Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Impact of patient demographics and intraoperative characteristics on abdominal aortic aneurysm sac following endovascular repair.

BACKGROUND: Endovascular aortic repair (EVAR) has become the preferred treatment for abdominal aortic aneurysm (AAA). Its main aim is to seal the perfusion of the aneurysmal sac and, thus, induce sac regression and subsequent aortic remodelling. Aneurysmal sac regression has been linked to the short- and long-term clinical outcomes post-EVAR. It has also been shown to be influenced by endograft device choice, with several of these available commercially. This review summarises and discusses current evidence on the influence of pre- and intraoperative factors on sac regression. Additionally, this review aims to highlight the device-specific variations in sac regression to provide an overall holistic approach to treating AAAs with EVAR. METHODS: A comprehensive literature search was conducted using multiple electronic databases to identify and extract relevant data. RESULTS: Female sex, >70 mm original sac diameters, higher pre-procedural fibrinogen levels, smoking and low intra-aneurysmal pressure were found to positively impact sac regression. Whereas renal impairment, ischemic heart disease, high intra-aneurysmal pressure and aneurysm neck thrombus negatively influenced sac regression. Patent lumbar arteries, age, statins and hypercholesterolaemia displayed conflicting evidence regarding sac regression. Regarding the EVAR endografts compared, newer generation devices such as the Anaconda mainly showed the most optimal results. CONCLUSION: Sac regression following EVAR in AAA is an important prognostic factor for morbidity and mortality. Nevertheless, several pre- and intraoperative factors can have an influence on sac regression. Therefore, it is necessary to take them into account when assessing AAA patients for EVAR to optimise outcomes. The choice of EVAR stent-graft can also affect sac regression, with evidence suggesting that the Fenestrated Anaconda is associated with the most favourable results.

Elevated cerebral perfusion and preserved cognition in elite Brazilian Jiu-Jitsu athletes: Evidence for neuroprotection.

Brazilian Jiu-Jitsu (BJJ) is a popular martial art that exposes participants to recurrent intermittent asphyxiation due to controlled application of neck chokes. To what extent the sport impacts the regulation of cerebral blood flow (CBF) and cognition has not been examined. This study compared eleven elite Brazilian Jiu-Jitsu athletes (aged 30 ± 8 y) who trained 12 ± 6 hours/week for 8 ± 4 years against eleven cardiorespiratory fitness (CRF)- and age-matched controls. Internal carotid (ICA) and vertebral artery (VA) blood flow were measured via duplex ultrasound to determine global cerebral blood flow (gCBF). Mild cognitive impairment and sub-domains of memory, attention/concentration/visual motor coordination, and executive function were determined by psychometric testing. There was no evidence of mild cognitive impairment in the athletes, and cognitive function was comparable between groups (all p > 0.05). In contrast, resting gCBF was selectively elevated in the athletes (741 ± 186 mL∙min-1 vs. 573 ± 166 mL∙min-1 , p = 0.037) due to combined differences in ICA (+65 mL∙min-1 , p = 0.079) and VA (+19 mL∙min-1 , p = 0.277) flow. In conclusion, the sustained elevation in resting cerebral perfusion provides preliminary evidence for adaptive neuroprotection that is independent of CRF and likely mediated by choke-induced cerebral preconditioning and/or lifelong exposure to BJJ-specific high-intensity interval training.

Redox-regulation of haemostasis in hypoxic exercising humans: a randomised double-blind placebo-controlled antioxidant study.

KEY POINTS: In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT: In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-α-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre-supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A•- )) increased during hypoxia (15,152 ± 1193 AU vs. 14,076 ± 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 ± 1616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin-antithrombin complex, at rest in normoxia (28.7 ± 6.4 vs. 4.3 ± 0.2 µg mL-1 pre-intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis.

Antioxidants improve vascular function in children conceived by assisted reproductive technologies: A randomized double-blind placebo-controlled trial.

