Stephen R. Thom

Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α

Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1alpha expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-L-arginine-methyl ester. Administration of SDF-1alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1alpha reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.

Carbon monoxide poisoning — a public health perspective

Carbon monoxide (CO) may be the cause of more than one-half of the fatal poisonings reported in many countries; fatal cases also are grossly under-reported or misdiagnosed by medical professionals. Therefore, the precise number of individuals who have suffered from CO intoxication is not known. The health effects associated with exposure to CO range from the more subtle cardiovascular and neurobehavioral effects at low concentrations to unconsciousness and death after acute or chronic exposure to higher concentrations of CO. The morbidity and mortality resulting from the latter exposures are described briefly to complete the picture of CO exposure in present-day society. The symptoms, signs, and prognosis of acute CO poisoning correlate poorly with the level of carboxyhemoglobin (COHb) measured at the time of hospital admission; however, because CO poisoning is a diagnosis frequently overlooked, the importance of measuring COHb in suspicious settings cannot be overstated. The early symptoms (headache, dizziness, weakness, nausea, confusion, disorientation, and visual disturbances) also have to be emphasized, especially if they recur with a regular periodicity or in the same environment. Complications occur frequently in CO poisoning. Immediate death is most likely cardiac in origin because myocardial tissues are most sensitive to the hypoxic effects of CO. Severe poisoning results in marked hypotension, lethal arrhythmias, and electrocardiographic changes. Pulmonary edema may occur. Neurological manifestation of acute CO poisoning includes disorientation, confusion, and coma. Perhaps the most insidious effect of CO poisoning is the development of delayed neuropsychiatric impairment within 2-28 days after poisoning and the slow resolution of neurobehavioral consequences. Carbon monoxide poisoning during pregnancy results in high risk for the mother by increasing the short-term complication rate and for the fetus by causing fetal death, developmental disorders, and chronic cerebral lesions. In conclusion, CO poisoning occurs frequently; has severe consequences, including immediate death; involves complications and late sequelae; and often is overlooked. Efforts in prevention and in public and medical education should be encouraged.

Delayed Neuropsychologic Sequelae After Carbon Monoxide Poisoning: Prevention by Treatment With Hyperbaric Oxygen

STUDY OBJECTIVE Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION DNS after CO poisoning cannot be predicted on the basis of a patients clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.

Hyperbaric oxygen – its mechanisms and efficacy

Background: This article outlines therapeutic mechanisms of hyperbaric oxygen therapy and reviews data on its efficacy for clinical problems seen by plastic and reconstructive surgeons. Methods: The information in this review was obtained from the peer-reviewed medical literature. Results: Principal mechanisms of hyperbaric oxygen are based on intracellular generation of reactive species of oxygen and nitrogen. Reactive species are recognized to play a central role in cell signal transduction cascades, and the discussion will focus on these pathways. Systematic reviews and randomized clinical trials support clinical use of hyperbaric oxygen for refractory diabetic wound-healing and radiation injuries; treatment of compromised flaps and grafts and ischemia-reperfusion disorders is supported by animal studies and a small number of clinical trials, but further studies are warranted. Conclusions: Clinical and mechanistic data support use of hyperbaric oxygen for a variety of disorders. Further work is needed to clarify clinical utility for some disorders and to hone patient selection criteria to improve cost efficacy.

Oxidative stress is fundamental to hyperbaric oxygen therapy.

The goal of this review is to outline advances addressing the role that reactive species of oxygen and nitrogen play in therapeutic mechanisms of hyperbaric oxygen. The review will be organized around major categories of problems or processes where controlled clinical trials have demonstrated clinical efficacy for hyperbaric oxygen therapy. Reactive species are now recognized to play a major role in cell signal transduction cascades, and the discussion will focus on how hyperbaric oxygen acts through these pathways to mediate wound healing and ameliorate postischemic and inflammatory injuries.

Pathophysiology and treatment of carbon monoxide poisoning.

Carbon monoxide poisoning is the leading cause of poisoning deaths in the US, and published reports of carbon monoxide related morbidity and mortality can vary widely. Common morbidity involves myocardial and/or neurologic injury including delayed neurologic sequelae. The pathophysiology of this entity is complex, involving hypoxic stress on the basis of interference with oxygen transport to the cells and possibly impairing electron transport. Carbon monoxide can also affect leukocytes, platelets and the endothelium, inducing a cascade of effects resulting in oxidative injury. Carboxyhemoglobin levels are valuable for confirming carbon monoxide exposure but cannot be used to stratify severity of poisoning, predict prognosis, or indicate a specific treatment plan. Oxygen therapy is the key treatment of carbon monoxide intoxication, and hyperbaric oxygen has been shown to interdict and improve clinical outcome in some patients. Immediate treatment with a high fraction of inspired oxygen and careful clinical evaluation are mandatory. Timely referral for hyperbaric oxygen is indicated for patients with any history of unconsciousness, cardiovascular instability or ischemia, and persistent mental and/or neurologic deficits. Hyperbaric oxygen should also be considered in certain other patient subsets.

