The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude.

Animals native to hypoxic environments have adapted by increasing their haemoglobin oxygen affinity, but in-vitro studies of the oxyhaemoglobin dissociation curve (ODC) in humans show no changes in affinity under physiological conditions at altitudes up to 4000m. We conducted the first in-vivo measurement of the ODC; inducing progressive isocapnic hypoxia in lowlanders at sea level, acutely acclimatized lowlanders at 3600m, and native Andeans at that altitude. ODC curves were determined by administering isocapnic steps of increasing hypoxia, and measuring blood oxygen partial pressure and saturation. The ODC data were fitted using the Hill equation and extrapolated to predict the oxygen partial pressure at which haemoglobin was 50% saturated (P50). In contrast to findings from in-vitro studies, we found a pH-related reduction in P50 in subjects at altitude, compared to sea-level subjects. We conclude that a pH-mediated increase in haemoglobin oxygen affinity in-vivo may be part of the acclimatization process in humans at altitude.

The interaction of carbon dioxide and hypoxia in the control of cerebral blood flow.

Both hypoxia and carbon dioxide increase cerebral blood flow (CBF), and their effective interaction is currently thought to be additive. Our objective was to test this hypothesis. Eight healthy subjects breathed a series of progressively hypoxic gases at three levels of carbon dioxide. Middle cerebral artery velocity, as an index of CBF; partial pressures of carbon dioxide and oxygen and concentration of oxygen in arterial blood; and mean arterial blood pressure were monitored. The product of middle cerebral artery velocity and arterial concentration of oxygen was used as an index of cerebral oxygen delivery. Two-way repeated measures analyses of variance (rmANOVA) found a significant interaction of carbon dioxide and hypoxia factors for both CBF and cerebral oxygen delivery. Regression models using sigmoidal dependence on carbon dioxide and a rectangular hyperbolic dependence on hypoxia were fitted to the data to illustrate this interaction. We concluded that carbon dioxide and hypoxia act synergistically in their control of CBF so that the delivery of oxygen to the brain is enhanced during hypoxic hypercapnia and, although reduced during normoxic hypocapnia, can be restored to normal levels with progressive hypoxia.

Measurement of cerebrovascular reactivity in pediatric patients with cerebral vasculopathy using blood oxygen level-dependent MRI.

BACKGROUND AND PURPOSE: Cerebrovascular reactivity (CVR) is an indicator of cerebral hemodynamics. In adults with cerebrovascular disease, impaired CVR has been shown to be associated with an increased risk of stroke. In children, however, CVR studies are not common. This may be due to the difficulties and risks associated with current CVR study methodologies. We have previously described the application of precise control of end-tidal carbon dioxide partial pressure for CVR studies in adults. Our aim is to report initial observations of CVR studies that were performed as part of a larger observational study regarding investigations in pediatric patients with cerebral vascular disease. METHODS: Thirteen patients between the ages of 10 and 16 years (10 with a diagnosis of Moyamoya vasculopathy and 3 with confirmed, or suspected, intracranial vascular stenosis) underwent angiography, MRI, and functional blood oxygen level-dependent MRI mapping of CVR to hypercapnia. The results of the CVR study were then related to both the structural imaging and clinical status. RESULTS: Sixteen blood oxygen level-dependent MRI CVR studies were performed successfully in 13 consecutive patients. Twelve of the 13 patients with angiographic abnormalities also had CVR deficits in the corresponding downstream vascular territories. CVR deficits were also seen in 8 of 9 symptomatic patients and 2 of the asymptomatic patients. Notably, in patients with abnormalities on angiography, the reductions in CVR extended beyond the ischemic lesions identified with MR structural imaging into normal-appearing brain parenchyma. CONCLUSIONS: This is the first case series reporting blood oxygen level-dependent MRI CVR in children with cerebrovascular disease. CVR studies performed so far provide information regarding hemodynamic compromise, which complements traditional clinical assessment and structural imaging.

Exaggerated increase in cardiac output during exercise in patients with peripheral high-flow arteriovenous malformations.

