were significantly higher from T3 to T8 (P < .05), lactic acid levels were significantly higher from T4 to T9 (P < .05), and recovery time in the post-anesthesia care unit (PACU) was significantly longer in the CD group (P < .05). Patient and surgeon satisfaction scores were significantly higher in the WH group than the CD group (P < .05). In addition, the times to first flatus/defecation and bowel movement were significantly longer in the CD group (P < .05). No significant differences were noted between the groups in the time to tolerance of semiliquid food and time of discharge (P > .05). The incidence of vomiting, diarrhea, and shivering was significantly lower in the WH group (P < .05). The number of patients with a shivering grade of 0 was significantly higher in the WH group, whereas the number with a shivering grade of 3 was significantly higher in the CD group (P < .05)., Conclusion: Warmed, humidified insufflation of CO2 in elderly patients undergoing laparoscopic colorectal surgery could stabilize hemodynamics, and reduce lactic acid levels, recovery time in the PACU, and the incidence of acute gastrointestinal injury-related symptoms.

To examine the influence of carboxytherapy on wound healing under venous insufficiency, full-thickness excisional wounds were created on Wistar rats. We used three groups with 32 rats each: Group (I): daily cleaning with 0.9% saline solution; Group Sulfadiazine (II): 1% silver sulfadiazine; and Carboxytherapy (III): subcutaneous application of 0.3 mL of carbon dioxide. The predetermined periods of analysis were the 3rd, 7th, 14th, and 30th day. The slides were stained with haematoxylin and eosin and Picrosirius red and submitted for immunohistochemistry. Groups II and III presented a statistically significant decrease in relation to the presence of neutrophilic and lymphocytic infiltrates. The presence of collagen significant increased in groups II and III. However, group III presented better organisation. Only group I maintained the neovascularisation until the 30th day. The new epithelium statistically significantly increased in groups II and III. On immunohistochemistry, regarding fibronectin expression, only group III demonstrated a statistically significant increase since the beginning of the healing process. Thus, the use of carboxytherapy promotes the formation of a tissue better structured and that may be an important resource for the treatment of wounds under venous insufficiency, especially those of recurrent re-openings., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: This study investigated whether therapeutic hypercapnia (TH) ameliorated blood-brain barrier (BBB) damage and improved the neurologic outcome in a rat model of lateral fluid percussion injury (FPI), and explored the possible underlying mechanism., Methods: Rats underwent lateral FPI and received inhalation of 30%O 2 -70%N 2 or 30%O 2 -N 2 plus CO 2 to maintain arterial blood CO 2 tension (PaCO 2 ) between 80 and 100 mmHg for 3 h. To further explore the possible mechanisms for the protective effects of TH, a PKC inhibitor staurosporine or PKCαβ inhibitor GÖ6976 was administered via intracerebral ventricular injection., Results: TH significantly improved neurological function 24 h, 48 h, 7 d, and 14 d after FPI. The wet/dry ratio, computed tomography values, Evans blue content, and histological lesion volume were significantly reduced by TH. Moreover, numbers of survived neurons and the expression of tight junction proteins (ZO-1, occludin, and claudin-5) were significantly elevated after TH treatment at 48-h post-FPI. TH significantly increased the expression of protein kinase Cε (PKCε) at 48-h post-FPI, but did not significantly change the expression of PKCα and PKCβII. PKC inhibitor staurosporine (but not the selective PKCαβ inhibitor-GÖ6976) inhibited the protective effect of TH., Conclusions: Therapeutic hypercapnia is a promising candidate that should be further evaluated for clinical treatment. It not only protects the traumatic penumbra from secondary injury and improves histological structure but also maintains the integrity of BBB and reduces neurologic deficits after trauma in a rat model of FPI.

