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.

Combined cone-beam CT imaging and microsurgical dissection of cadaver specimens to study cerebral venous anatomy: a technical note.

PURPOSE: Cadaver dissections and X-ray based 3D angiography are considered gold standards for studying neurovascular anatomy. We sought to develop a model that utilize the combination of both these techniques to improve current tools for anatomical research, teaching and preoperative surgical planning, particularly addressing the venous system of the brain. MATERIALS AND METHODS: Seven ethanol-fixed human cadaveric heads and one arm were injected with a latex-barium mixture into the internal jugular veins and the brachial artery. After the ethanol-based fixation, specimens were scanned by high-resolution cone-beam CT and images were post-processed on a 3D-workstation. Subsequent, microsurgical dissections were performed by an experienced neurosurgeon and venous anatomy was compared with relevant 3D venograms. RESULTS: Latex-barium mixtures resulted in a homogenous cast with filling of the cerebral venous structures down to 150 µm in diameter. The ethanol-based preparation of the cadaveric brains allowed for near-realistic microsurgical maneuverability during dissection. The model improves assessment of the venous system for anatomical education and hands-on surgical training. CONCLUSION: To our knowledge we describe the first preparation method which combines near-realistic microsurgical dissection of human heads with high-resolution 3D imaging of the cerebral venous system in the same specimens.

Regulation of the microvasculature during small muscle mass exercise in chronic obstructive pulmonary disease vs. chronic heart failure.

Aim: Skeletal muscle convective and diffusive oxygen (O2) transport are peripheral determinants of exercise capacity in both patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). We hypothesised that differences in these peripheral determinants of performance between COPD and CHF patients are revealed during small muscle mass exercise, where the cardiorespiratory limitations to exercise are diminished. Methods: Eight patients with moderate to severe COPD, eight patients with CHF (NYHA II), and eight age- and sex-matched controls were studied. We measured leg blood flow (Q̇leg) by Doppler ultrasound during submaximal one-legged knee-extensor exercise (KEE), while sampling arterio-venous variables across the leg. The capillary oxyhaemoglobin dissociation curve was reconstructed from paired femoral arterial-venous oxygen tensions and saturations, which enabled the estimation of O2 parameters at the microvascular level within skeletal muscle, so that skeletal muscle oxygen conductance (DSMO2) could be calculated and adjusted for flow (DSMO2/Q̇leg) to distinguish convective from diffusive oxygen transport. Results: During KEE, Q̇leg increased to a similar extent in CHF (2.0 (0.4) L/min) and controls (2.3 (0.3) L/min), but less in COPD patients (1.8 (0.3) L/min) (p <0.03). There was no difference in resting DSMO2 between COPD and CHF and when adjusting for flow, the DSMO2 was higher in both groups compared to controls (COPD: 0.97 (0.23) vs. controls 0.63 (0.24) mM/kPa, p= 0.02; CHF 0.98 (0.11) mM/kPa vs. controls, p= 0.001). The Q̇-adjusted DSMO2 was not different in COPD and CHF during KEE (COPD: 1.19 (0.11) vs. CHF: 1.00 (0.18) mM/kPa; p= 0.24) but higher in COPD vs. controls: 0.87 (0.28) mM/kPa (p= 0.02), and only CHF did not increase Q̇-adjusted DSMO2 from rest (p= 0.2). Conclusion: Disease-specific factors may play a role in peripheral exercise limitation in patients with COPD compared with CHF. Thus, low convective O2 transport to contracting muscle seemed to predominate in COPD, whereas muscle diffusive O2 transport was unresponsive in CHF.

A method for modelling the oxyhaemoglobin dissociation curve at the level of the cerebral capillary in humans.

NEW FINDINGS: What is the central question of this study? Can the change in haemoglobin's affinity for oxygen in the human cerebral circulation be modelled in vivo? What is the main finding and its importance? We provide a novel method for modelling the oxyhaemoglobin dissociation curve at the cerebral capillary level in humans, so that the cerebral capillary and mitochondrial oxygen tensions can reliably be estimated. This may be useful in future human-experimental studies on cerebral oxygen transport. ABSTRACT: We provide a method for modelling the oxyhaemoglobin dissociation curve (ODC) in the cerebral capillary in humans. In contrast to most previous approaches, our method involves the construction of an averaged ODC based on paired arterial-jugular venous blood gas values, which enables the estimation of oxygen parameters in cerebral capillary blood. The method was used to determine the mean cerebral capillary oxygen saturation and tension from data previously collected from 30 healthy volunteers. The averaged ODC provided systematically higher capillary oxygen tensions than when assuming a 'fixed' standard arterial ODC. When the averaged and measured arterial ODC were used for constructing the capillary ODC, similar values were obtained during resting breathing, but not when the arterial ODC was modulated by hypocapnia. The findings suggest that our method for modelling the cerebral capillary ODC provides robust and physiologically reliable estimates of the cerebral capillary oxygen tension, which may be of use in future studies of cerebral oxygen transport in humans.

Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans.

Hypoxaemia is present in many critically ill patients, and may contribute to encephalopathy. Changes in the passage of large neutral amino acids (LNAAs) across the blood-brain barrier (BBB) with an increased cerebral influx of aromatic amino acids into the brain may concurrently be present and also contribute to encephalopathy, but it has not been established whether hypoxaemia per se may trigger such changes. We measured cerebral blood flow (CBF) in 11 healthy men using the Kety-Schmidt technique and obtained paired arterial and jugular-venous blood samples for the determination of LNAAs by high performance liquid chromatography at baseline and after 9 hours of poikilocapnic normobaric hypoxia (12% O2). Transcerebral net exchange was determined by the Fick principle, and transport of LNAAs across the BBB was determined mathematically. Hypoxia increased both the systemic and corresponding cerebral delivery of the aromatic amino acid phenylalanine, and the branched-chain amino acids leucine and isoleucine. Despite this, the transcerebral net exchange values and mathematically derived brain extracellular concentrations for all LNAAs were unaffected. In conclusion, the observed changes in circulating LNAAs triggered by hypoxaemia do not affect the transcerebral exchange kinetics of LNAAs to such an extent that their brain extracellular concentrations are affected.

Snaring of a Glued Microcatheter During Embolization of an Arteriovenous Malformation with N-Butyl Cyanoacrylate.

BACKGROUND: Microcatheter entrapment during embolization of brain arteriovenous malformations (AVMs) represents a potentially harmful technical complication. Although several techniques have been reported for endovascular catheter retrieval from an Onyx cast, such methods have never been demonstrated with acrylic glues. We report a case of removal of a glued microcatheter from an N-butyl cyanoacrylate (NBCA) cast using a microsnare. METHODS AND RESULTS: A 26-year-old woman presented with an intracranial hemorrhage resulting from a ruptured right choroidal AVM. A microcatheter used for transarterial embolization was unintentionally glued into the NBCA cast. Because attempts to remove the catheter by simple traction failed, a microsnare was used and allowed withdrawal of the entrapped microcatheter without causing damage to the cerebral vasculature. The patient woke up without clinical sequelae. CONCLUSIONS: Although it is not recommended as routine practice, snaring a glued microcatheter is feasible and can be used in selected cases as a last resort if thromboembolic complications are feared.

Transcerebral net exchange of vasoactive peptides and catecholamines during lipopolysaccharide-induced systemic inflammation in healthy humans.

The systemic inflammatory response triggered by lipopolysaccharide (LPS) is associated with cerebral vasoconstriction, but the underlying mechanisms are unknown. We therefore examined whether a 4-hour intravenous LPS infusion (0.3 ng·kg-1) induces any changes in the transcerebral net exchange of the vasoactive peptides endothelin-1 (ET-1) and calcitonin-gene related peptide (CGRP) and catecholamines in human volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique, and paired arterial-to-jugular venous blood samples were obtained for estimating the transcerebral exchange of ET-1, CGRP, and catecholamines by the Fick principle in 12 volunteers before and after LPS infusion. The cerebrovascular release of ET-1 was enhanced, whereas the transcerebral net exchange of CGRP and catecholamines was unaffected. Our findings thus point towards locally produced ET-1 within the cerebrovasculature as a contributor to cerebral vasoconstriction after LPS infusion.

A reassessment of the blood-brain barrier transport of large neutral amino acids during acute systemic inflammation in humans.

We reassessed data from a previous study on the transcerebral net exchange of large neutral amino acids (LNAAs) using a novel mathematical model of blood-brain barrier (BBB) transport. The study included twelve healthy volunteers who received a 4-h intravenous lipopolysaccharide (LPS) infusion (total dose: 0·3 ng/kg), a human experimental model of the systemic inflammatory response during the early stages of sepsis. Cerebral blood flow and arterial-to-jugular venous LNAA concentrations were measured prior to and after LPS, and the BBB transport and brain extracellular concentrations of LNAAs were calculated. The arterial concentration and unidirectional cerebral influx of phenylalanine increased after LPS. The BBB transport of tyrosine was unaffected, while its concentration in the brain extracellular fluid increased. These findings suggest that LPS infusion leads to an increased cerebral uptake of phenylalanine, which is then metabolized to tyrosine. This may reflect a neuroprotective mechanism that 'detoxifies' excess intracerebral phenylalanine in the clinical setting of sepsis.