The reproducibility of breathing maneuvers as a vasoactive stimulus in the heart: an oxygenation-sensitive resonance imaging study.

BACKGROUND: Endothelial dysfunction and impaired oxygenation of the heart is a hallmark of several diseases, including coronary artery disease, hypertension, diabetes, and sleep apnea. Recent studies indicate that oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) imaging combined with breathing maneuvers may allow for assessing coronary vascular responsiveness as a marker for coronary vascular function in various clinical settings. However, despite the use of OS-CMR in evaluating tissue oxygenation, the reproducibility of these standardized, combined breathing maneuvers as a vasoactive stimulus has yet to be systematically assessed or validated. In this study, we aimed to assess the reproducibility of vasoactive breathing maneuvers to assess vascular function in a population of healthy volunteers. METHODS: Eighteen healthy volunteers were recruited for the study. Inclusion criteria were an age over 18 years and absence of any evidence or knowledge of cardiovascular, neurological, or pulmonary disease. MRI was performed on a clinical 3 T MRI system (MAGNETOM Skyra, Siemens Healthineers, Erlangen, Germany). The OS-CMR acquisition was performed as previously described (1 min hyperventilation followed by a maximal, voluntary breath-hold). Standard statistical tests were performed as appropriate. RESULTS: Data from 18 healthy subjects was analyzed. The healthy volunteers had a mean age of 42 ± 15 years and a mean BMI of 25.4 ± 2.8 kg/m2, with an average heart rate of 72 ± 11 beats per minute, and ten of whom (56%) were female. There were no significant differences between global myocardial oxygenation (%[Formula: see text] SI) after hyperventilation (HV1: - 7.82 [Formula: see text] 5.2; HV2: - 7.89 [Formula: see text] 6.4, p = 0.9) or breath-hold (BH1: 5.34 [Formula: see text] 3.1; BH2: 6.0 [Formula: see text] 3.3, p = 0.5) between the repeated breathing maneuvers. The Bland-Altman analysis showed good agreement (bias: 0.074, SD of bias: 2.93). CONCLUSION: We conclude that in healthy individuals, the myocardial oxygenation response to a standardized breathing maneuver with hyperventilation and a voluntary breath-hold is consistent and highly reproducible. These results corroborate previous evidence for breathing-enhanced OS-CMR as a robust test for coronary vascular function.

Effects of GB34 acupuncture on hyperventilation-induced carbon dioxide reactivity and cerebral blood flow velocity in the anterior and middle cerebral arteries of normal subjects.

OBJECTIVES: To determine whether acupuncture at GB34 affects cerebral blood flow (CBF) via the anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs). METHODS: This study included 10 healthy young male volunteers. CBF velocity and cerebrovascular reactivity (CVR) were measured using transcranial Doppler sonography (TCD). The changes in hyperventilation-induced carbon dioxide (CO2) reactivity and modified blood flow velocity at 40 mm Hg (CV40) were observed for both ACAs and MCAs before and after GB34 acupuncture treatment. Blood pressure and heart rate were also measured before and after GB34 acupuncture treatment. RESULTS: The CO2 reactivity of the ipsilateral MCA significantly increased after GB34 acupuncture treatment, compared with that at baseline (P=0.007). In contrast, the CO2 reactivity of both ACAs and the contralateral MCA remained unchanged. The CV40 of both ACAs and MCAs did not change after GB34 acupuncture treatment and neither did the mean arterial blood pressure and heart rate. CONCLUSIONS: GB34 acupuncture treatment increased CO2 reactivity specifically in the ipsilateral MCA, but had no effect on either the ACAs or the contralateral MCA. These data suggest that GB34 acupuncture treatment improves the vasodilatory potential of the cerebral vasculature to compensate for fluctuations caused by changes in external conditions and could potentially be useful for the treatment of disorders of the ipsilateral MCA circulation.

Pitt-Hopkins Syndrome: A Unique Case Study.