The study provided an algal treatment to achieve dual function with antibiotic elimination and CO 2 fixation simultaneously. Two widely used antibiotics, cefradine and amoxicillin were selected as the target compounds. First of all, we assessed the influence of light intensity on algal growth and antibiotic removal efficiency to obtain the optimal light intensity. Secondly, after the algal antibiotic treatment, the CO 2 capture capacities at varied CO 2 volume concentrations were assessed and compared. Significant improvement in the removal efficiency of cefradine occurred when CO 2 was added into the treatment. Change in the content of photosynthetic pigments and the activities of RuBisCO and carbonic anhydrase occurred as the algal responses to the treatment condition. Our results showed that Chlorella pyrenoidosa performed better than Microcystis aeruginosa in both the antibiotic removal efficiency and the CO 2 capture capacity. In the integrated algal treatment, the remove rate of antibiotic has been improved by 30.16% and at the same time, the CO 2 absorption rate has been promoted by 10.94%. Metabolite analyses also revealed the mechanism involved, which proved the crucial role of the algae in the biodegradation of the target antibiotic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The slowing of the aging process is subject of great research and attention in modern society, particularly aging of face. Processes involved are very complex. Mesotherapy. hyaluronic acid and carbon dioxide injection can be used for biorevitalization and skin rejuvenation., Methods: Three groups were made and 62 patients were enrolled. Patients with superficial wrinkles of the face, neck and/or décolleté, without presence of nasolabial folds and marionette wrinkles were included in group 1. Patients with superficial/medium depth wrinkles of the face, neck and/or décolleté, with moderate nasolabial folds but no marionette wrinkles were included in group 2. Patients with deep wrinkles of the face, with deep nasolabial folds and marionette wrinkles were included in group 3. Patients were treated with three different protocols that included injections of amino acids, vitamins and hyaluronic acid in association with carbon dioxide injection. We submitted the PAIS and GAIS scales and we analyzed the scores obtained with Wilcoxon's and Kolmogorov-Smirnov's tests. Statistical Product and Service Solutions (SPSS) softare was used. The p-value was considered acceptable if inferior to 0,05 (p>0,05)., Results: In according with these tests, the differences of values at one week and at the end of the study are significant (p<0,05) for both PAIS and GAIS. No side effects were reported., Conclusions: Protocol treatment used in this study gave statistically valid results in the rejuvenation of face for mild, moderate and severe aging.

Introduction: The risk of air microembolism during cardiopulmonary bypass (CPB) is high and influences the postoperative outcome, especially in elderly patients. The use of carbon dioxide (CO 2 ) atmosphere during cardiac surgery may reduce the risk of cerebral air microembolism. The aim of our study was to assess the influence of CO 2 field flooding on microembolism-induced brain damage assessed by the level of S100ß protein, regarded as a marker of brain damage., Materials and Methods: A group of 100 patients undergoing planned mitral valve operation through median sternotomy using standard CPB was recruited for the study. Echocardiography was performed prior to and after the CPB. CO 2 insufflation at 6 L/minute was conducted in the study group. Blood samples for S100ß protein analysis were collected after induction of anesthesia, 2 hours after aorta de-clamping, and 24 hours after operation., Results: The S100ß level in blood plasma did not differ significantly between the study and the control group (0.13±0.08 µg/L, 1.12±0.59 µg/L, and 0.26±0.23 µg/L and 0.18±0.19 µg/L, 1.31±0.62 µg/L, and 0.23±0.12 µg/L, P =0.7, 0.14, and 0.78). The mean increase of the S100ß concentration was 13% lower in the group with CO 2 protection than in the control group (0.988 µg/L vs 1.125 µg/L), although statistically insignificant. Tricuspid valve annuloplasties (TVAs) had significant impact on the increase in S100ß concentration in the treatment group after 24 hours (TVA [-] 0.21±0.09 vs TVA [+] 0.42±0.42, P =0.05). In patients <60 years, there were significant differences in the S100ß level 2 and 24 hours after the procedure (1.59±0.682 µg/L vs 1.223±0.571 µg/L, P =0.048, and 0.363±0.318 µg/L vs 0.229±0.105 µg/L, P =0.036) as compared with younger patients., Conclusion: The increase in S100ß concentration was lower in the group with CO 2 protection than in the control group. Age and an addition of TVA significantly influenced the level of S100ß concentration in the tests performed 2 hours after aortic clamp release., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background & Objectives: Leishmania parasites are sensitive to very low temperature. Cryotherapy is considered as an alternative to the existing pentavalent antimonials, for local treatment of cutaneous leishmaniasis (CL). Normally, liquid nitrogen (N 2 ) at a temperature of -196 °C, is used in cryotherapy of CL, but it's efficacy is not consistent. Recently, few studies have also reported the use of carbon dioxide (CO 2 ) slush at -78.5 °C in CL cryotherapy. This study was aimed to evaluate the effectiveness of N 2 vs CO 2 cryotherapy for CL treatment in mice. Methods: In total, 21 BALB/c mice were infected with Leishmania major strain [MRHO/IR/74/ER]. Samples were divided into three groups based on the intervention provided-Solid CO 2 cryotherapy, liquid N 2 cryotherapy and control group; with seven mice randomly assigned to each group. Control group received no intervention, and in the other two groups cryotherapy was used every two weeks for maximum of three months. Follow up examinations were scheduled at the time of cryotherapy, during which the size of each lesion was measured. For three mice in each study group, the spleen parasite DNA load was quantified using real-time PCR., Results: After treatment, the liquid N 2 cryotherapy showed significant reduction in size of the lesions (p = 0.029) as compared to the solid CO 2 cryotherapy and control group. Also, Leishmania DNA load in spleen was significantly lower in the mice receiving liquid N 2 cryotherapy (p <0.001)., Interpretation & Conclusion: Liquid N 2 cryotherapy is superior to CO 2 cryotherapy, and it can be an effective method for controlling L. major infection. Further investigations are essential to find optimal number of treatment sessions and time intervals., Competing Interests: The funder had no financial or proprietary interest in any material or method used in this study and had no role in study design, data collection and analysis, or preparation of the manuscript. The authors declare that there is no conflict of interests

