The effect of hyperbaric oxygen on mitochondrial and glycolytic energy metabolism: the caloristasis concept.

We present new data on the effects of HBOT on human kidney (HK-2) cell metabolism using a SeaHorse XF Analyzer to evaluate separately the state of mitochondrial and glycolytic energy metabolism. The data are discussed in the context of the concept of cellular caloristasis networks. The information on the changes in cellular energy metabolism stimulated by HBOT presented here provides new insights into the cellular energy state and mitochondrial environment in which sHSPs function. These data will be useful in forming testable hypotheses about the functions of translocated sHSPs in human mitochondria responding to stressors.

Early hyperbaric oxygen therapy improves survival in a model of severe sepsis.

Sepsis is a major clinical challenge, with therapy limited to supportive interventions. Therefore, the search for novel remedial approaches is of great importance. We addressed whether hyperbaric oxygen therapy (HBOT) could improve the outcome of sepsis using an acute experimental mouse model. Sepsis was induced in male CD-1 mice by cecal ligation and puncture (CLP) tailored to result in 80-90% mortality within 72 h of the insult. After CLP, mice were randomized into two groups receiving HBOT or not at different times after the initial insult or subjected to multiple HBOT treatments. HBOT conditions were 98% oxygen pressurized to 2.4 atmospheres for 1 h. HBOT within 1 h after CLP resulted in 52% survival in comparison with mice that did not receive the treatment (13% survival). Multiple HBOT at 1 and 6 h or 1, 6, and 21 h displayed an increase in survival of >50%, but they were not significantly different from a single treatment after 1 h of CLP. Treatments at 6 or 21 h after CLP, excluding the 1 h of treatment, did not show any protective effect. Early HBO treatment did not modify bacterial counts after CLP, but it was associated with decreased expression of TNF-α, IL-6, and IL-10 expression in the liver within 3 h after CLP. The decrease of cytokine expression was reproduced in cultured macrophages after exposure to HBOT. Early HBOT could be of benefit in the treatment of sepsis, and the protective mechanism may be related to a reduction in the systemic inflammatory response.

Might hyperbaric oxygen therapy (HBOT) reduce renal injury in diabetic people with diabetes mellitus? From preclinical models to human metabolomics.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure in the western world. Current treatment of diabetic kidney disease relies on nutritional management and drug therapies to achieve metabolic control. Here, we discuss the potential application of hyperbaric oxygen therapy (HBOT) for the treatment of diabetic kidney disease (DKD), a treatment which requires patients to breathe in 100% oxygen at elevated ambient pressures. HBOT has traditionally been used to diabetic foot ulcers (DFU) refractory to conventional medical treatments. Successful clinic responses seen in the DFU provide the underlying therapeutic rationale for testing HBOT in the setting of DKD. Both the DFU and DKD have microvascular endothelial disease as a common underlying pathologic feature. Supporting evidence for HBOT of DKD comes from previous animal studies and from our preliminary prospective clinical trial reported here. We report urinary metabolomic data obtained from patients undergoing HBOT for DFU, before and after exposure to 6 weeks of HBOT. The preliminary data support the concept that HBOT can reduce biomarkers of renal injury, oxidant stress, and mitochondrial dysfunction in patients receiving HBOT for DFU. Further studies are needed to confirm these initial findings and correlate them with simultaneous measures of renal function. HBOT is a safe and effective treatment for DFU and could also be for individuals with DKD.

Wound Healing Devices Brief Vignettes.

Significance: The demand for wound care therapies is increasing. New wound care products and devices are marketed at a dizzying rate. Practitioners must make informed decisions about the use of medical devices for wound healing therapy. This paper provides updated evidence and recommendations based on a review of recent publications. Recent Advances: The published literature on the use of medical devices for wound healing continues to support the use of hyperbaric oxygen therapy, negative pressure wound therapy, and most recently electrical stimulation. Critical Issue: To inform wound healing practitioners of the evidence for or against the use of medical devices for wound healing. This information will aid the practitioner in deciding which technology should be accepted or rejected for clinical use. Future Directions: To produce high quality, randomized controlled trials or acquire outcome-based registry databases to further test and improve the knowledge base as it relates to the use of medical devices in wound care.

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.

The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

Principles and practice of hyperbaric medicine: a medical practitioner's primer, part II.

