The O2-sensitive brain stem, hyperoxic hyperventilation, and CNS oxygen toxicity

Central nervous system oxygen toxicity (CNS-OT) is a complex disorder that presents, initially, as a sequence of cardio-respiratory abnormalities and nonconvulsive signs and symptoms (S/Sx) of brain stem origin that culminate in generalized seizures, loss of consciousness, and postictal cardiogenic pulmonary edema. The risk of CNS-OT and its antecedent “early toxic indications” are what limits the use of hyperbaric oxygen (HBO2) in hyperbaric and undersea medicine. The purpose of this review is to illustrate, based on animal research, how the temporal pattern of abnormal brain stem responses that precedes an “oxtox hit” provides researchers a window into the early neurological events underlying seizure genesis. Specifically, we focus on the phenomenon of hyperoxic hyperventilation, and the medullary neurons presumed to contribute in large part to this paradoxical respiratory response; neurons in the caudal Solitary complex (cSC) of the dorsomedial medulla, including putative CO2 chemoreceptor neurons. The electrophysiological and redox properties of O2-/CO2-sensitive cSC neurons identified in rat brain slice experiments are summarized. Additionally, evidence is summarized that supports the working hypothesis that seizure genesis originates in subcortical areas and involves cardio-respiratory centers and cranial nerve nuclei in the hind brain (brainstem and cerebellum) based on, respectively, the complex temporal pattern of abnormal cardio-respiratory responses and various nonconvulsive S/Sx that precede seizures during exposure to HBO2

Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). VOD may occur in up to 62% of patients undergoing SCT, with onset generally within the first month after SCT. In severe cases, 100-day mortality is in excess of 80%. Current management consists of best supportive care, with no agents to date approved for treatment in the USA or the EU. Defibrotide, a polydisperse oligonucleotide, has been shown in phase II and III trials to improve complete response and survival in patients undergoing SCT with severe VOD. This article reviews our current understanding of VOD, and examines recent clinical findings on defibrotide for the treatment and prophylaxis of VOD

Effects of Exogenous Ketone Therapy on Performance, Cardiorespiration, and Seizure Genesis During Exposure to HBO2 in the Sprague Dawley Rat

Hyperbaric oxygen (HBO2) is used for clinical HBO2 therapy and in undersea and aerospace medicine. HBO2 is a humanmade extreme environment and protracted exposures can cause several adverse physiological effects on the body. For example, HBO2 increases the partial pressure of oxygen (PO2) in the body leading to redox stress. Redox stress is, in part, a cause of oxygen toxicity that manifests as seizures in its most severe form (central nervous system oxygen toxicity, CNS-OT). This dissertation focuses on strategies to be employed specifically for the warfighter breathing HBO2. Currently, the only way to prevent CNS-OT is to lower the level of inspired PO2. Likewise, physiological markers (“physio-markers”) have been identified that predict onset of seizures during exposure to HBO2, e.g., hyperoxic hyperpnea. Finally, previous research has shown that [exogenous] ketone metabolic therapy significantly delays CNS-OT seizures. Accordingly, the goal of my dissertation was to identify an optimal dose of exogenous ketone ester (KE) that delays seizures during exposure to HBO2 without disrupting animal cognition and performance. A second goal was to determine the effects of ketosis on identified and postulated physio-markers of an impending seizure. First, a pharmacokinetic study verified that this new, lower dose induces therapeutic ketosis. Next, we determined that this new dose would not hinder cognitive or motor performance through a series of behavioral animal tests while breathing normobaric air. Third, we confirmed whether the lower dose would delay the onset of CNS-OT. Finally, in offline data analysis, we looked at the physiological markers of temperature, cardiovascular, and respiratory responses to detect if these “physio-markers” could be applied as predictive measures of CNS-OT. Our hypothesis was that the moderate dose of KE would not impair cognition or motor performance while providing neuroprotection and delay onset of CNS-OT. Moreover, we proposed that the physio-markers we assessed could be used to predict CNS-OT and would be unaffected by ketosis. Our results showed that the optimal dose of KE was 7.5g/kg, which maintained a state of ketosis for ~6 hours. Additionally, this [KE] had no deleterious effects on cognitive or motor performance. Furthermore, a single oral dose of KE increased the latency time to seizure by 307% when breathing 5 ATA O2. Lastly, we confirmed that the cardiovascular and respiratory physio-markers—hyperoxic bradycardia and hyperpnea—were changed significantly ~15 minutes prior to seizure onset (CNS-OT). Moreover, these two physio-markers were unchanged by ketone therapy and still predicted seizures ~15 minutes beforehand. By contrast, hyperoxic core hypothermia was not a useful physio-marker of CNS-OT. Taken together these results suggest that the moderate dose of KE used in our study are safe to use in mammals and effectively increase bottom time when breathing HBO2 without adverse effects on cognition, performance, and physio-markers that predict seizure genesis

