A mathematical model of cerebral blood flow control in anaemia and hypoxia.

Upon ascent to high altitude, cerebral blood flow (CBF) rises substantially before returning to sea-level values. The underlying mechanisms for these changes are unclear. We examined three hypotheses: (1) the balance of arterial blood gases upon arrival at and across 2 weeks of living at 5050 m will closely relate to changes in CBF; (2) CBF reactivity to steady-state changes in CO2 will be reduced following this 2 week acclimatisation period, and (3) reductions in CBF reactivity to CO2 will be reflected in an augmented ventilatory sensitivity to CO2. We measured arterial blood gases, middle cerebral artery blood flow velocity (MCAv, index of CBF) and ventilation () at rest and during steady-state hyperoxic hypercapnia (7% CO2) and voluntary hyperventilation (hypocapnia) at sea level and then again following 2–4, 7–9 and 12–15 days of living at 5050 m. Upon arrival at high altitude, resting MCAv was elevated (up 31 ± 31%; P < 0.01; vs. sea level), but returned to sea-level values within 7–9 days. Elevations in MCAv were strongly correlated (R2= 0.40) with the change in ratio (i.e. the collective tendency of arterial blood gases to cause CBF vasodilatation or constriction). Upon initial arrival and after 2 weeks at high altitude, cerebrovascular reactivity to hypercapnia was reduced (P < 0.05), whereas hypocapnic reactivity was enhanced (P < 0.05 vs. sea level). Ventilatory response to hypercapnia was elevated at days 2–4 (P < 0.05 vs. sea level, 4.01 ± 2.98 vs. 2.09 ± 1.32 l min−1 mmHg−1). These findings indicate that: (1) the balance of arterial blood gases accounts for a large part of the observed variability (∼40%) leading to changes in CBF at high altitude; (2) cerebrovascular reactivity to hypercapnia and hypocapnia is differentially affected by high-altitude exposure and remains distorted during partial acclimatisation, and (3) alterations in cerebrovascular reactivity to CO2 may also affect ventilatory sensitivity.

Cerebral cortical blood flow during changes of acid-base equilibrium of the brain.

Total and regional cerebral blood flow in unanesthetized dogs.

Nitrous oxide, in a concentration of 50% or more, is a known cerebral vasodilator. This study investigated whether a lower dose (30%) of nitrous oxide would also increase cerebral blood flow. In addition, the authors wished to study whether the increase in cerebral blood flow was accompanied by an increase in cerebral metabolism. Multimodal Magnetic Resonance Imaging at 3T was performed, and data were obtained in 17 healthy volunteers during three inhalation conditions: medical air, oxygen-enriched medical air (40% oxygen), and 30% nitrous oxide with oxygen-enriched medical air (40% oxygen). Arterial spin labeling was used to derive the primary tissue specific hemodynamic outcomes: cerebral blood flow, arterial blood volume and arterial transit times. Magnetic Resonance Susceptometry and proton Magnetic Resonance Spectroscopy were used for secondary metabolic outcomes: venous oxygenation, oxygen extraction fraction, cerebral metabolic oxygen rate and prefrontal metabolites. Nitrous oxide in 40% oxygen, but not 40% oxygen alone, significantly increased gray matter cerebral blood flow (22%; P < 0.05) and arterial blood volume (41%; P < 0.05). Venous oxygenation increased in both oxygen and nitrous oxide conditions. Compared with medical air inhalation, nitrous oxide condition caused a significantly larger decrease in oxygen extraction fraction than 40% oxygen alone (mean [SD] 11.3 [5.6]% vs. 8.3 [5.9]% P < 0.05), while global cerebral metabolic rate and prefrontal metabolites remained unchanged. This study demonstrates that 30% nitrous oxide in oxygen-enriched air (40% oxygen) significantly increases cerebral perfusion, and reduces oxygen extraction fraction, reflecting a strong arterial vasodilatory effect without associated increases in metabolism.

