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Background Letters of recommendation (LORs) are an important part of the application process for medical residency programs with most specialties preferring a narrative format. Given the inherent subjectivity of narrative LORs, the current study sought to determine whether the intended messages of narrative LORs written for applicants to anesthesiology residency programs are accurately interpreted by readers. Methodology Anonymous online surveys were sent via the Qualtrics platform to program directors (PDs) of the Accreditation Council for Graduate Medical Education-accredited anesthesiology residency programs in the Mid-Atlantic region as designated by the Electronic Residency Application Service, which consists of the states of New York, Pennsylvania, and New Jersey. Each PD participant received five surveys, each of which was attached to a de-identified LOR that was written by another PD located at an institution in the same region. Both the letter writer and study participants were asked to score LORs on a Likert-like scale. Participants were additionally asked whether the LORs, if received, would influence their decision to either offer an interview to the applicant or to rank the applicant. Finally, participants were asked to note any specific words or phrases within the LORs that they found to be particularly impactful. Results Overall, 10 of 34, 29.41%, PDs responded to the survey. There was a high correlation between the LOR intent and the respondents' assigned rating (Spearman's rho = 0.7973, p < 0.001). Responses were more accurate for "outstanding and excellent" LORs compared to the lower three categories. Results were unaffected after adjusting for respondents' years of experience as PDs. Additionally, 71.6% indicated that the LORs would influence the decision about offering an interview, and 56.5% stated that the LORs would influence a ranking decision. Conclusions Our results indicate that respondents' perception of LORs correlated strongly with the intent of the writer. Additionally, respondents seemed to value LORs for interview and ranking decisions., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. New York Medical College Institutional Review Board issued approval 19512. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pianello et al.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CB V ) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO 2 (ETCO 2 ; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CB V compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CB V reduction, we administered supplemental CO 2 , phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO 2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CB V . NEW & NOTEWORTHY We evaluated cognitive function before and after CO 2 , acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO 2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO 2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Fifty percent of patients with postural tachycardia syndrome (POTS) are hypocapnic during orthostasis related to initial orthostatic hypotension (iOH). We determined whether iOH drives hypocapnia in POTS by low BP or decreased cerebral blood velocity (CBv). We studied three groups; healthy volunteers ( n = 32, 18 ± 3 yr) were compared with POTS, grouped by presence [POTS-low end-tidal CO 2 (↓ETCO 2 ), n = 26, 19 ± 2 yr] or absence [POTS-normal upright end-tidal carbon dioxide (nlCO 2 ), n = 28, 19 ± 3 yr] of standing hypocapnia defined by end-tidal CO 2 (ETCO 2 ) ≤ 30 mmHg at steady-state, measuring middle cerebral artery CBv, heart rate (HR), and beat-to-beat blood pressure (BP). After 30 min supine, subjects stood for 5 min. Quantities were measured prestanding, at minimum CBv, minimum BP, peak HR, CBv recovery, BP recovery, minimum HR, steady-state, and 5 min. Baroreflex gain was estimated by α index. iOH occurred with similar frequency and minimum BP in POTS-↓ETCO 2 and POTS-nlCO 2 . Minimum CBv was reduced significantly ( P < 0.05) in POTS-↓ETCO 2 (48 ± 3 cm/s) preceding hypocapnia compared with POTS-nlCO 2 (61 ± 3 cm/s) or Control (60 ± 2 cm/s). The anticipatory increased BP was significantly larger ( P < 0.05) in POTS (8 ± 1 mmHg vs. 2 ± 1) and began ∼8 s prestanding. HR increased in all subjects, CBv increased significantly ( P < 0.05) in both POTS-nlCO 2 (76 ± 2 to 85 ± 2 cm/s) and Control (75 ± 2 to 80 ± 2 cm/s) consistent with central command. CBv decreased in POTS-↓ETCO 2 (76 ± 3 to 64 ± 3 cm/s) correlating with decreased baroreflex gain. Cerebral conductance [meanCBv/mean arterial blood pressure (MAP)] was reduced in POTS-↓ETCO 2 throughout. Data support the hypothesis that excessively reduced CBv during iOH may intermittently reduce carotid body blood flow, sensitizing that organ and producing postural hyperventilation in POTS-↓ETCO 2 . Excessive fall in CBv occurs in part during prestanding central command and is a facet of defective parasympathetic regulation in POTS. NEW & NOTEWORTHY Dyspnea is frequent in postural tachycardia syndrome (POTS) and is associated with upright hyperpnea and hypocapnia that drives sinus tachycardia. It is initiated by an exaggerated reduction in cerebral conductance and decreased cerebral blood flow (CBF) that precedes the act of standing. This is a form of autonomically mediated "central command." Cerebral blood flow is further reduced by initial orthostatic hypotension common in POTS. Hypocapnia is maintained during the standing response and might account for persistent postural tachycardia.