Effects of Exogenous Ketone Therapy on Performance, Cardiorespiration, and Seizure Genesis During Exposure to HBO2 in the Sprague Dawley Rat

Hyperbaric oxygen (HBO2) is used for clinical HBO2 therapy and in undersea and aerospace medicine. HBO2 is a humanmade extreme environment and protracted exposures can cause several adverse physiological effects on the body. For example, HBO2 increases the partial pressure of oxygen (PO2) in the body leading to redox stress. Redox stress is, in part, a cause of oxygen toxicity that manifests as seizures in its most severe form (central nervous system oxygen toxicity, CNS-OT). This dissertation focuses on strategies to be employed specifically for the warfighter breathing HBO2. Currently, the only way to prevent CNS-OT is to lower the level of inspired PO2. Likewise, physiological markers (“physio-markers”) have been identified that predict onset of seizures during exposure to HBO2, e.g., hyperoxic hyperpnea. Finally, previous research has shown that [exogenous] ketone metabolic therapy significantly delays CNS-OT seizures. Accordingly, the goal of my dissertation was to identify an optimal dose of exogenous ketone ester (KE) that delays seizures during exposure to HBO2 without disrupting animal cognition and performance. A second goal was to determine the effects of ketosis on identified and postulated physio-markers of an impending seizure. First, a pharmacokinetic study verified that this new, lower dose induces therapeutic ketosis. Next, we determined that this new dose would not hinder cognitive or motor performance through a series of behavioral animal tests while breathing normobaric air. Third, we confirmed whether the lower dose would delay the onset of CNS-OT. Finally, in offline data analysis, we looked at the physiological markers of temperature, cardiovascular, and respiratory responses to detect if these “physio-markers” could be applied as predictive measures of CNS-OT. Our hypothesis was that the moderate dose of KE would not impair cognition or motor performance while providing neuroprotection and delay onset of CNS-OT. Moreover, we proposed that the physio-markers we assessed could be used to predict CNS-OT and would be unaffected by ketosis. Our results showed that the optimal dose of KE was 7.5g/kg, which maintained a state of ketosis for ~6 hours. Additionally, this [KE] had no deleterious effects on cognitive or motor performance. Furthermore, a single oral dose of KE increased the latency time to seizure by 307% when breathing 5 ATA O2. Lastly, we confirmed that the cardiovascular and respiratory physio-markers—hyperoxic bradycardia and hyperpnea—were changed significantly ~15 minutes prior to seizure onset (CNS-OT). Moreover, these two physio-markers were unchanged by ketone therapy and still predicted seizures ~15 minutes beforehand. By contrast, hyperoxic core hypothermia was not a useful physio-marker of CNS-OT. Taken together these results suggest that the moderate dose of KE used in our study are safe to use in mammals and effectively increase bottom time when breathing HBO2 without adverse effects on cognition, performance, and physio-markers that predict seizure genesis