SUMMARY We studied the effects of cholinergic receptor activation on cerebral blood flow in dogs anesthetized with chloralose. Continuous measurements of cerebral blood flow, arterial and cerebral spinal fluid pressure, heart rate, and respiratory carbon dioxide tension were made during parasympathetic nerve stimulation and during intraarterial infusion of acetylcholine. Multiple samples of arterial and cerebral venous blood were taken before, during, and after cholinergic vasodilation and analyzed for oxygen tension, carbon dioxide tension, and pH. Dose-response curves obtained by intra-arterial infusion of acetylcholine at 0.27-1,080 /ig/min and stimulation frequency-response curves obtained by excitation of the major petrosal nerve at 2-40 Hz demonstrated a dose or frequency-dependent cerebral vasodilation. The maximum cerebral vasodilation (171% of control flow) was obtained with an acetylcholine infusion of 1,080 /xg/min. During infusion of 27 /tg of acetylcholine/min arterial blood gases showed little or no change and thus could not have produced the observed change in cerebral blood flow. The changes in cerebral venous blood were all consistent with the observed increase in cerebral blood flow; oxygen tension rose from 30.4 to 36.0 mm Hg, carbon dioxide tension fell from 45.7 to 42.3 mm Hg, and pH rose from 7.342 to 7.360. Ipsilateral stimulation of the major petrosal nerve at 10 Hz, with a 3-msec pulse duration and 60-second stimulation period, produced an increase in cerebral blood flow to 111% of control flow. Cholinergic receptor blockade with atropine (1 mg/kg, i.v.) completely eliminated the cerebral vasodilation produced by acetylcholine infusion at 27 figlmin and significantly reduced the vasodilation resulting from major petrosal nerve stimulation. We conclude that the cerebral circulation has the capacity for significant cholinergic vasodilation. THE ABUNDANT anatomical evidence demonstrating the existence of nerve fibers on the cerebral vessels has recently been reviewed. 1 The sympathetic autonomic component of this innervation has been shown to have the capacity for marked cerebral vasoconstriction via an aadrenergic receptor mechanism. 2 - 3 A parasympathetic cerebral vasodilator mechanism was suggested by early workers when they observed pial vessel in response to cranial nerve stimulation. 4 More recently, intravertebral atropine was shown to suppress the resulting from inhalation of 5% CO2, 5 and intravertebral neostigmine enhanced cerebral vasodilator reactivity to CO2. (i Atropine was also shown to eliminate autoregulatory dilation in unanesthetized rabbits. 7 Each of these observations is consistent with a parasympathetic cholinergic vasodilator mechanism for the cerebral circulation. None of these studies demonstrates a parasympathetic cholinergic increase in cerebral blood flow. A cholinergic vasodilator mechanism to compliment the adrenergic vasoconstrictor mechanism has, therefore, not been clearly defined for the control of cerebral blood flow. In the present study, parasympathetic nerve stimulation and intra-arterial infusion of a cholinergic agonist, acetylcholine, were used to test for a possible parasympathetic cholinergic cerebral vasodilator mechanism.

Carbon dioxide and the cerebral circulation.

On the theory of the indicator-dilution method for measurement of blood flow and volume.

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.

What is the topic of this review? What is the mechanism underlying the control of human cerebral blood flow in hypoxia and what are the consequences? What advances does it highlight? Although appropriate elevations in cerebral blood flow occur in acute and chronic hypoxia, neuronal processes are more sensitive to even small hypoxic insults; hence, they can result in maladaptive consequences despite maintenance of global oxygen delivery. Exposure to acute or chronic hypoxaemia in otherwise healthy humans results in compensatory increases in cerebral blood flow (CBF) at rest and during exercise, referred to as hypoxic cerebral vasodilatation. These elevations in CBF offset the reduction in arterial oxygen content and maintain cerebral O2 delivery, conforming to the conservation of mass principle. In this review, we discuss the fundamental principles that contribute to the defence of cerebral O2 delivery and the corresponding implications for metabolism. We critically address to what extent the increase in CBF reflects an adaptive or indeed maladaptive physiological response. The molecular mechanisms of CBF regulation in hypoxia are also briefly discussed and future directions proposed.

Cerebral energy metabolism, pH, and blood flow during seizures in the cat

We sought to characterize 1) the difference in the diffusion gradient of cellular oxygen delivery and 2) the presence of diffusion limitation physiology in hypoxic-ischemic brain injury patients with brain hypoxia, as defined by parenchymal brain tissue oxygen tension less than 20 mm Hg versus normoxia (brain tissue oxygen tension > 20 mm Hg). Post hoc subanalysis of a prospective study in hypoxic-ischemic brain injury patients dichotomized into those with brain hypoxia versus normoxia. Quaternary ICU. Fourteen adult hypoxic-ischemic brain injury patients after cardiac arrest. Patients underwent monitoring with brain oxygen tension, intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and jugular venous bulb oxygen saturation. Data were recorded in real time at 300Hz into the ICM+ monitoring software (Cambridge University Enterprises, Cambridge, United Kingdom). Simultaneous arterial and jugular venous bulb blood gas samples were recorded prospectively. Both the normoxia and hypoxia groups consisted of seven patients. In the normoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen tension, and cerebral perfusion pressure were 29 mm Hg (SD, 9), 45 mm Hg (SD, 9), and 80 mm Hg (SD, 7), respectively. In the hypoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen to brain tissue oxygen tension gradient, and cerebral perfusion pressure were 14 mm Hg (SD, 4), 53 mm Hg (SD, 8), and 72 mm Hg (SD, 6), respectively. There were significant differences in the jugular venous bulb oxygen tension-brain oxygen tension gradient (16 mm Hg [sd, 6] vs 39 mm Hg SD, 11]; p < 0.001) and in the relationship of jugular venous bulb oxygen tension-brain oxygen tension gradient to cerebral perfusion pressure (p = 0.004) when comparing normoxia to hypoxia. Each 1 mm Hg increase in cerebral perfusion pressure led to a decrease in the jugular venous bulb oxygen tension-brain oxygen tension gradient by 0.36 mm Hg (95% CI, -0.54 to 0.18; p < 0.001) in the normoxia group, but no such relation was demonstrable in the hypoxia group. In hypoxic-ischemic brain injury patients with brain hypoxia, there is an elevation in the jugular venous bulb oxygen tension-brain oxygen tension gradient, which is not modulated by changes in cerebral perfusion pressure.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Brain blood flow in the conscious and anesthetized rat.

Towards clinical assessment of cerebral blood flow regulation using ultrasonography : model applicability in clinical studies

Cerebral blood flow and oxygen consumption in man.