AIMS: Children conceived by assisted reproductive technology (ART) display vascular dysfunction. Its underlying mechanism, potential reversibility and long-term consequences for cardiovascular risk are unknown. In mice, ART induces arterial hypertension and shortens the life span. These problems are related to decreased vascular endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. The aim of this study was to determine whether ART-induced vascular dysfunction in humans is related to a similar mechanism and potentially reversible. To this end we tested whether antioxidants improve endothelial function by scavenging free radicals and increasing NO bioavailability. METHODS AND RESULTS: In this prospective double-blind placebo controlled study in 21 ART and 21 control children we assessed the effects of a four-week oral supplementation with antioxidant vitamins C (1 g) and E (400 IU) or placebo (allocation ratio 2:1) on flow-mediated vasodilation (FMD) of the brachial artery and pulmonary artery pressure (echocardiography) during high-altitude exposure (3454 m), a manoeuver known to facilitate the detection of pulmonary vascular dysfunction and to decrease NO bioavailability by stimulating oxidative stress. Antioxidant supplementation significantly increased plasma NO measured by ozone-based chemiluminescence (from 21.7 ± 7.9 to 26.9 ± 7.6 µM, p = 0.04) and FMD (from 7.0 ± 2.1 to 8.7 ± 2.0%, p = 0.004) and attenuated altitude-induced pulmonary hypertension (from 33 ± 8 to 28 ± 6 mm Hg, p = 0.028) in ART children, whereas it had no detectable effect in control children. CONCLUSIONS: Antioxidant administration to ART children improved NO bioavailability and vascular responsiveness in the systemic and pulmonary circulation. Collectively, these findings indicate that in young individuals ART-induced vascular dysfunction is subject to redox regulation and reversible.

Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome.

Both antioxidant supplementation and exercise training have been identified as interventions which may reduce oxidative stress and thus improve cardiovascular health, but the interaction of these interventions on arterial BP (blood pressure) and vascular function has not been studied in older humans. Thus in six older (71+/-2 years) mildly hypertensive men, arterial BP was evaluated non-invasively at rest and during small muscle mass (knee-extensor) exercise with and without a pharmacological dose of oral antioxidants (vitamins C and E, and alpha-lipoic acid). The efficacy of the antioxidant intervention to decrease the plasma free radical concentration was verified via EPR (electron paramagnetic resonance) spectroscopy, while changes in endothelial function in response to exercise training and antioxidant administration were evaluated via FMD (flow-mediated vasodilation). Subjects were re-evaluated after a 6-week aerobic exercise training programme. Prior to training, acute antioxidant administration did not change resting arterial BP or FMD. Six weeks of knee-extensor exercise training reduced systolic BP (from 150+/-8 mmHg at pre-training to 138+/-3 mmHg at post-training) and diastolic BP (from 91+/-5 mmHg at pre-training to 79+/-3 mmHg at post-training), and improved FMD (1.5+/-1 to 4.9+/-1% for pre- and post-training respectively). However, antioxidant administration after exercise training negated these improvements, returning subjects to a hypertensive state and blunting training-induced improvements in FMD. In conclusion, the paradoxical effects of these interventions suggest a need for caution when exercise and acute antioxidant supplementation are combined in elderly mildly hypertensive individuals.

Vitamin C prophylaxis promotes oxidative lipid damage during surgical ischemia-reperfusion.

Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia-reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n=10) or placebo (0.9% saline, n=12) administered 2 h prior to surgery. Blood samples were obtained from the arterial and venous circulation proximal to the respective sites of surgical repair (local) and from an antecubital vein (peripheral) during cross-clamping (ischemia) and within 60 s of clamp release (reperfusion). Ascorbate supplementation increased the venoarterial concentration difference (v-adiff) of lipid hydroperoxides (LH), interleukin (IL)-6 and vascular endothelial growth factor (VEGF) protein during ischemia. This increased the peripheral concentration of LH, total creatine phosphokinase (CPK), and VEGF protein during reperfusion (P<0.05 vs placebo). Electron paramagnetic resonance (EPR) spectroscopy confirmed that free iron was available for oxidative catalysis in the local ischemic venous blood of supplemented patients. An increased concentration of the ascorbate radical (A.-) and alpha-phenyl-tert-butylnitrone (PBN) adducts assigned as lipid-derived alkoxyl (LO.) and alkyl (LC.) species were also detected in the peripheral blood of supplemented patients during reperfusion (P<0.05 vs ischemia). In conclusion, these findings suggest that ascorbate prophylaxis may have promoted iron-induced oxidative lipid damage via a Fenton-type reaction initiated during the ischemic phase of surgery. The subsequent release of LH into the systemic circulation may have catalyzed formation of second-generation radicals implicated in the regulation of vascular permeability and angiogenesis.

Evidence against redox regulation of energy homoeostasis in humans at high altitude.