Advances in the treatment of chronic wounds* have steadily occurred over the past decade and include the specialized use of dynamic compression therapy, implementation of moist wound care techniques, chronic lymphedema therapy, negative pressure wound therapy, arterial compression therapy and application of off-loading devices. General medical practitioners should recognize when timely patient referral to a comprehensive wound care center is indicated. The clinical practice of HBOT and its scientific basis has also advanced significantly during this same time period. HBOT is a therapeutic tool with many qualities that are unique to medical care and enable difficult and otherwise untreatable conditions to be safely and effectively managed. Level 1 evidence exists for HBOT and the therapeutic indications are growing. It is the responsibility of all practitioners to become informed about the modern principles and practice of HBOT. Clinicians should take the advice of Mark Twain: "Supposing is good but finding out is better." It is the responsibility of educational institutions and medical societies to become informed and actively engaged in hyperbaric medical care, education and research. This will benefit our patients as well as our systems of medical care. There is now ample access to hyperbaric oxygen facilities and expertise with the state. There is a growing need for HBOT services due to the rising incidence of obesity and diabetes combined with an aging demographic. Appropriate networks and patterns of referral have lagged behind this demand due to a generalized lack of understanding of the true risks, benefits and indications for HBOT. This review will hopefully begin to address this problem. Hyperbaric medicine is in an early phase of development. The current and future demand for clinical services will drive development of research and educational programs. Only through continued efforts for perform high quality research and education will the full potential of HBOT be realized. Much remains to be done. As systems for the delivery of healthcare enter an era of population management, the regenerative potential of hyperbaric therapies should improve quality of and reduce costs and enable us to meet the challenge of providing care for the growing population of chronic wound patients.

Peripheral neuropathy may increase the risk for asymptomatic otic barotrauma during hyperbaric oxygen therapy: research report.

OBJECTIVE: Otic barotrauma (OBT) is an adverse event seen in patients receiving hyperbaric oxygen (HBO2) therapy. After encountering a case of painless tympanic perforation during HBO2 therapy of a diabetic patient with the diagnosis of neuropathic Wagner Grade III foot ulcer, we hypothesized that peripheral neuropathy of the lower extremity may be associated with an increased risk of asymptomatic OBT during HBO2 therapy. METHODS: The medical records of all HBO2 patients during a one-year period of time were reviewed. Subjects were selected based on otoscopic documentation of OBT and divided into two groups based on the presence or absence of lower extremity peripheral neuropathy. Time to therapeutic compression, presence or absence of ear-related symptoms and modified Teed (mTeed) scores were compared between the two groups. RESULTS: A total of 38 patients with OBT, 18 neuropathic and 20 non-neuropathic, were identified. Asymptomatic OBT occurred more frequently in the neuropathic vs. non-neuropathic group (56% vs. 5%, p < 0.001). mTeed scores were significantly greater in the neuropathic vs. non-neuropathic group (mTeed 1, 30% vs. 61%; mTeed 2, 65% vs. 36%; mTeed 3, 4% vs. 3%; p = 0.032). Mean compression times were shorter in the neuropathic vs. non-neuropathic group (10. 5 +/- 1.8 vs. 14.4 +/- 3.3 minutes, p < 0.001). CONCLUSIONS: The presence of peripheral neuropathy of the lower extremity may be associated with a significantly greater incidence of asymptomatic otic barotrauma during HBO2 therapy.

The Kent hospital Wound Recovery and Hyperbaric Medicine Center: a brief overview, 1998-2013.

A brief description of the Wound Recovery and Hyperbaric Medicine Center, now in its second decade of service, will inform the general medical community of this valuable asset. Demand for wound care services is predicted to grow steadily over the next several decades. Kent Hospital's vision for wound care is embodied in its thriving Wound Recovery and Hyperbaric Medicine Center. New cost- effective wound healing therapies must be developed and evidence-based practices established. New physicians and support staff must be trained. Only through a blending of high quality clinical care with research and education will these objectives be achieved and future successes in the management of patients and their wounds be made possible.

Principles and practice of hyperbaric medicine: a medical practitioner's primer, part I.

The purpose of this monograph is to narrow the knowledge gap between current medical practice and hyperbaric oxygen therapy. Graduate medical education has not kept pace with the expanding science and practice of hyperbaric medicine. The number of hyperbaric chambers in the state of Connecticut has increased by >400% during the past five years. A brief overview of the science and practice of hyperbaric oxygen therapy is presented, with additional resources identified where more in-depth coverage can be found. The reader will find the basics of hyperbaric medical practice reviewed and be able to recognize diagnoses that are appropriate for referral to a hyperbaric medical center. The intended audience is practitioners who have had no formal exposure to hyperbaric medicine or chronic wound care.

Hyperbaric oxygen preconditioning protects skin from UV-A damage.

