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The cerebral vasculature manages oxygen delivery by adjusting arterial blood in‐flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro‐ and macrovascular dilatation. This contemporary review focuses on in vivo human work – with reference to seminal preclinical work where necessary – on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a – likely non‐obligatory – combination of: (1) nitric oxide synthases, (2) deoxygenation‐coupled S‐nitrosothiols, (3) potassium channel‐related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin‐related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex‐, heredity‐, age‐, and disease‐related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury. [ABSTRACT FROM AUTHOR] more...

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. [ABSTRACT FROM AUTHOR] more...

Aim: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. Methods: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady‐state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial‐internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). Results: The CMRO2 was altered by 0.5 mL × min−1 (95% CI: −0.6 to −0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: −13.2 to −6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo‐ and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: −15.4 to −0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: −11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. Conclusion: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production. [ABSTRACT FROM AUTHOR] more...

The near-infrared spectroscopy (NIRS)-derived cerebral oximetry index (COx) has become popularized for non-invasive neuromonitoring of cerebrovascular function in post-cardiac arrest patients with hypoxic-ischemic brain injury (HIBI). We provide commentary on the physiologic underpinnings and assumptions of NIRS and the COx, potential confounds in the context of HIBI, and the implications for the assessment of cerebral autoregulation. [ABSTRACT FROM AUTHOR] more...

The role of cerebral blood flow (CBF) on a maximal breath-hold (BH) in ultra-elite divers was examined. Divers (n = 7) performed one control BH, and one BH following oral administration of the non-selective cyclooxygenase inhibitor indomethacin (1.2 mg/kg). Arterial blood gases and CBF were measured prior to (baseline), and at BH termination. Compared to control, indomethacin reduced baseline CBF and cerebral delivery of oxygen (CDO2) by about 26% (p < 0.01). Indomethacin reduced maximal BH time from 339 ± 51 to 319 ± 57 seconds (p = 0.04). In both conditions, the CDO2 remained unchanged from baseline to the termination of apnea. At BH termination, arterial oxygen tension was higher following oral administration of indomethacin compared to control (4.05 ± 0.45 vs. 3.44 ± 0.32 kPa). The absolute increase in CBF from baseline to the termination of apnea was lower with indomethacin (p = 0.01). These findings indicate that the impact of CBF on maximal BH time is likely attributable to its influence on cerebral H+ washout, and therefore central chemoreceptive drive to breathe, rather than to CDO2. more...

Passive hyperthermia causes cerebral hypoperfusion primarily from heat‐induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro‐inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water‐perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet‐poor plasma via cells expressing CD62E (activated endothelial cells), CD31+/CD42b− (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan‐leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P‐values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+/CD42b− (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2/pH‐mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. Key points: The hyperthermia‐induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow.We tested the hypothesis that the respiratory‐induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow.At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross‐brain microvesicle kinetics.However, when core temperature was increased by 2°C with CO2/pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2/pH‐mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia.These new findings suggest that the heat‐induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain. [ABSTRACT FROM AUTHOR] more...

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv‐aCO2)] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv‐aCO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end‐tidal forcing (ETF) protocols (termed: ETF‐1 and ETF‐2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF‐1 (n = 11) and ETF‐2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv‐aCO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF‐1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF‐2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv‐aCO2 difference did not change during the rebreathing protocol (−0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF‐1 (−3.9 ± 1.1 mmHg; P < 0.001) and ETF‐2 (−3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv‐aCO2 difference during ETF (−0.095 ± 0.089 mmHg cm−1 s−1; P = 0.001) but not during rebreathing (−0.028 ± 0.045 mmHg · cm−1 · s−1; P = 0.067). These findings suggest that, although the Pjv‐aCO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2. Key points: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow.We assessed these assumptions by measuring arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end‐tidal forcing.The difference between arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end‐tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end‐tidal forcing but not rebreathing.These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings. [ABSTRACT FROM AUTHOR] more...

The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic–ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI. [ABSTRACT FROM AUTHOR] more...

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S -nitrosothiol (RSNO) and nitrite ( NO 2 − ) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and NO 2 − . Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not NO 2 − , while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans. [ABSTRACT FROM AUTHOR] more...