Background: Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy., Aim: To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2)., Results: PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone., Conclusion: IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.

Introduction: Exposure to carbon monoxide (CO) is among the most common causes of acute and chronic poisonings worldwide. The crucial point of treatment of such acute poisonings is to eliminate CO from the body as fast as possible. There are currently two approaches to the management of the CO intoxication: hyperbaric oxygen therapy (HOT) and normobaric oxygen therapy (NOT). HOT is highly effective and capable of achieving the CO elimination half-time (T½) as low as 15 minutes. Unfortunately this method is expensive and not always readily available. The elimination of CO with the use of NOT (T½~70 min) is slower, but treatment can be started even on the site of the exposure and continued while the patient is transported to a hospital. The aim of the study was to evaluate the effectiveness of a method using therapeutic hyperventilation with maintenance of isocapnia (IH) in the elimination of CO in volunteers exposed to CO and to compare selected gasometric and respiratory parameters during IH with the values obtained during hyperventilation with pure oxygen ("non-isocapnic hyperventilation"-NIH)., Material and Methods: The study involved 13 healthy, chronically-smoking volunteers. Each of them participated in two independent hyperventilation tests: IH and NIH. The levels of carboxyhemoglobin (COHb) and selected gasometric, cardiac and respiratory parameters were measured at 0, 10 and 20 minutes during both tests. Among 13 volunteers (8 women and 5 men) the initial COHb level was 5.0±1.5% (mean±SD) before the IH tests and 5.1±1.9% before the NIH tests (p>0.05). After 20 minutes of the procedures the mean COHb level was 2.9±0.9% for IH and 3.6±1.2% for NIH (p<0.01). The T½ of COHb was 29.6±12.2 min and 47.3±19.2 min respectively (p<0.01). After 10 minutes of NIH respiratory alkalosis was noted in 11 participants (84.6%). Such problem was not seen during the IH procedures. No serious adverse effects were recorded during either IH or NIH. Mild symptoms such as: dyspnea, headache and paresthesias were reported by 6 volunteers (46%) during both IH and NIH tests. It is worth noting that paresthesias were only reported during NIH, by 2 participants (15.4%)., Conclusions: The elimination T½ of CO during IH was comparable with the values reported during HOT, and lower than can be achieved with NOT or NIH. No serious adverse effects were reported during IH procedures. Further studies, especially direct comparisons with NOT and HOT, are necessary to evaluate the effectiveness of IH in the treatment of acute CO poisoning., Competing Interests: The authors have declared that no competing interests exist.

Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA) ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30-39 mmHg, 40-49 mmHg, 50-59 mmHg, and 60-69 mmHg, respectively) or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60-80 mmHg) for 180 min. The mean artery pressure (MAP), blood gas, and cerebral blood flow (CBF) were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4) expression. In rats treated with severe hypoxia (PaO2 < 50 mmHg), hypercapnia augmented the decline of MAP with cortical CBF and damaged blood-brain barrier permeability (p < 0.05). In contrast, in rats treated with mild to moderate hypoxia (PaO2 > 50 mmHg), hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg); especially under mild hypoxemia (PaO2 > 60 mmHg), hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05). Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia., Competing Interests: The authors have declared that no competing interests exist.

Background/aims: Same-day bidirectional endoscopy (BDE) is a commonly performed procedure, but the optimal sequence of the procedure with carbon dioxide insufflation is not well established. In this study, we investigated the optimal sequence for same-day BDE without polypectomy under moderate sedation and carbon dioxide insufflation in terms of sedation doses and colonoscopy performance., Patients and Methods: We performed a prospective observational study of 63 asymptomatic patients who were admitted for physical check-ups. A colonoscopy-esophagogastroduodenoscopy (EGD) examination was performed first and then an EGD-colonoscopy examination was performed within 1.5 years., Results: The total procedure time, procedure complexity, bowel preparation quality, cecal intubation time, colon polyp detection rate, and adverse events were similar between the two study groups. The total doses of fentanyl and midazolam were significantly higher for the colonoscopy-EGD group than that for the EGD-colonoscopy group (70.8 ± 9.6 μg vs. 56.6 ± 9.2 μg and 6.1 ± 1.3 mg vs. 4.6 ± 1.1 mg, P < 0.0001 and P < 0.0001, respectively). The recovery time to discharge was significantly longer for the colonoscopy-EGD group compared to the EGD-colonoscopy group (38.5 ± 3.9 min vs. 31.9 ± 3.2 min, P < 0.001, respectively)., Conclusions: EGD-colonoscopy is the optimal sequence for same-day BDE. In this order, the procedures are better tolerated, the sedation doses are reduced, and the recovery time is shorter.

Background: A major challenge in treating acute asthma exacerbations is the need to open constricted airways rapidly enough to reestablish ventilation and allow delivery of conventional medication to diseased airways. The solution requires a new approach that considers both biophysical and pharmacological aspects of treatments used in acute asthma. The result of testing several formulations was S-1226: carbon dioxide-enriched air delivered in nebulized perflubron, a synthetic surfactant. These agents act synergistically to rapidly reopen closed airways within seconds. The bronchodilator effect is independent of β-adrenergic and cholinergic mediated-signaling pathways, offering a unique mechanism of action. S-1226 has a low toxicity profile and was effective in treating bronchoconstriction in animal models of asthma. The goal of the present study was to evaluate the safety and tolerability of S-1226 in healthy human subjects., Methods: The phase I study was a single-center, randomized, double-blind, placebo-controlled, sequential, single-ascending-dose study conducted in Canada. Thirty-six subjects were distributed into three cohorts. Within each cohort, subjects were randomized to receive a single dose of S-1226 or a matching placebo administered over a 2-minute nebulization period. S-1226 was formulated with perflubron and 4 %, 8 %, or 12 % CO2. The dose of CO2 was sequentially escalated by cohort. The safety and tolerability of S-1226 were evaluated through assessment of adverse events, vital signs, 12-lead electrocardiograms, clinical laboratory parameters, and physical examinations., Results: S-1226 was safe and well tolerated at all three CO2 levels (4 %, 8 %, and 12 %). A total of 28 adverse events were reported, and all were judged mild in severity. Twenty-four adverse events occurred in the S-1226 cohort, of which five were considered remotely related and six possibly related to S-1226., Conclusions: S-1226 is a novel drug being developed for the treatment of acute asthma exacerbations. It consists of CO2-enriched air and perflubron and has potential to offer rapid and potent bronchodilation. The results of the study indicate that S-1226 is safe and well tolerated. All adverse events were mild, reversible, and likely due to known side effects of CO2 inhalation., Trial Registration: ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015.