Hyperbaric oxygen therapy (HBOT) is used for a number of applications, including the treatment of diabetic foot ulcers and CO poisoning. However, we and others have shown that HBOT can mobilize cellular antioxidant defenses, suggesting that it may also be useful under circumstances in which tissue protection from oxidative damage is desired. To test the protective properties of hyperbaric oxygen (HBO) on a tissue level, we evaluated the ability of a preconditioning treatment regimen to protect cutaneous tissue from UV-A-induced oxidative damage. Three groups of hairless SKH1-E mice were exposed to UV-A 3 days per week for 22 weeks, with two of these groups receiving an HBO pretreatment either two or four times per week. UV-A exposure increased apoptosis and proliferation of the skin tissue, indicating elevated levels of epithelial damage and repair. Pretreatment with HBO significantly reduced UV-A-induced apoptosis and proliferation. A morphometric analysis of microscopic tissue folds also showed a significant increase in skin creasing following UV-A exposure, which was prevented by HBO pretreatment. Likewise, skin elasticity was found to be greatest in the group treated with HBO four times per week. The effects of HBO were also apparent systemically as reductions in caspase-3 activity and expression were observed in the liver. Our findings support a protective function of HBO pretreatment from a direct oxidative challenge of UV-A to skin tissue. Similar protection of other tissues may likewise be achievable.

Transcriptional pausing coordinates folding of the aptamer domain and the expression platform of a riboswitch.

Riboswitches are cis-acting elements that regulate gene expression by affecting transcriptional termination or translational initiation in response to binding of a metabolite. A typical riboswitch is made of an upstream aptamer domain and a downstream expression platform. Both domains participate in the folding and structural rearrangement in the absence or presence of its cognate metabolite. RNA polymerase pausing is a fundamental property of transcription that can influence RNA folding. Here we show that pausing plays an important role in the folding and conformational rearrangement of the Escherichia coli btuB riboswitch during transcription by the E. coli RNA polymerase. This riboswitch consists of an approximately 200 nucleotide, coenzyme B12 binding aptamer domain and an approximately 40 nucleotide expression platform that controls the ribosome access for translational initiation. We found that transcriptional pauses at strategic locations facilitate folding and structural rearrangement of the full-length riboswitch, but have minimal effect on the folding of the isolated aptamer domain. Pausing at these regulatory sites blocks the formation of alternate structures and plays a chaperoning role that couples folding of the aptamer domain and the expression platform. Pausing at strategic locations may be a general mechanism for coordinated folding and conformational rearrangements of riboswitch structures that underlie their response to environmental cues.

Wound healing from a cellular stress response perspective.

This meeting review highlights areas of mutual interest to investigators in the cellular stress response field and to those carrying out wound-healing research. Inflammation, perhaps the major unifying theme of this meeting, is an essential component of the adult wound response and understanding the control of inflammation is a common interest shared with researchers of the cellular stress response. The particular interest of the authors of this review is in chronic non-healing wounds that frequently occur in patients with major illnesses such as diabetes and diseases of the blood vessels. This orientation has undoubtedly influenced the selection of topics. It is fair to say that the authors were often surprised and certainly impressed with the overlapping interests and possibilities for collaboration among investigators of these two research areas.

Heavy metal ions in normal physiology, toxic stress, and cytoprotection.

As a group, heavy metals include both those essential for normal biological functioning (e.g., Cu and Zn), and nonessential metals (e.g., Cd, Hg, and Pb). Both essential and nonessential metals can be present at concentrations that disturb normal biological functions, and which evoke cellular stress responses. The cellular targets for metal toxicity include tissues of the kidney, liver, heart, and the immune response and nervous systems. Intriguingly, manipulations of specific metals, their reservoirs, and the cellular stress response can have therapeutic effects on certain diseases. In this minireview, we will consider both the biological responses to stressful levels of heavy metal cations, and experimental and clinical manipulations of these cations as a means to improve human health parameters.

Major hepatic trauma: warm ischemic tolerance of the liver after hemorrhagic shock.

BACKGROUND: The management of severe hepatic trauma frequently involves exposing the liver to varying periods of warm ischemia. The ischemic tolerance of the liver, in the setting of hemorrhagic shock (HS) and trauma, is presently unknown. We tested the hypothesis that warm ischemic tolerance of the porcine liver will be decreased following resuscitation from HS. MATERIALS AND METHODS: Twenty-three Yorkshire pigs were divided into three groups: 1) hepatic ischemia alone (HI, n = 9); 2) hemorrhagic shock alone (HS, n = 3); and 3) hemorrhagic shock plus hepatic ischemia combined (HSHI, n = 11). Following reperfusion, a liver biopsy was obtained and serial blood chemistries were sampled. RESULTS: Post-operative day 7 mortality was increased in the HSHI group (7/11) compared to the HI (0/9) group, P = 0.038. Notably, deaths did not result from acute liver failure, but rather from intra-operative hemodynamic collapse shortly following hepatic reperfusion. In addition, the HSHI group experienced significantly elevated lactic acid, serum creatinine and liver enzyme levels. Analysis of the liver biopsy samples is consistent with a more severe liver injury in the HSHI group. CONCLUSIONS: The warm ischemic tolerance of the liver following resuscitation from HS is significantly decreased in this porcine model compared to HS or HI alone. Mortality was associated with acute intra-operative hemodynamic collapse occurring shortly after hepatic reperfusion.

Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control.

OBJECTIVE: To investigate whether hyperglycemia in glucose-intolerant patients without diabetes could lead to increased nosocomial infections in the surgical intensive-care unit (ICU). METHODS: A prospective, randomized, controlled clinical trial was conducted in the surgical ICU of a large teaching hospital in Hartford, Connecticut. Adult patients admitted to a 12-bed surgical ICU requiring treatment of hyperglycemia (glucose values > or = 140 mg/dL) were randomly assigned to receive standard insulin therapy (target glucose range, 180 to 220 mg/dL) or strict insulin therapy (target glucose range, 80 to 120 mg/dL) throughout their ICU stay. Demographic data, comorbidities, and confounding variables were analyzed. Outcome measures included mean daily serum glucose values, mean daily insulin doses, and number of nosocomial infections during the ICU stay. RESULTS: The study was completed by 61 critically ill surgical patients (27 in the standard glucose control group and 34 in the strict glucose control group). A significant reduction (P<0.001) in mean daily glucose level was achieved in the strict glycemic control group (125 +/- 36 mg/dL) in comparison with the standard glycemic control group (179 +/- 61 mg/dL). Furthermore, a significant reduction (P<0.05) in the incidence of total nosocomial infections, including intravascular device, bloodstream, intravascular device-related bloodstream, and surgical site infections, was observed in the strict glucose control group in comparison with the standard glucose control group. The incidence of hypoglycemia (glucose levels <60 mg/dL) was significantly increased (P<0.001) in the strict glycemic control group in comparison with the standard glycemic control group (32% versus 7.4% of patients or 0.8% versus 0.1% of total serum glucose values, respectively). CONCLUSION: Strict glycemic control is a safe and effective method for reducing the incidence of nosocomial infections in a predominantly nondiabetic, general surgical ICU patient population.

Development and evaluation of the advanced trauma operative management course.

BACKGROUND: The Advanced Trauma Operative Management (ATOM) course was developed as a model for teaching operative trauma techniques to surgical residents, fellows, and attending surgeons as the number of these cases decreases. METHODS: The ATOM course consists of lectures and a porcine operative experience. Comprehensive evaluation of ATOM was designed to assess participant learning in the cognitive, affective, and psychomotor domains. Data on the first 50 participants were prospectively collected and analyzed. RESULTS: Participants included 20 expert traumatologists, 9 general surgeons, 9 trauma fellows, 8 general surgery fifth-year residents, and 4 general surgery fourth-year residents. All groups showed improvement in knowledge, with results in the expert and fellow groups reaching statistical significance. Self-efficacy (self-confidence) also improved, with all groups reaching statistical significance. CONCLUSION: This course creates life-like situations in a standardized fashion that, along with didactic instruction, improves knowledge and operative confidence for practicing surgeons and surgeons-in-training.

Preoperative stress conditioning prevents paralysis after experimental aortic surgery: increased heat shock protein content is associated with ischemic tolerance of the spinal cord.

BACKGROUND: All forms of surgical therapy are stressful and injurious. The problems of paralysis, renal dysfunction, and colonic ischemia associated with aortic occlusion are due to acute ischemia-reperfusion injury at the cellular level. Acute-anterior spinal cord ischemia is the most devastating outcome of these iatrogenic-ischemic events. The majority of surgical procedures are performed electively and therefore provide an opportunity to preoperatively condition the patient to minimize these ischemia-related morbidities. OBJECTIVES: We sought to determine whether acute spinal cord injury associated with aortic occlusion can be prevented by induction of the cellular stress response by means of preoperative administration of whole-body hyperthermia or stannous chloride. METHODS: The study consisted of an experimental rabbit model of infrarenal aortic occlusion for 20 minutes at normothermic body temperature. RESULTS: Control rabbits experienced an 88% (7/8) incidence of paralysis after spinal cord ischemia induced by 20 minutes of aortic occlusion, whereas animals treated preoperatively with either whole-body hyperthermia (0/9) or stannous chloride (0/4) never became paralyzed (P <.001 for control vs treated groups). Ischemic protection of the spinal cord was associated with increased content of stress proteins within tissues of pretreated animals. CONCLUSION: Prior induction of the heat shock response in the whole animal will increase the content of stress proteins within the spinal cord and other tissues and result in the prevention of hind-limb paralysis associated with aortic occlusion. We have designated the preoperative induction of the cellular stress response for the prevention of ischemic tissue injury stress conditioning. We suggest that stress-conditioning protocols represent the opportunity to practice preventative medicine at the molecular level.