OBJECTIVES: Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Most cases are characterized by severe intellectual disability, absent speech, motor delays, and autism spectrum disorder. Many have abnormal brain imaging, dysmorphic facial features, and medical comorbidities: myopia, constipation, epilepsy, and apneic spells. The present case study expands existing understanding of this disorder by presenting a unique phenotype with higher cognitive abilities and fewer medical comorbidities. METHODS: The present case study reports on a 13-year-old, Caucasian male with a recent diagnosis of PTHS following genetic testing (i.e., whole exome sequencing). He was referred for a neuropsychological evaluation to document his neurocognitive functioning to assist with intervention planning. RESULTS: Evaluation of intellectual, attention/executive, memory, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning revealed global impairment across all areas of functioning. However, he demonstrated abilities beyond what has been detailed in the literature, including use of full sentences, capacity to learn and solve novel problems, basic academic functioning, and independent ambulation. CONCLUSIONS: Children with PTHS may demonstrate a spectrum of abilities beyond what has been documented in the literature thus far. Failure to recognize this spectrum can result in late identification of an accurate diagnosis. (JINS, 2018, 24, 995-1002).

A case of Pitt-hopkins Syndrome with de novo mutation in TCF4: Clinical features and treatment for epilepsy.

Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes, is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized by distinctive facial appearance, intermittent hyperventilation, intellectual disability and developmental delay. Although patients with PTHS generally have various systemic symptoms, most of them with a TCF4 mutation manifest the central nervous system (CNS) disorders. We described the first Chinese case with Pitt-Hopkins syndrome based on clinical presentations and genetic findings. In addition to the typical features of PTHS, the girl also had paroxysms of tachypnea followed by cyanosis and recurrent seizures. Comprehensive medical examinations were performed including metabolic screening, hepatic and renal function evaluation, abdominal and cardiac ultrasounds. The presence of epileptic discharges in electroencephalography and abnormal brain magnetic resonance imaging were found. High-throughput sequencing was used to detect genetic mutations associated with CNS disorders. Sanger sequencing was used to confirm the mutations in the patient. The c.2182C＞T (p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4 gene of the patient. In conclusion, we have identified a de novo nonsense mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting in a reduction of the seizures.

Repeated Spontaneous Intracranial Epidural Hemorrhage After Hysterical Crying.

BACKGROUND: Spontaneous epidural hemorrhage (EDH) is a rare occurrence that may be caused by vascular anomalies, infections, coagulopathies, or tumors. Spontaneous EDH occurring in patients without specific underlying disease has been reported only as intraspinal lesion but has never been demonstrated in the intracranial area. This study presents a 19-year-old patient with repeated spontaneous intracranial EDH caused twice by hysterical crying. CASE DESCRIPTION: The patient had spontaneous left frontal EDH after hysterical crying. Two years later, she had a similar episode after crying and a new spontaneous right frontal EDH was revealed. There was no obvious risk factor revealed by laboratory and radiologic survey. We postulated that hyperventilation during crying resulted in a sudden decrease in intracranial pressure. The intracranial hypotension induced detachment of the dura from the skull and spontaneous EDH occurred. CONCLUSIONS: Crying or hyperventilation may trigger spontaneous EDH and should be suspected when there are signs of persisting headache and increased intracranial pressure. The prognosis is excellent if early diagnosis and surgical decompression are achieved.

Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease.

The present study examined whether preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. Among 65 adult patients with ischemic moyamoya disease, 19 had misery perfusion in the precentral region on preoperative 15O positron emission tomography and underwent arterial bypass surgery for that region. Brain technetium-99 m-labeled ethyl cysteinate dimer single-photon emission computed tomography (SPECT) was preoperatively performed with and without hyperventilation challenge and relative cerebrovascular contractile reactivity to hypocapnia (RCVCRhypocap) (%/mmHg) was calculated in the precentral region. Development of cerebral hyperperfusion syndrome was determined using perioperative changes of symptoms and brain N-isopropyl-p-[123I]-iodoamphetamine SPECT performed after surgery. RCVCRhypocap was significantly lower in the 6 patients with cerebral hyperperfusion syndrome (-2.85 ± 1.10%/mmHg) than in the 13 patients without cerebral hyperperfusion syndrome (0.18 ± 1.97%/mmHg; p = 0.0050). Multivariate analysis demonstrated low RCVCRhypocap as an independent predictor of cerebral hyperperfusion syndrome (95% confidence interval, 0.04-0.96; p = 0.0433). Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease.

Diffusional kurtosis imaging (DKI) incorporation into an intravoxel incoherent motion (IVIM) MR model to measure cerebral hypoperfusion induced by hyperventilation challenge in healthy subjects.