Context: Spinal cord injury (SCI) causes disruption of the efferent input to and afferent input from respiratory muscles, which impairs respiratory motor and sensory functions, respectively. This disturbs the injured individual's ability to respond to ventilatory loads and may alter the respiratory perceptual sensitivity of applied loads. Acute intermittent hypoxia with elevated CO(2) (AIH treatment) has been shown to induce ventilatory long-term facilitation in individuals with chronic SCI. This study evaluated the effect of ten days of AIH treatment on ventilatory load compensation and respiratory perceptual sensitivity to inspiratory resistive loads (IRL), in an individual with chronic, incomplete cervical SCI., Methods: Case report and literature review., Findings: We report a case of a 55-year-old female with a C4 chronic, incomplete SCI (American Spinal Injury Association Impairment Scale D). The subject underwent evaluation at four time-points: Baseline, Post Sham, AIH Day 1 and AIH Day 10. Significant improvements in airflow generated in response to applied IRL were found after AIH treatment compared to Baseline. There were no significant changes in the respiratory perceptual sensitivity to applied IRL after AIH treatment., Clinical Relevance: Rehabilitative interventions after SCI demand restoration of the respiratory motor function. However, they must also ensure that the respiratory perceptual sensitivity of the injured individual does not hinder their capability to compensate to ventilatory challenges.

Purpose: The peritoneum is the serous membrane that covers the abdominal cavity and most of the intra-abdominal organs. It is a very delicate layer highly susceptible to damage and it is not designed to cope with variable conditions such as the dry and cold carbon dioxide (CO2) during laparoscopic surgery. The aim of this review was to evaluate the effects caused by insufflating dry and cold gas into the abdominal cavity after laparoscopic surgery., Methods: A literature search using the Pubmed was carried out. Articles identified focused on the key issues of laparoscopy, peritoneum, morphology, pneumoperitoneum, humidity, body temperature, pain, recovery time, post-operative adhesions and lens fogging., Results: Insufflating dry and cold CO2 into the abdomen causes peritoneal damage, post-operative pain, hypothermia and post-operative adhesions. Using humidified and warm gas prevents pain after surgery. With regard to hypothermia due to desiccation, it can be fully prevented using humidified and warm gas. Results relating to the patient recovery are still controversial., Conclusions: The use of humidified and warm insufflation gas offers a significant clinical benefit to the patient, creating a more physiologic peritoneal environment and reducing the post-operative pain and hypothermia. In animal models, although humidified and warm gas reduces post-operative adhesions, humidified gas at 32 °C reduced them even more. It is clear that humidified gas should be used during laparoscopic surgery; however, a question remains unanswered: to achieve even greater clinical benefit to the patient, at what temperature should the humidified gas be when insufflated into the abdomen? More clinical trials should be performed to resolve this query.

Background: One-lung ventilation (OLV) can result in local and systemic inflammation. This prospective, randomized trial was to evaluate the effect of therapeutic hypercapnia on lung injury after OLV., Method: Fifty patients aged 20 to 60 yr undergoing lobectomy were randomly provided with air or carbon dioxide (partial pressure of carbon dioxide: 35 to 45 mmHg or 60 to 70 mmHg). Peak pressure, plateau pressure, and lung compliance were recorded. Bronchoalveolar lavage fluid (BALF) and blood samples were collected. Adverse events were monitored. The primary outcome was the concentration of BALF tumor necrosis factor, and the secondary outcomes were serum cytokine concentrations., Results: The BALF tumor necrosis factor was lower in the carbon dioxide group than in the air group (median [range], 51.1 [42.8 to 76.6] vs. 71.2 [44.8 to 92.7]; P = 0.034). Patients in the carbon dioxide group had lower concentrations of serum and BALF interleukin (IL)-1, IL-6, and IL-8, but higher serum concentrations of IL-10, accompanied by reduced numbers of cells and neutrophils as well as lower concentrations of protein in the BALF. Also, patients in the carbon dioxide group had lower peak (mean ± SD, 22.2 ± 2.9 vs. 29.8 ± 4.6) and plateau pressures (20.5 ± 2.4 vs. 27.1 ± 2.9), but higher dynamic compliance (46.6 ± 5.8 vs. 38.9 ± 6.5). Furthermore, patients in the carbon dioxide group had higher postoperation oxygenation index values. Ten patients experienced slightly increased blood pressure and heart rate during OLV in the carbon dioxide group., Conclusion: Under intravenous anesthesia, therapeutic hypercapnia inhibits local and systematic inflammation and improves respiratory function after OLV in lobectomy patients without severe complications.

