Marat Slessarev

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.

Comparison of the effects of independently-controlled end-tidal PCO2 and PO2 on blood oxygen level–dependent (BOLD) MRI

To assess the effect of changes in end‐tidal partial pressure of O2 (PETO2) on cerebrovascular reactivity (CVR) estimated from changes in blood oxygen level–dependent (BOLD) signal during cyclic changes in end‐tidal partial pressure of CO2 (PETCO2).

Precise control of end‐tidal carbon dioxide and oxygen improves BOLD and ASL cerebrovascular reactivity measures

In‐depth investigation of cerebrovascular blood flow and MR mechanisms underlying the blood oxygenation level dependent signal requires precise manipulation of the arterial partial pressure of carbon dioxide and oxygen, measured by their noninvasive surrogates, the end‐tidal values. The traditional methodology consists of administering a fixed fractional concentration of inspired CO2, but this causes a variable ventilatory response across subjects, resulting in different values of end‐tidal partial pressures of CO2 and O2. In this study, we investigated whether fine control of these end‐tidal partial pressures would improve stability and predictability of blood oxygenation level dependent and arterial spin labeling signals for studying cerebrovascular reactivity. In 11 healthy volunteers, we compared the MR signals generated by the traditional fixed fractional concentration of inspired CO2 method to those of an automated feed‐forward system, a simpler, safer, and more compact alternative to dynamic end‐tidal forcing systems, designed to target constant end‐tidal partial pressures of CO2 and O2. We found that near square‐wave changes in end‐tidal partial pressure of CO2 of 5, 7.5, and 10 mm Hg (±1.01 mm Hg within two to three breaths) and constrained changes in the end‐tidal partial pressure of O2 (<10 mm Hg) induced cerebral vascular reactivity measurements with faster transitions, together with improved stability and gradation, than those achieved with the traditional fixed fractional concentration of inspired CO2 method. Magn Reson Med, 2010.

Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of “fitness” for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

Impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations

Epileptic seizures are a common presentation in patients with newly diagnosed brain arteriovenous malformations, but the pathophysiological mechanisms causing the seizures remain poorly understood. We used magnetic resonance imaging-based quantitative cerebrovascular reactivity mapping and conventional angiography to determine whether seizure-prone patients with brain arteriovenous malformations exhibit impaired cerebrovascular reserve or morphological angiographic features predictive of seizures. Twenty consecutive patients with untreated brain arteriovenous malformations were recruited (10 with and 10 without epileptic seizures) along with 12 age-matched healthy controls. Blood oxygen level-dependent MRI was performed while applying iso-oxic step changes in end-tidal partial pressure of CO(2) to obtain quantitative cerebrovascular reactivity measurements. The brain arteriovenous malformation morphology was evaluated by angiography, to determine to what extent limitations of arterial blood supply or the presence of restricted venous outflow and tissue congestion correlated with seizure susceptibility. Only patients with seizures exhibited impaired peri-nidal cerebrovascular reactivity by magnetic resonance imaging (0.11 ± 0.10 versus 0.25 ± 0.07, respectively; P < 0.001) and venous drainage patterns suggestive of tissue congestion on angiography. However, cerebrovascular reactivity changes were not of a magnitude suggestive of arterial steal, and were probably compatible with venous congestion in aetiology. Our findings demonstrate a strong association between impaired peri-nidal cerebrovascular reserve and epileptic seizure presentation in patients with brain arteriovenous malformation. The impaired cerebrovascular reserve may be associated with venous congestion. Quantitative measurements of cerebrovascular reactivity using blood oxygen level-dependent MRI appear to correlate with seizure susceptibility in patients with brain arteriovenous malformation.

BOLD signal responses to controlled hypercapnia in human spinal cord.

Functional MRI of the spinal cord is challenging due to the small cross section of the cord and high level of physiological noise. Though blood oxygenation level-dependent (BOLD) contrast has been used to study specific responses of the spinal cord to various stimuli, it has not been demonstrated using a controlled stimulus. In this paper, we use hypercapnic manipulation to study the sensitivity and specificity of functional MRI in the human cervical spinal cord. Simultaneous MR imaging in the brain and spinal cord was performed for direct comparison with the brain, in which responses to hypercapnia have been more extensively characterized. Original contributions include: (i) prospectively controlled hypercapnic changes in end-tidal PCO(2), (ii) simultaneous recording of BOLD responses in the brain and spinal cord, and (iii) generation of statistical maps of BOLD responses throughout the brain and spinal cord, taking into account physiological noise sources. Results showed significant responses in all subjects both in the brain and the spinal cord. In anatomically-defined regions of interest, mean percent changes were 0.6% in the spinal cord and 1% in the brain. Analysis of residual variance demonstrated significantly larger contribution of physiological noise in the spinal cord (P<0.005). To obtain more reliable results from fMRI in the spinal cord, it will be necessary to improve sensitivity through the use of highly parallelized coil arrays and better modeling of physiological noise. Finely, we believe that the use of controlled global stimuli, such as hypercapnia, will help assess the effectiveness of new acquisition techniques.