PURPOSE: To test the hypothesis that cardiac output (Q) in patients with arteriovenous malformations (AVMs) is normal at rest and increases disproportionately during exercise. MATERIALS AND METHODS: Q was measured in eight patients with large peripheral AVMs and in nine healthy subjects using a noninvasive carbon dioxide (CO2)-based differential Fick method. Subjects were tested while seated at rest and during mild exercise (repeated leg straightening while sitting). Oxygen consumption (VO2) was monitored as an index of the degree of exercise. RESULTS: Average resting Q was similar between AVM patients and healthy subjects (7.40 L/min ± 3.29 vs 6.13 L/min ± 0.94, respectively, P = .29). During exercise, AVM patients showed a smaller increment in VO2 (0.50 L/min ± 0.11 vs 0.78 L/min ± 0.26, P = .012) but with more apparent effort and shortness of breath compared with healthy subjects. The change in Q per unit change in VO2 (ΔQ/ΔVO2) was greater in AVM patients than in healthy subjects (16.00 L/min ± 6.50 vs 9.79 L/min ± 5.33, P < .045). CONCLUSIONS: Exercise intolerance in AVM patients may be due to an imbalance in ΔQ/ΔVO2 resulting from increased shunting through the AVM. Exercise provocation may increase the sensitivity of Q in the clinical evaluation of AVM patients.

Differences in the control of breathing between Andean highlanders and lowlanders after 10 days acclimatization at 3850 m.

We used Duffin's isoxic hyperoxic ( mmHg) and hypoxic ( mmHg) rebreathing tests to compare the control of breathing in eight (7 male) Andean highlanders and six (4 male) acclimatizing Caucasian lowlanders after 10 days at 3850 m. Compared to lowlanders, highlanders had an increased non-chemoreflex drive to breathe, characterized by higher basal ventilation at both hyperoxia (10.5 +/- 0.7 vs. 4.9 +/- 0.5 l min(1), P = 0.002) and hypoxia (13.8 +/- 1.4 vs. 5.7 +/- 0.9 l min(1), P < 0.001). Highlanders had a single ventilatory sensitivity to CO(2) that was lower than that of the lowlanders (P < 0.001), whose response was characterized by two ventilatory sensitivities (VeS1 and VeS2) separated by a patterning threshold. There was no difference in ventilatory recruitment thresholds (VRTs) between populations (P = 0.209). Hypoxia decreased VRT within both populations (highlanders: 36.4 +/- 1.3 to 31.7 +/- 0.7 mmHg, P < 0.001; lowlanders: 35.3 +/- 1.3 to 28.8 +/- 0.9 mmHg, P < 0.001), but it had no effect on basal ventilation (P = 0.12) or on ventilatory sensitivities in either population (P = 0.684). Within lowlanders, VeS2 was substantially greater than VeS1 at both isoxic tensions (hyperoxic: 9.9 +/- 1.7 vs. 2.8 +/- 0.2, P = 0.005; hypoxic: 13.2 +/- 1.9 vs. 2.8 +/- 0.5, P < 0.001), although hypoxia had no effect on either of the sensitivities (P = 0.192). We conclude that the control of breathing in Andean highlanders is different from that in acclimatizing lowlanders, although there are some similarities. Specifically, acclimatizing lowlanders have relatively lower non-chemoreflex drives to breathe, increased ventilatory sensitivities to CO(2), and an altered pattern of ventilatory response to CO(2) with two ventilatory sensitivities separated by a patterning threshold. Similar to highlanders and unlike lowlanders at sea-level, acclimatizing lowlanders respond to hypobaric hypoxia by decreasing their VRT instead of changing their ventilatory sensitivity to CO(2).

A simple and portable breathing circuit designed for ventilatory muscle endurance training (VMET).