OBJECTIVES: The objectives were to investigate the diffusional kurtosis imaging (DKI) incorporation into the intravoxel incoherent motion (IVIM) model for measurements of cerebral hypoperfusion in healthy subjects. MATERIALS AND METHODS: Eight healthy subjects underwent a hyperventilation challenge with a 4-min diffusion weighted imaging protocol, using 8 b values chosen with the Cramer-Rao Lower Bound optimization approach. Four regions of interest in gray matter (GM) were analyzed with the DKI-IVIM model and the bi-exponential IVIM model, for normoventilation and hyperventilation conditions. RESULTS: A significant reduction in the perfusion fraction (f) and in the product fD* of the perfusion fraction with the pseudodiffusion coefficient (D*) was found with the DKI-IVIM model, during the hyperventilation challenge. In the cerebellum GM, the percentage changes were f: -43.7 ± 40.1, p = 0.011 and fD*: -50.6 ± 32.1, p = 0.011; in thalamus GM, f: -47.7 ± 34.7, p = 0.012 and fD*: -47.2 ± 48.7, p = 0.040. In comparison, using the bi-exponential IVIM model, only a significant decrease in the parameter fD* was observed for the same regions of interest. In frontal-GM and posterior-GM, the reduction in f and fD* did not reach statistical significance, either with DKI-IVIM or the bi-exponential IVIM model. CONCLUSION: When compared to the bi-exponential IVIM model, the DKI-IVIM model displays a higher sensitivity to detect changes in perfusion induced by the hyperventilation condition.

Delayed refractory hyperventilation following endoscopic third ventriculostomy in a 5-year-old boy.

We present the case of a 5-year-old boy who developed a delayed onset intractable hyperventilation following endoscopic third ventriculostomy. The proposed aetiology of this exceptionally rare phenomenon is discussed. To our knowledge, previous cases have only been reported in the adult population.

Aging blunts hyperventilation-induced hypocapnia and reduction in cerebral blood flow velocity during maximal exercise.

Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO(2peak)) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO(2peak). In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO(2peak). Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA V (mean); transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO(2) (P(ET)CO(2)) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO(2peak), despite greater elevations in BP in OA, the change in MCA V(mean) was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO(2peak), the hyperventilation-induced declines in both P(ET)CO(2) (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA V(mean) (-21% (YA) vs. -7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO(2peak)), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.

Dynamic cerebral autoregulation assessed by respiratory manoeuvres in non-insulin-treated Type 2 diabetes mellitus.

AIMS: This study investigated dynamic cerebral autoregulation in Type 2 diabetes, where dynamic cerebral autoregulation may be impaired as a consequence of microvascular changes and/or autonomic neuropathy. METHODS: Eleven healthy control subjects and 11 age- and sex-matched patients with Type 2 diabetes controlled with lifestyle modifications or oral anti-diabetes treatment were recruited. Dynamic cerebral autoregulation was calculated by the autoregressive moving average autoregulatory index from a continuous blood pressure and R-R interval (time between each ventricular systole) recording. End-tidal carbon dioxide was also monitored and changes in response to breath holding and hyperventilation as a metabolic stimulus were measured. RESULTS: No significant differences were seen in cerebral blood flow velocity at baseline, or in response to breath holding between people with diabetes and control subjects, although the cerebral blood flow velocity response associated with hyperventilation was significantly reduced in the diabetes group. No significant differences in dynamic cerebral autoregulation were seen at baseline or in response to respiratory manoeuvres between the groups. CONCLUSIONS: Dynamic cerebral autoregulation is not impaired in patients with Type 2 diabetes, although a small difference could not be excluded as the study was only powered to detect an autoregulatory index difference > 2 units. Further study in a larger population with a spectrum of disease severity may reveal clinically important differences.

Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.

In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model.

Inconsistent detection of changes in cerebral blood volume by near infrared spectroscopy in standard clinical tests.