Nitric oxide production and perivascular nitration in brain after carbon monoxide poisoning in the rat.

Nitric oxide is a short-lived free radical and physiological mediator which has the potential to cause cytotoxicity. Studies were conducted to investigate whether nitric oxide, and the potent oxidant peroxynitrite, were generated in brain during experimental carbon monoxide (CO) poisoning in the rat. Nitric oxide production was documented by electron paramagnetic resonance spectroscopy, and found to be increased by ninefold immediately after CO poisoning. Evidence that peroxynitrite was generated was sought by looking for nitrotyrosine in the brains of CO-poisoned rats. Nitrotyrosine was found deposited in vascular walls, and also diffusely throughout the parenchyma in inummocytochemical studies. The affinity and specificity of an anti-nitrotyrosine antibody was investigated and a solid phase immunoradiochemical assay was developed to quantity nitrotyrosine in brain homogenates. A 10-fold increase in nitrotyrosine was found in the brains of CO-poisoned rats. Platelets were involved with production of nitrotyrosine in the early phase of exposure to CO. However, nitrotyrosine formation and leukocyte sequestration were not decreased in thrombocytopenic rats poisoned with CO according to the standard model. When rats were pre-treated with the nitric oxide synthase inhibitor, L-nitroarginine methyl ester, formation of both nitric oxide and nitrotyrosine in response to CO poisoning were abolished, as well as leukocyte sequestration in the microvasculature, endothelial xanthine dehydrogenase conversion to xanthine oxidase, and brain lipid peroxidation. We conclude that perivascular reactions mediated by peroxynitrite are important in the cascade of events which lead to brain oxidative stress in CO poisoning.

Carbon monoxide poisoning: a review epidemiology, pathophysiology, clinical findings, and treatment options including hyperbaric oxygen therapy.

Carbon monoxide (CO) poisoning is the leading cause of poisoning deaths (accidental and intentional) in the United States. While confirmation of CO poisoning is easily obtained via assessment of carboxyhemoglobin (COHgb) levels, evaluation of the severity of intoxication is both difficult and inconsistent. Acute intoxication most commonly results in neurologic dysfunction and/or myocardial injury. Delayed neurologic sequelae are observed in approximately 10% of patients. New information from clinical observations and animal research has prompted a re-evaluation of the clinical assessment of the severity of CO intoxication and its resultant pathophysiology. Patients at the extremes of age (the very young and the elderly), those with pre-existing cardiovascular and/or pulmonary disease, as well as pregnancy are at increased risk. Once the diagnosis of CO poisoning has been established, treatment with 100% O2 is indicated. Based on the body of clinical, basic and scientific information currently available, patients who manifest signs of serious intoxication (i.e., unconsciousness or altered neurologic function, cardiac or hemodynamic instability) should be considered candidates for hyperbaric oxygen therapy (HBO) in addition to other appropriate supportive and intensive care. Any patient who has suffered an interval of unconsciousness, regardless of the patients clinical exam on arrival, warrants HBO therapy. Treatment plans based on any specific COHgb level are not well founded.

Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen

The effects of oxygen at 1, 2, and 3, atmospheres absolute (ATA) were assessed on brain lipid peroxidation caused by carbon monoxide (CO) poisoning in a rat model. Oxygen at 3 ATA, but not 1 ATA, was found to prevent brain lipid peroxidation when administered to rats for 45 min, beginning 45 min subsequent to CO poisoning. Oxygen at 2 ATA had an intermediate effect. The action of hyperbaric oxygen could not be attributed to a more rapid diminution of carboxyhemoglobin, and appears to occur at the level of the brain tissue.

Practice Recommendations in the Diagnosis, Management, and Prevention of Carbon Monoxide Poisoning

Carbon monoxide (CO) poisoning is common in modern society, resulting in significant morbidity and mortality in the United States annually. Over the past two decades, sufficient information has been published about carbon monoxide poisoning in the medical literature to draw firm conclusions about many aspects of the pathophysiology, diagnosis, and clinical management of the syndrome, along with evidence-based recommendations for optimal clinical practice. This article provides clinical practice guidance to the pulmonary and critical care community regarding the diagnosis, management, and prevention of acute CO poisoning. The article represents the consensus opinion of four recognized content experts in the field. Supporting data were drawn from the published, peer-reviewed literature on CO poisoning, placing emphasis on selecting studies that most closely mirror clinical practice.