High‐altitude (HA) hypoxia may alter the structural–functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex‐, age‐ and body mass index‐matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light‐chain (NF‐L) and T‐tau were consistently lower and cognition comparable to lowlanders following chronic‐HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. Key points: High‐altitude (HA) hypoxia has the potential to alter the structural–functional integrity of the neurovascular unit (NVU) in humans.For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders.Despite lowlanders presenting with a reduction in systemic oxidative–nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment.Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau.These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. [ABSTRACT FROM AUTHOR] more...

This study investigated the influence of acute reductions in arterial O2 content (CaO2) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m2). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO2 washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO2 (PaCO2) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound. CVR was determined as the slope of the gCBF response and PaCO2. Replacement of ∼20% of blood volume with an equal volume of 5% human serum albumin (Alburex® 5%) reduced haemoglobin (13.8 ± 0.8 vs. 11.3 ± 0.6 g/dL; P < 0.001) and CaO2 (18.9 ± 1.0 vs 15.0 ± 0.8 mL/dL P < 0.001), elevated gCBF (+18 ± 11%; P = 0.002), preserved cerebral oxygen delivery (P = 0.49), and elevated CO2 washout (+11%; P = 0.01). The net cerebral uptake of nitrite (11.6 ± 14.0 nmol/min; P = 0.027) at baseline was abolished following haemodilution (−3.6 ± 17.9 nmol/min; P = 0.54), perhaps underpinning the conservation of CVR (61.7 ± 19.0 vs. 69.0 ± 19.2 mL/min/mmHg; P = 0.23). These findings demonstrate that the cerebrovascular responses to acute anaemia in healthy humans are sufficient to support the maintenance of CVR. [ABSTRACT FROM AUTHOR] more...

New Findings: What is the central question of this study?What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia?What is the main finding and its importance?In healthy young adults, shear‐mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α₁‐adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α₁‐adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α₁‐adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end‐tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end‐tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α₁‐adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo‐controlled, double‐blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α₁‐adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear‐mediated vasodilatation in the BA. [ABSTRACT FROM AUTHOR] more...

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross‐species study using small and large animals, we comprehensively tested the agreement and validity of multiple single‐beat surrogate metrics of LV contractility against the field‐standard metrics derived from inferior vena cava occlusion (IVCO). Fifty‐six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single‐beat metrics of LV contractility. All single‐beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load‐independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single‐beat metrics, only LV maximal pressure normalized to end‐diastolic volume (EDV), end‐systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate‐to‐excellent agreement with their IVCO‐derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large‐animal models. Our findings demonstrate that single‐beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small‐ and large‐animal models Key points: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology.We comprehensively test the underlying assumptions of multiple single‐beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs.We show that when performing caval occlusion is unfeasible, single‐beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species.We report that maximal left‐ventricular (LV)‐pressure normalized to end‐diastolic volume (EDV), LV end‐systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single‐beat metrics to measure cardiac inotropic function in both small‐ and large‐animal models. [ABSTRACT FROM AUTHOR] more...

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO3−]) and carbon dioxide tension (PCO2) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO2 (PaCO2) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO3−] increased by 0.15 ± 0.05 mmol ⋅ l−1 per mmHg elevation in PaCO2 across a wide physiological range (35 to 60 mmHg PaCO2; P < 0.001). The narrowing of the venous-arterial [HCO3−] and PCO2 differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO3−] exchange (CBF × venous-arterial [HCO3−] difference) was reduced indicating a shift from net release toward net uptake of [HCO3−] (P = 0.004). Arterial [HCO3−] was reduced by −0.48 ± 0.15 mmol ⋅ l−1 per nmol ⋅ l−1 increase in arterial [H+] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO3−] difference and arterial [H+] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO3−] exchange was unaltered throughout exercise when indexed against arterial [H+] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO3−] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO3−] exchange). [ABSTRACT FROM AUTHOR] more...