The attractive possibility of near infrared spectroscopy (NIRS) to noninvasively assess cerebral blood volume and oxygenation is challenged by the possible interference from extracranial tissues. However, to what extent this may affect cerebral NIRS monitoring during standard clinical tests is ignored. To address this issue, 29 healthy subjects underwent a randomized sequence of three maneuvers that differently affect intra- and extracranial circulation: Valsalva maneuver (VM), hyperventilation (HV), and head-up tilt (HUT). Putative intracranial ("i") and extracranial ("e") NIRS signals were collected from the forehead and from the cheek, respectively, and acquired together with cutaneous plethysmography at the forehead (PPG), cerebral blood velocity from the middle cerebral artery, and arterial blood pressure. Extracranial contribution to cerebral NIRS monitoring was investigated by comparing Beer-Lambert (BL) and spatially resolved spectroscopy (SRS) blood volume indicators [the total hemoglobin concentration (tHb) and the total hemoglobin index, (THI)] and by correlating their changes with changes in extracranial circulation. While THIe and tHbe generally provided concordant indications, tHbi and THIi exhibited opposite-sign changes in a high percentage of cases (VM: 46%; HV: 31%; HUT: 40%). Moreover, tHbi was correlated with THIi only during HV (P < 0.05), not during VM and HUT, while it correlated with PPG in all three maneuvers (P < 0.01). These results evidence that extracranial circulation may markedly affect BL parameters in a high percentage of cases, even during standard clinical tests. Surface plethysmography at the forehead is suggested as complementary monitoring helpful in the interpretation of cerebral NIRS parameters.

Shrinking lung syndrome in pregnancy complicated by antiphospholipid antibody syndrome.

BACKGROUND: Shrinking lung syndrome is characterized by pulmonary compromise secondary to unilateral or bilateral paralysis of the diaphragm. CASE: Shrinking lung syndrome was diagnosed in a patient with antiphospholipid syndrome after a cesarean delivery at 28 4/7 weeks of gestation. Signs and symptoms included unexplained right-side chest pain, dyspnea, tachypnea, and absent breath sounds at the right base of the lungs. After initiation of corticosteroids, her symptoms resolved. CONCLUSION: Although seen in association with systemic lupus erythematosus, shrinking lung syndrome has not been described with antiphospholipid syndrome or during pregnancy. Diagnosis and awareness are important because treatment with moderate- to high-dose corticosteroids appears to improve the clinical outcome.

Feeling lightheaded: the role of cerebral blood flow.

OBJECTIVE: The main aims of this study were a) to investigate the relationship between lightheadedness and cerebral blood flow velocity (CBFv) during hyperventilation-induced hypocapnia, and b) to investigate whether and why the relationship between lightheadedness and CBFv may change after several episodes of this sensation. METHODS: Three hypocapnic and three normocapnic overbreathing trials were administered in a semirandomized order to healthy participants (N = 33). Each type of breathing trial was consistently paired with one odor. Afterward, participants were presented each odor once in two spontaneous breathing and in two normocapnic overbreathing trials. CBFv in the right middle cerebral artery was measured by transcranial Doppler ultrasonography (TCD). Also breathing behavior and self-reported lightheadedness were measured continuously. Each trial was followed by a symptom checklist. RESULTS: Self-reported lightheadedness was closely related to changes in CBFv in the hypocapnic overbreathing trials. During the subsequent normocapnic trials, however, participants experienced more lightheadedness and "feeling unreal" to the odor that had previously been paired with hyperventilation-induced hypocapnia. These complaints were not accompanied by changes in end-tidal CO(2) nor in CBFv. CONCLUSIONS: The results show that lightheadedness is associated with changes in CBFv but that after a few episodes, the underlying mechanism for this symptom may shift to perceptual-cognitive processes. These findings may help to understand why lightheadedness occurs during emotional distress and panic. In addition, altered cerebral blood flow is unlikely to play a primary precipitating role in recurrent symptoms of lightheadedness.

Vasomotor properties of the M2 segment of the middle cerebral artery.