Purpose: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders., Methods: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition., Results: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses., Conclusion: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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Reduced systolic/diastolic blood pressure (BP) by >40/20 mmHg defines initial orthostatic hypotension (IOH). Rapid resolution of hypotension and lightheadedness follows, but tachycardia may be prolonged. We aimed to examine IOH in controls and patients with postural tachycardia syndrome (POTS) using indices of spontaneous fluctuations of heart rate (HR) and systolic BP as measures of cardiac baroreflex differences. We recruited otherwise healthy IOH patients without POTS ( n = 20, 16 ± 3 yr), healthy volunteers ( n = 32, 17 ± 3 yr), and POTS patients ( n = 39, 17 ± 4 yr). Subjects were instrumented for electrocardiography and beat-to-beat BP. After 10 min supine, subjects stood for 5 min. Following supine recovery, subjects underwent 70° head-up tilt for 10 min to test for POTS. BP, HR, and time, referenced to standing, were measured at events during standing: minimum BP, BP recovery, peak HR, HR minimum, and steady state. Baseline HR and BP were higher in POTS compared with healthy groups. IOH occurred in 13% of controls and 51% of POTS patients. The BP minimum was lower in POTS. Parasympathetic modulation of cardiac baroreflex was decreased in all POTS and control-IOH subjects. Sympathetic indices were increased. Events following BP minimum occurred progressively later in all POTS and control-IOH subjects compared with non-IOH controls. IOH is more frequent in POTS than in controls with a lower minimum BP. POTS has markedly reduced heart rate variability and baroreflex, indicating reduced HR buffering of BP. POTS-IOH and control-IOH subjects had similar peak HR despite decreased minimum BP in POTS. IOH data indicate modest parasympathetic and cardiovagal baroreflex deficits in control-IOH subjects. Parasympathetic deficits are more severe in all POTS patients. NEW & NOTEWORTHY Significant initial orthostatic hypotension (IOH) occurs in ~50% of postural tachycardia syndrome (POTS) patients and 13% of controls. Heart rate and blood pressure recovery are prolonged in IOH sustaining lightheadedness; IOH is more prevalent and severe in POTS. Altered cerebral blood flow and cardiorespiratory regulation are more prevalent in POTS. Altered heart rate variability and baroreflex gain may cause nearly instantaneous lightheadedness in POTS. IOH alone fails to confer a strong probability of POTS.

Background: Upright posture reduces venous return, stroke volume, and cardiac output (CO) while causing reflex sinus rate (heart rate [HR]) increase. Yet, in inappropriate sinus tachycardia (IST), postural tachycardia syndrome (POTS), and vasovagal syncope (VVS), symptomatic excessive HR occurs. We hypothesized that CO reaches maximum as function of HR in all., Methods: We recruited 12 healthy controls, 9 IST, 30 VVS, and 30 POTS patients (13-23years) selected randomly by disorder not by HR, each fulfilled appropriate diagnostic criteria. Subjects were instrumented for electrocardiography, beat-to-beat blood pressure, respiratory rate, CO-Modelflow algorithm, and central blood volume from impedance cardiography; 10-minute data were collected supine; subjects were tilted head-up for ≤10 minutes. We computed phase differences, ΔΦ, between fluctuations of HR (ΔHR) and CO (ΔCO) tabulating data when phases were synchronized, determined by a squared nonlinear phase synchronization index >0.5, describing extent/validity of CO/HR coupling. We graphed results supine, 1-minute post-tilt-up, mid-tilt, and pre-tilt-down using polar coordinates (HR-radius, ΔΦ-angle) plotting cos(ΔΦ) versus HR to determine if transition HR exists at which in-phase shifts to antiphase above which CO decreases when HR further increases., Results: At baseline HR, diastolic and mean arterial pressures in IST and POTS were higher versus controls. Upright HR increased most in POTS then IST and VVS, with diverse changes in CO, SVR, and central blood volume. Each patient grouping was separately and collectively analyzed for HR change showing transition from in-phase to anti-phase (ΔΦ) as HR increased: HR transition =115±6 (IST), 123±8 (POTS), 124±7 (VVS), P =ns. Controls never reached transitional HR., Conclusions: Excessive HR independently and equivalently reduces upright CO, in IST, POTS, and VVS.