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear‐mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)‐dependency of CVR and cSMD. Eleven volunteers underwent a steady‐state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA) or volume‐matched saline (placebo; single‐blinded and counter‐balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra‐arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$. Paired arterial and jugular venous blood sampling allowed for the determination of trans‐cerebral NO2− exchange (ozone‐based chemiluminescence). l‐NMMA reduced arterial NO2− by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady‐state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. −1.8 ± 8.2 nM/min at 120 s post‐CO2; P = 0.044) shifted trans‐cerebral NO2− exchange towards a greater net release (a negative value indicates release). Although this trans‐cerebral NO2− release was abolished by l‐NMMA, CVR did not differ between the saline and l‐NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l‐NMMA impact peak internal carotid artery dilatation during the steady‐state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l‐NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady‐state CVR. Further, our novel transient CO2 test of cSMD is largely NO‐dependent and provides an in vivo bioassay of NO‐mediated cerebrovascular function in humans. Key points: Emerging evidence indicates that a transient CO2 stimulus elicits shear‐mediated dilatation of the internal carotid artery, termed cerebral shear‐mediated dilatation.Whether or not cerebrovascular reactivity to a steady‐state CO2 stimulus is NO‐dependent remains unclear in humans.During both a steady‐state cerebrovascular reactivity test and a transient CO2 test of cerebral shear‐mediated dilatation, trans‐cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non‐selective NO synthase inhibitor NG‐monomethyl‐l‐arginine.NO synthase blockade did not alter cerebrovascular reactivity in the steady‐state CO2 test; however, cerebral shear‐mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG‐monomethyl‐l‐arginine.NO is not obligatory for cerebrovascular reactivity to CO2, but is a key contributor to cerebral shear‐mediated dilatation. [ABSTRACT FROM AUTHOR] more...

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations—where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (~3,800, ~4,300, and ~5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders. [ABSTRACT FROM AUTHOR] more...

New Findings: What is the central question of this study?During a steady‐state cerebrovascular CO2 reactivity test, do different data extraction time points change the outcome for cerebrovascular CO2 reactivity?What is the main finding and its importance?Once steady‐state end‐tidal pressure of CO2 and haemodynamics were achieved, cerebral blood flow was stable, and so cerebrovascular CO2 reactivity values remained unchanged regardless of data extraction length (30 vs. 60 s) and time point (at 2–5 min). This study assessed cerebrovascular CO2 reactivity (CVR) and examined data extraction time points and durations with the hypotheses that: (1) there would be no difference in CVR values when calculated with cerebral blood flow (CBF) measures at different time points following the attainment of physiological steady‐state, (2) once steady‐state was achieved there would be no difference in CVR values derived from 60 to 30 s extracted means, and (3) that changes in V̇E would not be associated with any changes in CVR. We conducted a single step iso‐oxic hypercapnic CVR test using dynamic end‐tidal forcing (end‐tidal PCO2, +9.4 ± 0.7 mmHg), and transcranial Doppler and Duplex ultrasound of middle cerebral artery (MCA) and internal carotid artery (ICA), respectively. From the second minute of hypercapnia onwards, physiological steady‐state was apparent, with no subsequent changes in end‐tidal PCO2, PO2 or mean arterial pressure. Therefore, CVR measured in the ICA and MCA was stable following the second minute of hypercapnia onwards. Data extraction durations of 30 or 60 s did not give statistically different CVR values. No differences in CVR were detected following the second minute of hypercapnia after accounting for mean arterial pressure via calculated conductance or covariation of mean arterial pressure. These findings demonstrate that, provided the PCO2 stimulus remains in a steady‐state, data extracted from any minute of a CVR test during physiological steady‐state conditions produce equivalent CVR values; any change in the CVR value would represent a failure of CVR mechanisms, a change in the magnitude of the stimulus, or measurement error. [ABSTRACT FROM AUTHOR] more...

Hemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signaling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: 1) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic hemodilution (n = 10, aged 29 ± 7 yr); 2) at altitude (6 ± 2 days acclimatization at 5,050 m), before and during hypervolumic hemodilution (n = 11, aged 27 ± 5 yr) with room air and additional hypoxia [fraction of inspired oxygen (FIO2 )= 0.15]; and 3) at altitude (4,340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; n = 6, aged 39 ± 17 yr), before and during isovolumic hemodilution with room air and hyperoxia (end-tidal PO2 = 100 mmHg). At sea level, hemodilution mildly increased pulmonary artery systolic pressure (PASP; +1.6 ± 1.5 mmHg, P = 0.01) and pulmonary vascular resistance (PVR; þ0.7 ± 0.8 wu, P = 0.04). In contrast, after acclimation to 5,050 m, hemodilution did not significantly alter PASP (22.7 ± 5.2 vs. 24.5 ± 5.2 mmHg, P = 0.14) or PVR (2.2 ± 0.9 vs. 2.3 ± 1.2 wu, P = 0.77), although both remained sensitive to additional acute hypoxia. In Andeans with EE at 4,340 m, hemodilution lowered PVR in room air (2.9 ± 0.9 vs. 2.3 ± 0.8 wu, P = 0.03), but PASP remained unchanged (31.3 ± 6.7 vs. 30.9 ± 6.9 mmHg, P = 0.80) due to an increase in cardiac output. Collectively, our series of studies reveal that HPV is modified by the duration of exposure and the prevailing hematocrit level. In application, these findings emphasize the importance of accounting for hematocrit and duration of exposure when interpreting the pulmonary vascular responses to hypoxemia. [ABSTRACT FROM AUTHOR] more...

Purpose: Following return of spontaneous circulation after cardiac arrest, hypoxic ischemic brain injury is the primary cause of mortality and disability. Goal-directed care using invasive multimodal neuromonitoring has emerged as a possible resuscitation strategy. We evaluated whether goal-directed care was associated with improved neurologic outcome in hypoxic ischemic brain injury patients after cardiac arrest.Design: Retrospective, single-center, matched observational cohort study.Setting: Quaternary academic medical center.Patients: Adult patients admitted to the ICU following return of spontaneous circulation postcardiac arrest with clinical evidence of hypoxic ischemic brain injury defined as greater than or equal to 10 minutes of cardiac arrest with an unconfounded postresuscitation Glasgow Coma Scale of less than or equal to 8.Interventions: We compared patients who underwent goal-directed care using invasive neuromonitoring with those treated with standard of care (using both total and matched groups).Measurements and Main Results: Goal-directed care patients were matched 1:1 to standard of care patients using propensity scores and exact matching. The primary outcome was a 6-month favorable neurologic outcome (Cerebral Performance Category of 1 or 2). We included 65 patients, of whom 21 received goal-directed care and 44 patients received standard of care. The median age was 50 (interquartile range, 35-61), 48 (74%) were male, and seven (11%) had shockable rhythms. Favorable neurologic outcome at 6 months was significantly greater in the goal-directed care group (n = 9/21 [43%]) compared with the matched (n = 2/21 [10%], p = 0.016) and total (n = 8/44 [18%], p = 0.034) standard of care groups. Goal-directed care group patients had higher mean arterial pressure (p < 0.001 vs total; p = 0.0060 vs matched) and lower temperature (p = 0.007 vs total; p = 0.041 vs matched).Conclusions: In this preliminary study of patients with hypoxic ischemic brain injury postcardiac arrest, goal-directed care guided by invasive neuromonitoring was associated with a 6-month favorable neurologic outcome (Cerebral Performance Category 1 or 2) versus standard of care. Significant work is required to confirm this finding in a prospectively designed study. [ABSTRACT FROM AUTHOR] more...

Key points: We investigated the influence of arterial PCO2 (PaCO2) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC).We assessed stepwise iso‐oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3–].The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+]/pH.The NVC response was attenuated by 27–38% with −10 mmHg PaCO2 and the absolute peak change was reduced by −19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3–].The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre‐clinical work indicates that arterial PCO2 (PaCO2) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus‐evoked NVC test during matched stepwise iso‐oxic alterations in PaCO2 (hypocapnia: −5, −10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO3–] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27–38% with −10 mmHg PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by −19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3–] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans. Key points: We investigated the influence of arterial PCO2 (PaCO2) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC).We assessed stepwise iso‐oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3–].The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+]/pH.The NVC response was attenuated by 27–38% with −10 mmHg PaCO2 and the absolute peak change was reduced by −19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3–].The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. [ABSTRACT FROM AUTHOR] more...