Vasomotor response can be tested by means of transcranial Doppler sonography. It is assumed that flow changes during hyperventilation or breath-holding are due to altered resistance caused by changes in the diameter of vessels distal to the M1 segment of the middle cerebral artery. Evaluating velocities of the M2 and M1 segments together may help elucidate the vasomotor properties of distal segments. We simultaneously evaluated the vasomotor properties of the M1 and M2 segments of the middle cerebral artery in ten healthy volunteers (mean age 21.6 +/- 0.9 years) with breath-holding and hyperventilation. The radius index (RI), defined as the ratio of the M1-M2 segment radii, was estimated after 20 s and after the maximum duration of breath-holding, as well as at the first, second, and third minute of hyperventilation, in relation to velocity ratios. RI values in the resting state were compared with the values after activation procedures. The RI estimated with basal velocities ranged from 0.72 to 0.97 (mean 0.81 +/- 0.07). The RI ranged from 0.73 to 0.97 (mean 0.82 +/- 0.07) after 20 s and 0.75 to 0.90 (mean 0.82 +/- 0.06) after the maximum duration of breath-holding. The RI was 0.72-1.02 (mean 0.85 +/- 0.11), 0.71-1.03 (mean 0.86 +/- 0.12), and 0.71-1.14 (mean 0.88 +/- 0.15) at the first, second, and third minute of hyperventilation, respectively. The differences between RI values in the resting state and during each activation procedure were not statistically significant. These results suggest that the diameter ratio of the M1-M2 segments did not change after vasomotor activation, indicating that the two segments have similar vasomotor properties.

Tissue pulsatility imaging of cerebral vasoreactivity during hyperventilation.

Tissue pulsatility imaging (TPI) is an ultrasonic technique that is being developed at the University of Washington to measure tissue displacement or strain as a result of blood flow over the cardiac and respiratory cycles. This technique is based in principle on plethysmography, an older nonultrasound technology for measuring expansion of a whole limb or body part due to perfusion. TPI adapts tissue Doppler signal processing methods to measure the "plethysmographic" signal from hundreds or thousands of sample volumes in an ultrasound image plane. This paper presents a feasibility study to determine if TPI can be used to assess cerebral vasoreactivity. Ultrasound data were collected transcranially through the temporal acoustic window from four subjects before, during and after voluntary hyperventilation. In each subject, decreases in tissue pulsatility during hyperventilation were observed that were statistically correlated with the subject's end-tidal CO2 measurements. (

Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism.

OBJECTIVE: To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Ten healthy volunteers and 30 patients within 10 days of closed head injury. INTERVENTIONS: Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36+/-3 and 29+/-2 torr. MEASUREMENTS AND MAIN RESULTS: We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17+/-22 vs. 2+/-3 mL; p

Transcranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing.

Clinical transcranial Doppler assessment of cerebral vasomotor reactivity (CVMR) uses linear regression of cerebral blood flow velocity (CBFV) vs. end-tidal CO(2) (Pet(CO(2))) under steady-state conditions. However, the cerebral blood flow (CBF)-Pet(CO(2)) relationship is nonlinear, even for moderate changes in CO(2). Moreover, CBF is increased by increases in arterial blood pressure (ABP) during hypercapnia. We used a modified rebreathing protocol to estimate CVMR during transient breath-by-breath changes in CBFV and Pet(CO(2)). Ten healthy subjects (6 men) performed 15 s of hyperventilation followed by 5 min of rebreathing, with supplemental O(2) to maintain arterial oxygen saturation constant. To minimize effects of changes in ABP on CVMR estimation, cerebrovascular conductance index (CVCi) was calculated. CBFV-Pet(CO(2)) and CVCi-Pet(CO(2)) relationships were quantified by both linear and nonlinear logistic regression. In three subjects, muscle sympathetic nerve activity was recorded. From hyperventilation to rebreathing, robust changes occurred in Pet(CO(2)) (20-61 Torr), CBFV (-44 to +104% of baseline), CVCi (-39 to +64%), and ABP (-19 to +23%) (all P < 0.01). Muscle sympathetic nerve activity increased by 446% during hypercapnia. The linear regression slope of CVCi vs. Pet(CO(2)) was less steep than that of CBFV (3 vs. 5%/Torr; P = 0.01). Logistic regression of CBF-Pet(CO(2)) (r(2) = 0.97) and CVCi-Pet(CO(2)) (r(2) = 0.93) was superior to linear regression (r(2) = 0.91, r(2) = 0.85; P = 0.01). CVMR was maximal (6-8%/Torr) for Pet(CO(2)) of 40-50 Torr. In conclusion, CBFV and CVCi responses to transient changes in Pet(CO(2)) can be described by a nonlinear logistic function, indicating that CVMR estimation varies within the range from hypocapnia to hypercapnia. Furthermore, quantification of the CVCi-Pet(CO(2)) relationship may minimize the effects of changes in ABP on the estimation of CVMR. The method developed provides insight into CVMR under transient breath-by-breath changes in CO(2).