Objective: To evaluate whether equal volumes of oral rehydration solution (ORS) or intravenous (IV) saline provide similar improvements in cardiovascular status during controlled orthostatic challenge when administered to subjects with postural tachycardia syndrome (POTS) with orthostatic intolerance., Study Design: We studied the neurovascular response to fluid loading during orthostatic stress using lower body negative pressure (LBNP) in 10 subjects with POTS with orthostatic intolerance and 15 controls, and on subsequent days before and 1 hour after IV saline infusion or ingestion of ORS., Results: Subjects with POTS exhibited reduced tolerance to LBNP (P < .0001) compared with controls (Orthostatic Index of 35 715 ± 3469 vs 93 980 ± 7977, respectively). In POTS, following ORS but not saline infusion, cerebral blood flow velocity (CBF v ) was significantly higher than that with no treatment, at -45 mm Hg (P < .0005). Although fluid loading did not confer any advantage in controls, subjects with POTS experienced a significant improvement in orthostatic tolerance following both saline infusion (100 ± 9.7 vs 134.5 ± 17.4; P < .05) and ORS (100 ± 9.7 vs 155.6 ± 15.7; P < .001) when evaluated by normalized orthostatic index (P < .001, compared with untreated baseline)., Conclusions: Maintenance of CBF v may have resulted in the improved short-term orthostatic tolerance exhibited by the subjects with POTS following ORS administration. ORS is a convenient, safe, and effective therapy for short-term relief of orthostatic intolerance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Upright tilt table testing has been used to test for vasovagal syncope (VVS) but can result in "false positives" in which tilt-induced fainting (tilt+) occurs in the absence of real-world fainting. Tilt+ occurs in healthy volunteers and in patients with postural tachycardia syndrome (POTS) and show enhanced susceptibility to orthostatic hypotension. We hypothesized that the mechanisms for hypotensive susceptibility differs between tilt+ healthy volunteers (Control-Faint (N = 12)), tilt+ POTS patients (POTS-Faint (N = 12)) and a non-fainter control group of (Control-noFaint) (N = 10). Subjects were studied supine and during 70° upright tilt while blood pressure (BP), cardiac output (CO), and systemic vascular resistance (SVR), were measured continuously. Impedance plethysmography estimated regional blood volumes, flows, and vascular resistance. Heart rate was increased while central blood volume was decreased in both Faint groups. CO increased in Control-Faint because of reduced splanchnic vascular resistance; splanchnic pooling was similar to Control-noFaint. Splanchnic blood flow in POTS-Faint decreased and resistance increased similar to Control-noFaint but splanchnic blood volume was markedly increased. Decreased SVR and splanchnic arterial vasoconstriction is the mechanism for faint in Control-Faint. Decreased CO caused by enhanced splanchnic pooling is the mechanism for faint in POTS-Faint. We propose that intrahepatic resistance is increased in POTS-Faint resulting in pooling and that both intrahepatic resistance and splanchnic arterial vasoconstriction are reduced in Control-Faint resulting in increased splanchnic blood flow and reduced splanchnic resistance., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Upright hyperventilation occurs in ~25% of our patients with postural tachycardia syndrome (POTS). Poikilocapnic hyperventilation alone causes tachycardia. Here, we examined changes in respiration and hemodynamics comprising cardiac output (CO), systemic vascular resistance (SVR), and blood pressure (BP) measured during head-up tilt (HUT) in three groups: patients with POTS and hyperventilation (POTS-HV), patients with panic disorder who hyperventilate (Panic), and healthy controls performing voluntary upright hyperpnea (Voluntary-HV). Though all were comparably tachycardic during hyperventilation, POTS-HV manifested hyperpnea, decreased CO, increased SVR, and increased BP during HUT; Panic patients showed both hyperpnea and tachypnea, increased CO, and increased SVR as BP increased during HUT; and Voluntary-HV were hyperpneic by design and had increased CO, decreased SVR, and decreased BP during upright hyperventilation. Mechanisms of hyperventilation and hemodynamic changes differed among POTS-HV, Panic, and Voluntary-HV subjects. We hypothesize that the hyperventilation in POTS is caused by a mechanism involving peripheral chemoreflex sensitization by intermittent ischemic hypoxia. NEW & NOTEWORTHY Hyperventilation is common in postural tachycardia syndrome (POTS) and has distinctive cardiovascular characteristics when compared with hyperventilation in panic disorder or with voluntary hyperventilation. Hyperventilation in POTS is hyperpnea only, distinct from panic in which tachypnea also occurs. Cardiac output is decreased in POTS, whereas peripheral resistance and blood pressure (BP) are increased. This is distinct from voluntary hyperventilation where cardiac output is increased and resistance and BP are decreased and from panic where they are all increased.