This study compared functional and physical collateral damage to a nerve when operating a Codman MALIS Bipolar Electrosurgical System CMC-III or a CO2 laser coupled to a laser, with correlation to an in vitro model of heating profiles created by the devices in thermochromic ink agarose. Functional damage of the rat sciatic nerve after operating the MALIS or CO2 laser at various power settings and proximities to the nerve was measured by electrically evoked nerve action potentials, and histology of the nerve was used to assess physical damage. Thermochromic ink dissolved in agarose was used to model the spatial and temporal profile of the collateral heating zone of the electrosurgical system and the laser ablation cone. We found that this laser can be operated at 2 W directly above the nerve with minimal damage, while power settings of 5 W and 10 W resulted in acute functional and physical nerve damage, correlating with the maximal heating cone in the thermochromic ink model. MALIS settings up to 40 (11 W) did not result in major functional or physical nerve damage until the nerve was between the forceps tips, correlating with the hottest zone, localized discretely between the tips.

Hypercapnia and hypocapnia commonly complicate conditions that are present in critically ill patients. Both conditions have important physiologic effects that may impact the clinical management of these patients. For instance, hypercapnia results in bronchodilation and enhanced hypoxic vasoconstriction, leading to improved ventilation/perfusion matching. Hypocapnia reduces cerebral blood volume through arterial vasoconstriction. These effects have also been exploited for therapeutic aims. In patients with traumatic brain injury (TBI), hypocapnia is often utilized to control intracranial pressure. However, this effect is not sustained, and prolonged hypocapnia increases the risk of mortality and severe disability in patients with TBI. Hypercapnia and hypercapnic acidosis are common consequences of lung-protective ventilation in ARDS. Hypercapnic acidosis reduces ischemic lung injury and preserves lung compliance, but concern has arisen over hypercapnia-induced immunosuppression and the potential for bacterial proliferation in sepsis. Experimental studies suggest that buffering hypercapnic acidosis attenuates these effects, whereas hypocapnia appears to potentiate lung injury through increased capillary permeability and decreased lung compliance. Several areas of uncertainty surround the role of hypercapnia/hypocapnia in treating TBI and ARDS. Current data support recommendations to avoid hypocapnia in treating TBI, with the exception of emergent treatment of elevated intracranial pressure, while awaiting definitive management. Permissive hypercapnia is commonly accepted as a consequence of lung-protective ventilation in ARDS, but there is insufficient evidence to support the induction of hypercapnic acidosis in clinical practice. Buffering hypercapnic acidosis should be considered only for a specific clinical indication (eg, hemodynamic instability). For clinicians choosing to buffer hypercapnic acidosis, tris-hydroxymethyl aminomethane is recommended over sodium bicarbonate, as it is more effective in correcting pH and is not associated with increased carbon dioxide production. Future studies should aim to address these areas of uncertainty to help guide clinicians in the therapeutic use and management of hypercapnia/hypocapnia in critically ill patients., (Copyright © 2014 by Daedalus Enterprises.)

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO2), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n=36) and Sprague-Dawley rats (n=23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO2 (PaCO2) was modulated by hyper- or hypoventilation or by inhalation of 10% CO2. In rats, CO2-mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO2 caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO2. This lack of microvascular CO2 reactivity was accompanied by a complete loss of CO2-induced hyperemia. Our data show that CO2 is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO2.

Background: Gasless laparoendoscopic single-port surgery (GasLESS) for radical nephrectomy (GasLESSRN) in the flank position is a minimally invasive treatment option for patients with T1-3 renal cell carcinoma (RCC). However, RCC patients considered suitable for supine positioning rather than flank positioning for radical nephrectomy are occasionally encountered. This study evaluated the safety and feasibility of approach via a small retroperitoneal anterior subcostal incision (RASI) in the supine position for GasLESSRN (RASI-GasLESSRN) on the basis of our initial experience., Methods: RASI-GasLESSRN was performed on 42 patients with RCC or suspected RCC from 2011-2013. The RASI, which was 6 cm long in principle, was made parallel to the tip of the rib from the lateral border of rectus abdominis muscle toward the flank in the supine position. The specimen was extracted via the RASI using a retrieval device. All procedures were performed retroperitoneally under flexible endoscopy with reusable instruments and without carbon dioxide insufflation or insertion of hands into the operative field., Results: RASI-GasLESSRN was successfully performed in all patients without complications. The mean incision length was 6.3 cm, mean operative time was 198 minutes, and mean blood loss was 284 mL. All 42 patients were classified as Clavien grade I. The mean times to oral feeding and walking were 1.1 and 2 days, respectively. The mean number of postoperative days required for patients to be dischargeable was 3.7 days., Conclusions: The approach via a small RASI in the supine position for GasLESSRN is a safe and feasible technique. RASI-GasLESSRN in the supine position is an alternative minimally invasive treatment option, especially for RCC patients considered suitable for supine positioning.

Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial., Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient., Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed., Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732)., (©2014 AACR)

Purpose: To investigate the effects of pneumoperitoneum on colonic anastomosis healing., Methods: Colonic anastomosis was performed in 120 rats divided into four groups: Group I - pneumoperitoneum before laparotomy, Group II - pneumoperitoneum after laparorrhaphy, Group III - pneumoperitoneum before laparotomy and after laparorrhaphy, Group IV - no pneumoperitoneum (control group). Pneumoperitoneum pressure was 5 mmHg. Animals were killed on the 3rd, 7th and 14th postoperative day. Histopathological features, anastomosis breaking strength, collagen histomorphometry and hydroxyproline concentration were assessed., Results: Breaking strength between groups: (day 3, p=0.165; day 7, p=0.219; day 14, p=0.539). Histopathology revealed that group II had, on day 7, less infiltration of mononuclear cells (p=0.006), greater infiltration of polymorphonuclear cells (p=0.001) and greater necrosis (p=0.001); and on day 14, less fibrosis. Histomorphometry revealed a decrease in collagen in groups I and III (p<0.001) on day 7 and an increase in groups I and II on day 14 (p<0.001). Hydroxyproline concentration was similar for groups on days 3 (p=0.152), 7 (p=0.913) or 14 (p=0.981)., Conclusion: Carbon dioxide does not impair the healing of colonic anastomosis in rats.

Purpose: To investigate the effect of carboxytherapy in auricular composite grafts in rabbits., Methods: An experimental study was conducted using 20 rabbits randomly assigned to a treatment group of carboxytherapy or a control group of saline solution. In each ear, a circular graft with 1.5 cm or 2 cm of diameter was amputated and reattached. Animals underwent carbon dioxide or saline injection four times during the experiment. We analyzed clinical evolution of the animals, grafts survival, histopathology features and histomorphometry of collagen., Results: The treated group had a significantly lower weight gain (p=0.038). Histopathology was not significantly different between groups. There was an increase in amount of collagen in 2 cm grafts submitted to carbon dioxide therapy (p=0.003). Carboxytherapy didn't influence graft survival rate for 1.5 cm grafts or 2 cm grafts (p=0.567 and p=0.777, respectively)., Conclusions: Carbon dioxide therapy increased the amount of collagen in 2 cm grafts. CO2 was not significantly different from saline infusion on composite grafts survival, but this study suggests that there is a mechanical effect caused by distension which favored graft survival.

Background: 2-8% of all children aged between 6 months and 5 years have febrile seizures. Often these seizures cease spontaneously, however depending on different national guidelines, 20-40% of the patients would need therapeutic intervention. For seizures longer than 3-5 minutes application of rectal diazepam, buccal midazolam or sublingual lorazepam is recommended. Benzodiazepines may be ineffective in some patients or cause prolonged sedation and fatigue. Preclinical investigations in a rat model provided evidence that febrile seizures may be triggered by respiratory alkalosis, which was subsequently confirmed by a retrospective clinical observation. Further, individual therapeutic interventions demonstrated that a pCO2-elevation via re-breathing or inhalation of 5% CO2 instantly stopped the febrile seizures. Here, we present the protocol for an interventional clinical trial to test the hypothesis that the application of 5% CO2 is effective and safe to suppress febrile seizures in children., Methods: The CARDIF (CARbon DIoxide against Febrile seizures) trial is a monocentric, prospective, double-blind, placebo-controlled, randomized study. A total of 288 patients with a life history of at least one febrile seizure will be randomized to receive either carbogen (5% CO2 plus 95% O2) or placebo (100% O2). As recurrences of febrile seizures mainly occur at home, the study medication will be administered by the parents through a low-pressure can fitted with a respiratory mask. The primary outcome measure is the efficacy of carbogen to interrupt febrile seizures. As secondary outcome parameters we assess safety, practicability to use the can, quality of life, contentedness, anxiousness and mobility of the parents., Prospect: The CARDIF trial has the potential to develop a new therapy for the suppression of febrile seizures by redressing the normal physiological state. This would offer an alternative to the currently suggested treatment with benzodiazepines. This study is an example of academic translational research from the study of animal physiology to a new therapy., Trial Registration: ClinicalTrials.gov identifier: NCT01370044.