The present study examined if free radicals and associated inflammatory sequelae influenced metabolic biomarkers involved in the neuro-endocrinological regulation of energy homoeostasis at high altitude. Sixteen mountaineers (11 males/five females) were matched for physical fitness and caloric intake and assigned in a double-blind manner to either antioxidant (n=8) or placebo (n=8) supplementation, which was enforced for 7 days at sea level and during an 11-day ascent to 4780 m. Enteral prophylaxis incorporated a daily bolus dose of 1 g of L-ascorbate, 400 international units of D,L-alpha-tocopherol acetate and 600 mg of alpha-lipoic acid. EPR (electron paramagnetic resonance) spectroscopic detection of PBN (alpha-phenyl-tert-butylnitrone) adducts confirmed an increase in the venous concentration of carbon-centred radicals at high altitude in the placebo group, whereas a decrease was observed in the antioxidant group (P<0.05 compared with that at sea level). EPR detection of DMSO/A*- (DMSO-supplemented ascorbate free radical) demonstrated that the increase in carbon-centred radicals at high altitude was associated with a decrease in ascorbate (r2=0.63; P<0.05). Ascent to high altitude (pooled placebo+antioxidant groups) also increased the expression of pro-inflammatory cytokines (P<0.05 compared with that at sea level) and biomarkers of skeletal tissue damage (P<0.05). Despite a general decrease in leptin, insulin and glucose at high altitude (pooled placebo+antioxidant groups; P<0.05 compared with that at sea level), persistent anorexia resulted in a selective loss of body fat (P<0.05). In conclusion, antioxidant prophylaxis decreased the concentration of carbon-centred radicals at high altitude (P<0.05 compared with the placebo group), but did not influence markers of inflammation, appetite-related peptides, ad libitum nutrient intake or body composition. Thus free radicals do not appear to be involved in the inflammatory response and subsequent control of eating behaviour at high altitude.

Acute mountain sickness: controversies and advances.

This review discusses the impact of recent publications on pathophysiologic concepts and on practical aspects of acute mountain sickness (AMS). Magnetic resonance imaging studies do not provide evidence of total brain volume increase nor edema within the first 6 to 10 h of exposure to hypoxia despite symptoms of AMS. After 16 to 32 h at about 4500 m, brain volume increases by 0.8% to 2.7%, but morphological changes do not clearly correlate with symptoms of AMS, and lumbar cerebrospinal fluid pressure was unchanged from normoxic values in individuals with AMS. These data do not support the prevailing hypothesis that AMS is caused by cerebral edema and increased intracranial pressure. Direct measurement of increased oxygen radicals in hypoxia and a first study reducing AMS when lowering oxygen radicals by antioxidants suggest that oxidative stress is involved in the pathophysiology of AMS. Placebo-controlled trials demonstrate that theophylline significantly attenuates periodic breathing without improving arterial oxygen saturation during sleep. Its effects on AMS are marginal and clearly inferior to acetazolamide. A most recent large trial with Ginkgo biloba clearly showed that this drug does not prevent AMS in a low-risk setting in which acetazolamide in a low dose of 2 x 125 mg was effective. Therefore, acetazolamide remains the drug of choice for prevention and the recommended dose remains 2 x 250 mg daily until a lower dose has been tested in a high-risk setting and larger clinical trials with antioxidants have been performed.

Electron paramagnetic resonance spectroscopic evidence of increased free radical generation and selective damage to skeletal muscle following lightning injury.

The present case study examined changes in peripheral markers of free radical metabolism and skeletal/myocardial muscle damage 30 h after a mountaineer had survived a lightning storm, having experienced contact with what was considered to be "upward leaders" at 4200 m. Sea-level control data were available between 3 and 8 weeks prior to the altitude sojourn for comparative purposes. Follow-up measurements were obtained for the same individual 3 weeks following the incident after simulated exposure to the combined stresses of inspiratory hypoxia and physical exercise. Venous blood was assayed for molecular markers of skeletal [myoglobin and total creatine phosphokinase (CPK)] and myocardial [cardiac troponin I (cTnI)] muscle damage. Ex-vivo spin trapping with alpha-phenyl-tert-butylnitrone (PBN) combined with electron paramagnetic resonance (EPR) spectroscopy was incorporated for the direct detection of free radicals. The relative increases [post-exposure/preexposure x 100 (%)] in the concentration of the PBN adduct, myoglobin, and CPK in the "lightning blood" were markedly greater than those observed following the simulation study (PBN: 276 vs. 129%; CPK: 1130 vs. 182%; myoglobin: 205 vs. 115%). In contrast, no changes were observed for cTnI. A marked decrease in the PBN adduct, myoglobin, and CPK was observed within 2 h of completing the simulation study, following oral administration of water and lipid-soluble antioxidant vitamins in normoxia. These findings are the first to document lightning-induced free radical generation and selective damage to skeletal muscle in a high altitude mountaineer. Furthermore, free radicals may contribute to the pathogenesis of lightning injury, and dietary supplementation with antioxidant vitamins may prove of some benefit against associated tissue damage.