Background: Postural tachycardia syndrome (POTS) is a heterogeneous condition. We stratified patients previously evaluated for POTS on the basis of supine resting cardiac output (CO) or with the complaint of platypnea or "shortness of breath" during orthostasis. We hypothesize that postural hyperventilation is one cause of POTS and that hyperventilation-associated POTS occurs when initial reduction in CO is sufficiently large. We also propose that circulatory abnormalities normalize with restoration of CO 2 ., Methods and Results: Fifty-eight enrollees with POTS were compared with 16 healthy volunteer controls. Low CO in POTS was defined by a resting supine CO <4 L/min. Patients with shortness of breath had hyperventilation with end tidal CO 2 <30 Torr during head-up tilt table testing. There were no differences in height or weight between control patients and patients with POTS or differences between the POTS groups. Beat-to-beat blood pressure was measured by photoplethysmography, and CO was measured by ModelFlow. Systemic vascular resistance was defined as mean arterial blood pressure/CO. End tidal CO 2 and cerebral blood flow velocity of the middle cerebral artery were only reduced during head-up tilt in the hyperventilation group, whereas blood pressure was increased compared with control. We corrected the reduced end tidal CO 2 in hyperventilation by addition of exogenous CO 2 into a rebreathing apparatus. With added CO 2 , heart rate, blood pressure, CO, and systemic vascular resistance in hyperventilation became similar to control., Conclusions: We conclude that all POTS is related to decreased CO, decreased central blood volume, and increased systemic vascular resistance and that a variant of POTS is consequent to postural hyperventilation., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Orthostatic intolerance (OI), having difficulty tolerating an upright posture because of symptoms or signs that abate when returned to supine, is common in pediatrics. For example, ∼40% of people faint during their lives, half of whom faint during adolescence, and the peak age for first faint is 15 years. Because of this, we describe the most common forms of OI in pediatrics and distinguish between chronic and acute OI. These common forms of OI include initial orthostatic hypotension (which is a frequently seen benign condition in youngsters), true orthostatic hypotension (both neurogenic and nonneurogenic), vasovagal syncope, and postural tachycardia syndrome. We also describe the influences of chronic bed rest and rapid weight loss as aggravating factors and causes of OI. Presenting signs and symptoms are discussed as well as patient evaluation and testing modalities. Putative causes of OI, such as gravitational and exercise deconditioning, immune-mediated disease, mast cell activation, and central hypovolemia, are described as well as frequent comorbidities, such as joint hypermobility, anxiety, and gastrointestinal issues. The medical management of OI is considered, which includes both nonpharmacologic and pharmacologic approaches. Finally, we discuss the prognosis and long-term implications of OI and indicate future directions for research and patient management., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Boris has served as a paid expert witness on the subject of postural orthostatic tachycardia syndrome. H. Lundbeck A/S (which underwrote a meeting of the Pediatric Subgroup of the American Autonomic Society) produces Northera (droxidopa) to treat orthostatic intolerance as well as citalopram and escitalopram; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Introduction The aim of this paper is to describe and demonstrate how a new bioimpedance analytical procedure can be used to monitor cellular hydration of End Stage Renal Disease (ESRD) patients during hemodialysis (HD). Methods A tetra-polar bioimpedance spectroscope (BIS), (UFI Inc., Morro Bay, CA), was used to measure the tissue resistance and reactance of the calf of 17 ESRD patients at 40 discrete frequencies once a minute during dialysis treatment. These measurements were then used to derive intracellular, interstitial, and intravascular compartment volume changes during dialysis. Findings The mean (± SD) extracellular resistance increased during dialysis from 92.4 ± 3.5 to 117.7 ± 5.8 Ohms. While the mean intracellular resistance decreased from 413.5 ± 11.7 to 348.5 ± 8.2 Ohms. It was calculated from these data that the mean intravascular volume fell 9.5%; interstitial volume fell 33.4%; and intracellular volume gained 20.3%. Discussion These results suggest that an extensive fluid shift into the cells may take place during HD. The present research may contribute to a better understanding of how factors that influence fluid redistribution may affect an ESRD patient during dialysis. In light of this finding, it is concluded that the rate of vascular refill is jointly determined with the rate of "cellular refill" and the transfer of fluid from the intertitial compartment into the intravascular space., (© 2016 International Society for Hemodialysis.