Purpose: To evaluate the healing effect of carbon dioxide therapy on skin wounds induced on the back of rats., Methods: Sixteen rats underwent excision of a round dermal-epidermal dorsal skin flap of 2.5 cm in diameter. The animals were divided into two groups, as follows: carbon dioxide group - subcutaneous injections of carbon dioxide on the day of operation and at three, six and nine days postoperatively; control group - no postoperative wound treatment. Wounds were photographed on the day of operation and at six and 14 days postoperatively for analysis of wound area and major diameter. All animals were euthanized on day 14 after surgery. The dorsal skin and the underlying muscle layer containing the wound were resected for histopathological analysis., Results: There was no statistically significant difference between groups in the percentage of wound closure, in histopathological findings, or in the reduction of wound area and major diameter at 14 days postoperatively., Conclusion: Under the experimental conditions in which this study was conducted, carbon dioxide therapy had no effects on the healing of acute skin wounds in rats.

Purpose: Vascular disorders and viral infections are considered the main causes of sudden hearing loss (SHL), although its pathogenesis remain unclear. Treatments include carbogen inhalation and lipo-prostaglandin E1 (lipo-PGE1), both of which have circulation-enhancing effects. We investigated the effectiveness of carbogen inhalation and lipo-PGE1 in SHL., Materials and Methods: This retrospective review included 202 patients with idiopathic SHL who visited our clinic within 14 days of symptom onset between January 2006 and June 2010. All patients received oral prednisolone for 10 days. Of the 202 patients, 44 received no additional treatment, 106 received additional carbogen inhalation, and 52 received additional lipo-PGE1. Hearing improvement was measured using Siegel's criteria., Results: Overall recovery rates were 67.9% in the carbogen group, 53.8% in the lipo-PGE1 group, and 52.3% in the steroid-only control group (p=0.097). Limited to type 1 and type 2 categories of Sigels's criteria, the carbogen group had a significantly higher recovery rate (53.8%) than the lipo-PGE1 group (26.9%) and the steroid-only control group (38.6%) (p=0.005)., Conclusion: Carbogen inhalation added to steroid was a more effective treatment than lipo-PGE1 added to steroid or steroid alone in patients with SHL.

Objective: To determine the effects of carbon dioxide (CO(2)) and nitrogen (N(2)) pneumoperitoneums on endometriosis (EMs) lesions., Methods: Female Wistar rats were randomized into the following 3 groups: CO(2) (N = 20), N(2) (N = 22) and air pneumoperitoneums (N = 9). After 5 weeks of establishment models, do the pneumoperitoneums. Then measure the size of EMs lesions and the related factors of serum and tissue after 1, 2, and 4 weeks of pneumoperitoneums., Results: (1) One week after the pneumoperitoneum was established, the EMs lesions in the CO(2) group were largest in volume, whereas at 4 weeks the EMs lesions in the CO(2) group were smaller than the N(2) group. (2) The level of ICAM-1 and TIMP-2 of serum in CO(2) and N(2) group after 2 weeks of pneumoperitoneum were higher than air group. (3) The expression of CD44v6, ICAM-1, MMP-2 and VEGF of tissue in CO(2) and N(2) group after 1, 2 and 4 weeks of pneumoperitoneum were lower than air group, TIMP-2 and ENS were higher than air group., Conclusion: After a CO(2) pneumoperitoneum, EMs lesions were reduced in volume, suggesting an inhibitory effect on EMs lesions.