BACKGROUND: Ventilatory muscle endurance training (VMET) involves increasing minute ventilation (V (E)) against a low flow resistance at rest to simulate the hyperpnea of exercise. Ideally, VMET must maintain normocapnia over a wide range of V (E). This can be achieved by providing a constant fresh gas flow to a sequential rebreathing circuit. The challenge to make VMET suitable for home use is to provide a source of constant fresh gas flow to the circuit without resorting to compressed gas. METHODS: Our VMET circuit was based on a commercial sequential gas delivery breathing circuit (Pulmanex Hi-Ox, Viasys Healthcare, Yorba Linda, CA USA). Airflow was provided either by a small battery-driven aquarium air pump or by the entrainment of air down a pressure gradient created by the recoil of a hanging bellows that was charged during each inhalation. In each case, fresh gas flow was adjusted to be just less than resting V (E). Eight subjects then breathed from the circuit for three 10min periods consisting of relaxed breathing, breathing at 20 and then at 40L/min. We monitored V (E), end-tidal PCO2 (PetCO2) and hemoglobin O2 saturation (SpO2). RESULTS: During hyperpnea at 20 and 40L/min, PetCO2 did not differ significantly from resting levels with either method of supplying fresh gas. SpO2 remained greater than 96% during all tests. CONCLUSION: Isocapnic VMET can be reliably accomplished with a simple self-regulating, sequential rebreathing circuit without the use of compressed gas.

Retinal arteriolar and capillary vascular reactivity in response to isoxic hypercapnia.

The aim of the study was to compare the magnitude of vascular reactivity of the retinal arterioles in terms of percentage change to that of the retinal capillaries using a novel, standardized methodology to provoke isoxic hypercapnia. Ten healthy subjects (mean age 25 years, range 21-31) were recruited. Subjects attended a single visit comprising two study sessions separated by 30 min. Subjects were fitted with a sequential re-breathing circuit connected to a computer-controlled gas blender. Each session consisted of breathing at rest for 10 min (baseline), increase of P(ET)CO(2) (maximum partial pressure of CO(2) during expiration) by 15% above baseline whilst maintaining isoxia for 20 min, and returning to baseline conditions for 10 min. Retinal hemodynamic measurements were performed using the Canon Laser Blood Flowmeter and the Heidelberg Retina Flowmeter in random order across sessions. Retinal arteriolar diameter, blood velocity and flow increased by 3.3%, 16.9% and 24.9% (p<0.001), respectively, during isoxic hypercapnia. There was also an increase of capillary blood flow of 34.8%, 21.6%, 24.9% (p< or =0.006) at the optic nerve head neuroretinal rim, nasal macula and fovea, respectively. The coefficient of repeatability (COR) was 5% of the average P(ET)CO(2) both at baseline and during isoxic hypercapnia and was 10% and 7% of the average P(ET)O(2) (minimum partial pressure of oxygen at end exhalation), respectively. The overall magnitude of retinal capillary vascular reactivity was equivalent to the arteriolar vascular reactivity with respect to percentage change of flow. The magnitude of isoxic hypercapnia was repeatable.

BOLD-MRI cerebrovascular reactivity findings in cocaine-induced cerebral vasculitis.

BACKGROUND: An 18-year-old woman presented to a regional stroke center with dysphasia and right hemiparesis 2 days after consuming alcohol and inhaling cannabis and -- for the first time -- cocaine. INVESTIGATIONS: Physical examination, blood tests for inflammatory markers, vasculitis and toxicology screen, echocardiography, electrocardiography, CT scanning, brain MRI, magnetic resonance angiography, magnetic resonance vessel wall imaging, catheter angiography, and correlation of blood oxygen level-dependent (BOLD)-MRI signal intensity with changes in end-tidal partial pressure of carbon dioxide. DIAGNOSIS: Cocaine-induced cerebral vasculitis. MANAGEMENT: No specific therapy was initiated. The patient's vital signs and neurological status were monitored during her admission. Follow-up medical imaging was performed after the patient's discharge from hospital.

Cardiovascular response to functional electrical stimulation and dynamic tilt table therapy to improve orthostatic tolerance.

Orthostatic hypotension is a common condition for individuals with stroke or spinal cord injury. The inability to regulate the central nervous system will result in pooling of blood in the lower extremities leading to orthostatic intolerance. This study compared the use of functional electrical stimulation (FES) and passive leg movements to improve orthostatic tolerance during head-up tilt. Four trial conditions were assessed during head-up tilt: (1) rest, (2) isometric FES of the hamstring, gastrocnemius and quadriceps muscle group, (3) passive mobilization using the Erigo dynamic tilt table; and (4) dynamic FES (combined 2 and 3). Ten healthy male subjects experienced 70 degrees head-up tilt for 15 min under each trial condition. Heart rate, blood pressure and abdominal echograms of the inferior vena cava were recorded for each trial. Passive mobilization and dynamic FES resulted in an increase in intravascular blood volume, while isometric FES only resulted in elevating heart rate. No significant differences in blood pressure were observed under each condition. We conclude that FES combined with passive stepping movements may be an effective modality to increase circulating blood volume and thereby tolerance to postural hypotension in healthy subjects.