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis. This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep. Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound. Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common. Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.

We measured changes in transcranial Doppler ultrasound (TCD) and near infrared spectroscopy (NIRS) during 70° upright tilt in patients with recurrent vasovagal syncope (VVS, N  = 20), postural tachycardia syndrome (POTS, N  = 20), and healthy controls ( N  = 12) aged 15-27 years old. VVS was included if they fainted during testing within 5-15 min of upright tilt. We combined TCD and NIRS to obtain estimates of percent change in the cerebral metabolic rate of oxygen consumption (CMRO 2 ), cerebral blood flow velocity (CBFv), and oxygen extraction fraction (OEF). Over the course of 10 min of upright tilt, CBFv decreased from a baseline of 70 ± 5 to 63 ± 5 cm/sec in controls and 74 ± 3 to 64 ± 3 cm/sec in POTS while decreasing from 74 ± 4 to 44 ± 3 cm/sec in VVS CMRO 2 was unchanged in POTS and controls during tilt while OEF increased by 19 ± 3% and 15 ± 3%, respectively. CMRO 2 decreased by 31 ± 3% in VVS during tilt while OEF only increased by 7 ± 3%. Oxyhemoglobin decreased by 1.1 ± 1.3  μ mol/kg brain tissue in controls, by 1.1 ± 1.3  μ mol/kg in POTS, and 11.1 ± 1.3  μ mol/kg in VVS CBFv and CMRO 2 fell steadily in VVS during upright tilt. The deficit in CMRO 2 in VVS results from inadequate OEF in the face of greatly reduced CBF., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background and Objectives: Recurrent postural vasovagal syncope (VVS) is caused by transient cerebral hypoperfusion from episodic hypotension and bradycardia; diagnosis is made by medical history. VVS contrasts with postural tachycardia syndrome (POTS), defined by chronic daily symptoms of orthostatic intolerance with excessive upright tachycardia without hypotension. POTS has recently been conflated with VVS when excessive tachycardia is succeeded by hypotension during tilt testing. We hypothesize that excessive tachycardia preceding hypotension and bradycardia is part of the vasovagal response during tilt testing of patients with VVS., Methods: We prospectively performed head-up tilt (HUT) testing on patients with recurrent VVS ( n = 47, 17.9 ± 1.1 y), who fainted at least 3 times within the last year, and control subjects ( n = 15, 17.1 ± 1.0 y), from age and BMI-matched volunteers and measured blood pressure, heart rate (HR), cardiac output, total peripheral resistance, and end tidal carbon dioxide., Results: Baseline parameters were the same in both groups. HR (supine versus 5 and 10 minutes HUT) significantly increased in control (65 ± 2.6 vs 83 ± 3.6 vs 85 ± 3.7, P < .001) and patients with VVS (69 ± 1.6 vs 103 ± 2.3 vs 109 ± 2.4, P < .001). HUT in controls maximally increased HR by 20.3 ± 2.9 beats per minute; the increase in patients with VVS of 39.8 ± 2.1 beats per minute was significantly greater ( P < .001). An increase in HR of ≥40 beats per minute by 5 and 10 minutes or before faint with HUT, occurred in 26% and 44% of patients with VVS, respectively, but not in controls., Conclusions: Orthostasis in VVS is accompanied by large increases in HR that should not be construed as POTS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Neurovascular coupling (NVC) describes the link between an increase in task-related neural activity and increased cerebral blood flow denoted "functional hyperemia." We previously showed induced cerebral blood flow oscillations suppressed functional hyperemia; conversely functional hyperemia also suppressed cerebral blood flow oscillations. We used lower body negative pressure (OLBNP) oscillations to force oscillations in middle cerebral artery cerebral blood flow velocity (CBFv). Here, we used N-back testing, an intellectual memory challenge as a neural activation task, to test the hypothesis that OLBNP-induced oscillatory cerebral blood flow can reduce functional hyperemia and NVC produced by a working memory task and can interfere with working memory. We used OLBNP (-30 mmHg) at 0.03, 0.05, and 0.10 Hz and measured spectral power of CBFv at all frequencies. Neither OLBNP nor N-back, alone or combined, affected hemodynamic parameters. 