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 patients vital signs and neurological status were monitored during her admission. Follow-up medical imaging was performed after the patients discharge from hospital.

Cerebral Vasodilatation to Exogenous NO Is a Measure of Fitness for Life at Altitude

Background and Purpose— Andean highlanders, unlike Ethiopians, develop chronic mountain sickness (CMS), a maladaptation to their native land. Ambient hypoxia induces NO-mediated vasodilatation. Fitness for life at altitude might be revealed by cerebrovascular responses to NO. Methods— Nine altitude-native men were examined at 3622 and 794 m in Ethiopia and compared with 9 altitude-native Andean men tested at 4338 and 150 m in Peru. We assessed CMS scores, hematocrits, end-tidal pressure of carbon dioxide (PETco2), oxygen saturations, and cerebral blood flow velocity (CBV). We evaluated fitness for life at altitude from the cerebrovascular response to an exogenous NO donor. Results— At high altitude, CMS scores and hematocrits were higher in Andeans, and they had lower oxygen saturations. Ethiopians had higher PETco2 at all study sites. At low altitude, saturations were similar in both groups. Responsiveness of the cerebral circulation to NO was minimal in Ethiopians at low altitude, whereas Andeans had a large response. In contrast, at high altitude, Ethiopians showed large responses, and Peruvians had minimal responses. Conclusions— By our measure, high altitude–native Peruvians were well-adapted lowlanders, whereas Ethiopian highlanders were well adapted to altitude life. Environmental pressures were sufficient for human adaptation to chronic hypoxia in Africa but not South America. The mechanisms underlying these differences are unknown, although studies of neurovascular diseases suggest that this may be related to a NO receptor polymorphism.

Cerebrovascular Responses to Hypoxia and Hypocapnia in Ethiopian High Altitude Dwellers

Background and Purpose— Cerebrovascular responses to hypoxia and hypocapnia in Peruvian altitude dwellers are impaired. This could contribute to the high incidence of altitude-related illness in Andeans. Ethiopian high altitude dwellers may show a different pattern of adaptation to high altitude. We aimed to examine cerebral reactivity to hypoxia and hypocapnia in healthy Ethiopian high altitude dwellers. Responses were compared with our previous data from Peruvians. Methods— We studied 9 Ethiopian men at their permanent residence of 3622 m, and one day after descent to 794 m. We continuously recorded cerebral blood flow velocity (CBFV; transcranial Doppler). End-tidal oxygen (PETo2) was decreased from 100 mm Hg to 50 mm Hg with end-tidal carbon dioxide (PETco2) clamped at the subject’s resting level. PETco2 was then manipulated by voluntary hyper- and hypoventilation, with PETo2 clamped at 100 mm Hg (normoxia) and 50 mm Hg (hypoxia). Results— During spontaneous breathing, PETco2 increased after descent, from 38.2±1.0 mm Hg to 49.8±0.6 mm Hg (P<0.001). There was no significant response of CBFV to hypoxia at either high (−0.19±3.1%) or low (1.1±2.9%) altitudes. Cerebrovascular reactivity to normoxic hypocapnia at high and low altitudes was 3.92±0.5%.mm Hg−1 and 3.09±0.4%.mm Hg−1; reactivity to hypoxic hypocapnia was 4.83±0.7%.mm Hg−1 and 2.82±0.5%.mm Hg−1. Responses to hypoxic hypocapnia were significantly smaller at low altitude. Conclusions— The cerebral circulation of Ethiopian high altitude dwellers is insensitive to hypoxia, unlike Peruvian high altitude dwellers. Cerebrovascular responses to PETco2 were greater in Ethiopians than Peruvians, particularly at high altitude. This, coupled with their high PETco2 levels, would lead to high cerebral blood flows, and may be advantageous for altitude living.

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

We used Duffins 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 CO2 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 CO2, and an altered pattern of ventilatory response to CO2 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 CO2.