Non-invasive prospective targeting of arterial P(CO2) in subjects at rest.

Accurate measurements of arterial P(CO(2)) (P(a,CO(2))) currently require blood sampling because the end-tidal P(CO(2)) (P(ET,CO(2))) of the expired gas often does not accurately reflect the mean alveolar P(CO(2)) and P(a,CO(2)). Differences between P(ET,CO(2)) and P(a,CO(2)) result from regional inhomogeneities in perfusion and gas exchange. We hypothesized that breathing via a sequential gas delivery circuit would reduce these inhomogeneities sufficiently to allow accurate prediction of P(a,CO(2)) from P(ET,CO(2)). We tested this hypothesis in five healthy middle-aged men by comparing their P(ET,CO(2)) values with P(a,CO(2)) values at various combinations of P(ET,CO(2)) (between 35 and 50 mmHg), P(O(2)) (between 70 and 300 mmHg), and breathing frequencies (f; between 6 and 24 breaths min(-1)). Once each individual was in a steady state, P(a,CO(2)) was collected in duplicate by consecutive blood samples to assess its repeatability. The difference between P(ET,CO(2)) and average P(a,CO(2)) was 0.5 +/- 1.7 mmHg (P = 0.53; 95% CI -2.8, 3.8 mmHg) whereas the mean difference between the two measurements of P(a,CO(2)) was -0.1 +/- 1.6 mmHg (95% CI -3.7, 2.6 mmHg). Repeated measures ANOVAs revealed no significant differences between P(ET,CO(2)) and P(a,CO(2)) over the ranges of P(O(2)), f and target P(ET,CO(2)). We conclude that when breathing via a sequential gas delivery circuit, P(ET,CO(2)) provides as accurate a measurement of P(a,CO(2)) as the actual analysis of arterial blood.

Retinal arteriolar and middle cerebral artery responses to combined hypercarbic/hyperoxic stimuli.

PURPOSE: The relative effect of simultaneously administered oxygen and carbon dioxide on the retinal and cerebral vessels is still controversial. The purpose of this study was to quantify and compare the superior-temporal retinal arteriole (RA) and middle cerebral artery (MCA) responses to hypercarbic and combined hypercarbic/hyperoxic stimuli. METHODS: Twelve young, healthy volunteers participated in the study. End-tidal pressure of carbon dioxide was raised and maintained at 22% from baseline (hypercarbia), while end-tidal pressures of oxygen (P(ET)O(2)) of 100 (normoxia), 500, and 300 mm Hg (hyperoxia) were instituted. RA diameter and blood velocity were measured with laser Doppler velocimetry and simultaneous vessel densitometry; MCA blood velocity was measured with transcranial Doppler ultrasound. RESULTS: Normoxic hypercarbia increased RA blood velocity by +17% and calculated flow by +21%. Hypercarbia/hyperoxia-500 mm Hg decreased RA diameter by -8%, velocity by -16% and calculated flow by -29%. MCA blood velocity increased by +45% in response to normoxic hypercarbia, significantly greater than RA blood velocity (P < 0.001). Increase in P(ET)O(2) did not affect the hypercarbia-induced increase in MCA blood velocity. CONCLUSIONS: Hyperoxia reversed hypercarbia-induced vasodilation in RA in a concentration-dependent manner. Hypercarbia induced greater vasodilation in the MCA than in the RA but MCA blood velocity was unaffected by increases in P(ET)O(2).

Comparison of the effects of independently-controlled end-tidal PCO(2) and PO(2) on blood oxygen level-dependent (BOLD) MRI.