2-Back power and OLBNP individually were compared with 2-back power during OLBNP. 2-Back alone produced a narrow band increase in oscillatory arterial pressure (OAP) and oscillatory cerebral blood flow power centered at 0.0083 Hz. Functional hyperemia in response to 2-back was reduced to near baseline and 2-back memory performance was decreased by 0.03-, 0.05-, and 0.10-Hz OLBNP. OLBNP alone produced increased oscillatory power at frequencies of oscillation not suppressed by added 2-back. However, 2-back preceding OLBNP suppressed OLBNP power. OLBNP-driven oscillatory CBFv blunts NVC and memory performance, while memory task reciprocally interfered with forced CBFv oscillations. This shows that induced cerebral blood flow oscillations suppress functional hyperemia and functional hyperemia suppresses cerebral blood flow oscillations. NEW & NOTEWORTHY We show that induced cerebral blood flow oscillations suppress functional hyperemia produced by a working memory task as well as memory task performance. We conclude that oscillatory cerebral blood flow produces causal reductions of memory task neurovascular coupling and memory task performance. Reductions of functional hyperemia are constrained by autoregulation., (Copyright © 2017 the American Physiological Society.)

Background: Syncope is a sudden transient loss of consciousness and postural tone caused by cerebral hypoperfusion. The most common form is vasovagal syncope (VVS). Presyncopal progressive early hypotension in older VVS patients is caused by reduced cardiac output (CO); younger patients have reduced systemic vascular resistance (SVR). Using a priori criteria for reduced CO (↓CO) and SVR (↓SVR), we studied 48 recurrent young fainters comparing subgroups of VVS with VVS-↓CO, VVS-↓SVR, and both VVS-↓CO&↓SVR., Methods and Results: Subjects were studied supine and during 70-degrere upright tilt with a Finometer to continuously measure blood pressure, CO, and SVR and impedance plethysmography to estimate thoracic, splanchnic, pelvic, and calf blood volumes, blood flows, and vascular resistances and electrocardiogram to measure heart rate and rhythm. Central blood volume was decreased in all VVS compared to control. VVS-↓CO was associated with decreased splanchnic blood flow and increased splanchnic blood pooling compared to control. Seventy-five percent of VVS patients had reduced SVR, including 23% who also had reduced CO. Many VVS-↓SVR increased CO during tilt, with no difference in splanchnic pooling, caused by significant increases in splanchnic blood flow and reduced splanchnic resistance. VVS-↓CO&↓SVR patients had splanchnic pooling comparable to VVS-↓CO patients, but SVR comparable to VVS-↓SVR. Splanchnic vasodilation was reduced, compared to VVS-↓SVR, and venomotor properties were similar to control. Combined splanchnic pooling and reduced SVR produced the earliest faints among the VVS groups., Conclusions: Both ↓CO and ↓SVR occur in young VVS patients. ↓SVR is predominant in VVS and is caused by impaired splanchnic vasoconstriction., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS, gravitational pooling excessively reduces central blood volume and cardiac output. In VVS, as in hemorrhage, impaired adrenergic vasoconstriction and venoconstriction result in hypotension. We hypothesized that impaired adrenergic responsiveness because of excess nitric oxide can be reversed by reducing nitric oxide., Methods and Results: We recorded cardiopulmonary dynamics in supine syncope patients and healthy volunteers (aged 15-27 years) challenged with a dose-response using the α1-agonist phenylephrine (PE), with and without the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA). Systolic and diastolic pressures among control and VVS were the same, although they increased after L-NMMA and saline+PE (volume and pressor control for L-NMMA). Heart rate was significantly reduced by L-NMMA (P<0.05) for control and VVS compared with