In 1959, Niels Lassen illustrated the cerebral autoregulation curve in the classic review article entitled Cerebral Blood Flow and Oxygen Consumption in Man. This concept suggested a relatively broad mean arterial pressure range (~60–150 mmHg) wherein cerebral blood flow remains constant. However, the assumption that this wide cerebral autoregulation plateau could be applied on a within‐individual basis is incorrect and greatly variable between individuals. Indeed, each data point on the autoregulatory curve originated from independent samples of participants and patients and represented interindividual relationships between cerebral blood flow and mean arterial pressure. Nonetheless, this influential concept remains commonly cited and illustrated in various high‐impact publications and medical textbooks, and is frequently taught in medical and science education without appropriate nuances and caveats. Herein, we provide the rationale and additional experimental data supporting the notion we need to lose this dogmatic view of cerebral autoregulation. [ABSTRACT FROM AUTHOR] more...

Key points: We investigated the influence of arterial PCO2 (PaCO2) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m.At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3−).Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3−] (i.e. buffering capacity) were effectively altered.The cerebrovascular responses to changes in arterial [H+]/pH were consistent with the altered relationship between PaCO2 and [H+]/pH following ACZ at high altitude (i.e. leftward x‐intercept shifts).Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. Alterations in acid‐base balance with progressive acclimatization to high altitude have been well‐established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid‐base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ ‐0.07 ± 0.04 and base excess: Δ ‐5.7 ± 1.9 mEq⋅l–1, trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO3−; pH: Δ ‐0.01 ± 0.04 and base excess: Δ ‐1.5 ± 2.1 mEq⋅l–1, trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO2 (PaCO2), i.e. cerebrovascular CO2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ ‐3.4 ± 2.3 mmHg PaCO2, trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ‐mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO2‐pH and CBV‐pH responses across the CO2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO2 – rather than pH – the absolute CBV and sensitivity of CBV‐PaCO2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO2‐mediated changes in cerebrovascular tone rather than arterial [H+]/pH is integral to CBF regulation at high altitude. Key points: We investigated the influence of arterial PCO2 (PaCO2) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m.At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3−).Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3−] (i.e. buffering capacity) were effectively altered.The cerebrovascular responses to changes in arterial [H+]/pH were consistent with the altered relationship between PaCO2 and [H+]/pH following ACZ at high altitude (i.e. leftward x‐intercept shifts).Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. [ABSTRACT FROM AUTHOR] more...

The use of cerebral autoregulation monitoring to identify patient-specific optimal mean arterial pressure (MAPOPT) has emerged as a technique to augment cerebral oxygen delivery in post-cardiac arrest patients. Our systematic review aims to determine (a) the average MAPOPT in these patients, (b) the feasibility of identifying MAPOPT, (c) the brain tissue oxygenation levels when MAP is within proximity to the MAPOPT and (d) the relationship between neurological outcome and MAPOPT-targeted resuscitation strategies. We carried out this review in accordance with the PRISMA guidelines. We included all studies that used cerebral autoregulation to determine MAPOPT in adult patients (> 16 years old) who achieved return of spontaneous circulation (ROSC) following cardiac arrest. All studies had to include our primary outcome of MAPOPT. We excluded studies where the patients had any history of traumatic brain injury, ischemic stroke or intracranial hemorrhage. We identified six studies with 181 patients. There was wide variability in cerebral autoregulation monitoring methods, length of monitoring, calculation and reporting of MAPOPT. Amongst all studies, the median or mean MAPOPT was consistently above 65 mmHg (range 70-114 mmHg). Definitions of feasibility varied among studies and were difficult to summarize. Only one study noted that brain tissue oxygenation increased as patients' MAP approached MAPOPT. There was no consistent association between targeting MAPOPT and improved neurological outcome. There is considerable heterogeneity in MAPOPT due to differences in monitoring methods of autoregulation. Further research is needed to assess the clinical utility of MAPOPT-guided strategies on decreasing secondary injury and improving neurological outcomes after ROSC. [ABSTRACT FROM AUTHOR] more...