PURPOSE: To assess the effect of changes in end-tidal partial pressure of O(2) (PETO(2)) on cerebrovascular reactivity (CVR) estimated from changes in blood oxygen level-dependent (BOLD) signal during cyclic changes in end-tidal partial pressure of CO(2) (PETCO(2)). MATERIALS AND METHODS: BOLD response to fixed cyclic step changes in PETCO(2) (range = 30.4-48.8 mmHg) and PETO(2) (range = 100.6-444.0 mmHg) was studied in four healthy volunteers. RESULTS: The BOLD reactivity to PETCO(2) and PETO(2) were 0.283 (0.188-0.379) (median, range) and 0.004 (0.003-0.006)%/mmHg, respectively, in the whole brain; 0.438 (0.382-0.614) vs. 0.006 (0.004-0.009)%/mmHg, respectively, in the gray matter; and 0.075 (0.065-0.093) vs. 0.002 (0.001-0.002)%/mmHg, respectively, in the white matter. CONCLUSION: The BOLD reactivity to PETO(2) was much smaller than that to PETCO(2). However, BOLD reactivity can be significantly distorted by CO(2)-induced changes in PETO(2). We conclude that PETO(2) should be carefully controlled during studies that use BOLD reactivity as an indicator of CVR.

Prospective targeting and control of end-tidal CO2 and O2 concentrations.

Current methods of forcing end-tidal PCO2 (PETCO2) and PO2 (PETO2) rely on breath-by-breath adjustment of inspired gas concentrations using feedback loop algorithms. Such servo-control mechanisms are complex because they have to anticipate and compensate for the respiratory response to a given inspiratory gas concentration on a breath-by-breath basis. In this paper, we introduce a low gas flow method to prospectively target and control PETCO2 and PETO2 independent of each other and of minute ventilation in spontaneously breathing humans. We used the method to change PETCO2 from control (40 mmHg for PETCO2 and 100 mmHg for PETO2) to two target PETCO2 values (45 and 50 mmHg) at iso-oxia (100 mmHg), PETO2 to two target values (200 and 300 mmHg) at normocapnia (40 mmHg), and PETCO2 with PETO2 simultaneously to the same targets (45 with 200 mmHg and 50 with 300 mmHg). After each targeted value, PETCO2 and PETO2 were returned to control values. Each state was maintained for 30 s. The average difference between target and measured values for PETCO2 was +/-1 mmHg, and for PETO2 was +/-4 mmHg. PETCO2 varied by +/-1 mmHg and PETO2 by +/-5.6 mmHg (s.d.) over the 30 s stages. This degree of control was obtained despite considerable variability in minute ventilation between subjects (+/-7.6 l min(-1)). We conclude that targeted end-tidal gas concentrations can be attained in spontaneously breathing subjects using this prospective, feed-forward, low gas flow system.

Modified N95 mask delivers high inspired oxygen concentrations while effectively filtering aerosolized microparticles.

STUDY OBJECTIVE: In a pandemic, hypoxic patients will require an effective oxygen (O2) delivery mask that protects them from inhaling aerosolized particles produced by others, as well as protecting the health care provider from exposure from the patient. We modified an existing N95 mask to optimize O2 supplementation while maintaining respiratory isolation. METHODS: An N95 mask was modified to deliver O2 by inserting a plastic manifold consisting of a 1-way inspiratory valve, an O2 inlet and a gas reservoir. In a prospective repeated-measures study, we studied 10 healthy volunteers in each of 3 phases, investigating (1) the fractional inspiratory concentrations of O2 (F(I)O2) delivered by the N95 O2 mask, the Hi-Ox80 O2 mask, and the nonrebreathing mask during resting ventilation and hyperventilation, each at 3 O2 flow rates; (2) the ability of the N95 mask, the N95 O2 mask, and the nonrebreathing mask to filter microparticles from ambient air; and (3) to contain microparticles generated inside the mask. RESULTS: The F(I)O2s (median [range]) delivered by the Hi-Ox80 O2 mask, the N95 O2 mask, and the nonrebreathing mask during resting ventilation, at 8 L/minute O2 flow, were 0.90 (0.79 to 0.96), 0.68 (0.60 to 0.85), and 0.59 (0.52 to 0.68), respectively. During hyperventilation, the FiO2s of all 3 masks were clinically equivalent. The N95 O2 mask, but not the nonrebreathing mask, provided the same efficiency of filtration of internal and external particles as the original N95, regardless of O2 flow into the mask. CONCLUSION: An N95 mask can be modified to administer a clinically equivalent FiO2 to a nonrebreathing mask while maintaining its filtration and isolation capabilities.