baseline, but there was no significant difference in heart rate between L-NMMA and saline+PE. Cardiac output and splanchnic blood flow were reduced by L-NMMA for control and VVS (P<0.05) compared with baseline, while total peripheral resistance increased (P<0.05). PE dose-response for splanchnic flow and resistance were blunted for VVS compared with control after saline+PE, but enhanced after L-NMMA (P<0.001). Postsynaptic α1-adrenergic vasoconstrictive impairment was greatest in the splanchnic vasculature, and splanchnic blood flow was unaffected by PE. Forearm and calf α1-adrenergic vasoconstriction were unimpaired in VVS and unaffected by L-NMMA., Conclusions: Impaired postsynaptic α1-adrenergic vasoconstriction in young adults with VVS can be corrected by nitric oxide synthase inhibition, demonstrated with our use of L-NMMA., (© 2016 American Heart Association, Inc.)

Neurovascular coupling refers to the link between an increase in neural activity in response to a task and an increase in cerebral blood flow denoted "functional hyperemia." Recent work on postural tachycardia syndrome indicated that increased oscillatory cerebral blood flow velocity (CBFv) was associated with reduced functional hyperemia. We hypothesized that a reduction in functional hyperemia could be causally produced in healthy volunteers by using oscillations in lower body negative pressure (OLBNP) to force oscillations in CBFv. CBFv was measured by transcranial Doppler ultrasound of the left middle cerebral artery. We used passive arm flexion applied during eight periodic 60-s flexion/60-s relaxation epochs to produce 120-s periodic changes in functional hyperemia (at 0.0083 Hz). We used -30 mmHg of OLBNP at 0.03, 0.05, and 0.10 Hz, the range for cerebral autoregulation, and measured spectral power of CBFv at all frequencies. Arm flexion power performed without OLBNP was compared with arm flexion power during OLBNP. OLBNP power performed in isolation was compared with power during OLBNP plus arm flexion. Cerebral flow velocity oscillations at 0.05 Hz reduced and at 0.10 Hz eliminated functional hyperemia, while 0.03 Hz did not reach significance. In contrast, arm flexion reduced OLBNP-induced oscillatory power at all frequencies. The interactions between OLBNP-driven CBFv oscillations and arm flexion-driven CBFv oscillations are reciprocal. Thus induced cerebral blood flow oscillations suppress functional hyperemia, and functional hyperemia suppresses cerebral blood flow oscillations. We conclude that oscillatory cerebral blood flow produces a causal reduction of functional hyperemia., (Copyright © 2016 the American Physiological Society.)

We hypothesize that upright cognitive impairment in patients with postural tachycardia syndrome (POTS) is caused by reduced cerebral blood flow (CBF). The CBF velocity (CBF(v)) measured by transcranial Doppler ultrasound decreased excessively during 70° tilt in a minority of patients with intermittent hyperpnea/hypocapnia. Incremental tilt showed no difference in mean CBF(v). But N-back memory tasking indicated progressive compromised memory, reduced functional hyperemia, and reduced neurovascular coupling. Orthostasis caused slow oscillations in CBF(v) linked to oscillations in arterial pressure in patients with POTS. We also hypothesize that oscillatory CBF(v) degrades neurovascular coupling. We performed 2-back testing when subjects were in supine position and during incremental tilts to 15°, 30°, 45°, and 60° in 11 patients with POTS and 9 controls. Oscillatory arterial pressure, oscillatory CBF(v), and neurovascular coupling were similar in supine position. The oscillatory arterial pressure increased by 31%, 45%, 67%, and 93% in patients with POTS during tilt and remained unchanged in the controls. Oscillatory CBF(v) increased by 61%, 82%, 161%, and 264% in patients with POTS during tilt and remained unchanged in the controls. Functional hyperemia decreased from 4.1% to 3.0%, 1.1%, 0.2%, and to 0.04% in patients with POTS, but it was unchanged at 4% in the controls. Percent correct N-back responses decreased from 78% to 33% in patients with POTS, whereas they remained at 89% in the controls. In patients with POTS, oscillatory CBF(v) was linearly correlated with functional hyperemia (r(2)=0.76). Increased oscillatory CBF is associated with reduced neurovascular coupling and diminished cognitive performance in patients with POTS., (© 2014 American Heart Association, Inc.)

Chronic fatigue syndrome (CFS) with orthostatic intolerance is characterized by neurocognitive deficits and impaired working memory, concentration, and information processing. In CFS, upright tilting [head-up tilt (HUT)] caused decreased cerebral blood flow velocity (CBFv) related to hyperventilation/hypocapnia and impaired cerebral autoregulation; increasing orthostatic stress resulted in decreased neurocognition. We loaded the baroreflex with phenylephrine to prevent hyperventilation and performed n-back neurocognition testing in 11 control subjects and 15 CFS patients. HUT caused a significant increase in heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decrease in end-tidal CO2 (ETCO2; 42.8 ± 1.2 vs. 33.9 ± 1.1 Torr, P < 0.05) in CFS vs. control. HUT caused CBFv to decrease 8.7% in control subjects but fell 22.5% in CFS. In CFS, phenylephrine prevented the HUT-induced hyperventilation/hypocapnia and the significant drop in CBFv with HUT (-8.1% vs. -22.5% untreated). There was no difference in control subject n-back normalized response time (nRT) comparing supine to HUT (106.1 ± 6.9 vs. 97.6 ± 7.1 ms at n = 4), and no difference comparing control to CFS while supine (97.1 ± 7.1 vs 96.5 ± 3.9 ms at n = 4). However, HUT of CFS subjects caused a significant increase in nRT (148.0 ± 9.3 vs. 96.4 ± 6.0 ms at n = 4) compared with supine. Phenylephrine significantly reduced the HUT-induced increase in nRT in CFS to levels similar to supine (114.6 ± 7.1 vs. 114.6 ± 9.3 ms at n = 4). Compared with control subjects, CFS subjects are more sensitive both to orthostatic challenge and to baroreflex/chemoreflex-mediated interventions. Increasing blood pressure with phenylephrine can alter CBFv. In CFS subjects, mitigation of the HUT-induced CBFv decrease with phenylephrine has a beneficial effect on n-back outcome., (Copyright © 2014 the American Physiological Society.)

Cognitive deficits are characteristic of postural tachycardia syndrome (POTS). Intact nitrergic nitric oxide (NO) is important to cerebral blood flow (CBF) regulation, neurovascular coupling, and cognitive efficacy. POTS patients often experience defective NO-mediated vasodilation caused by oxidative stress. We have previously shown dilation of the middle cerebral artery in response to a bolus administration of the NO donor sodium nitroprusside (SNP) in healthy volunteers. In the present study, we hypothesized a blunted middle cerebral artery response to SNP in POTS. We used combined transcranial Doppler-ultrasound to measure CBF velocity and near-infrared spectroscopy to measure cerebral hemoglobin oxygenation while subjects were in the supine position. The responses of 17 POTS patients were compared with 12 healthy control subjects (age: 14-28 yr). CBF velocity in POTS patients and control subjects were not different at baseline (75 ± 3 vs. 71 ± 2 cm/s, P = 0.31) and decreased to a lesser degree with SNP in POTS patients (to 71 ± 3 vs. 62 ± 2 cm/s, P = 0.02). Changes in total and oxygenated hemoglobin (8.83 ± 0.45 and 8.13 ± 0.48 μmol/kg tissue) were markedly reduced in POTS patients compared with control subjects (14.2 ± 1.4 and 13.6 ± 1.6 μmol/kg tissue), primarily due to increased venous efflux. The data indicate reduced cerebral oxygenation, blunting of cerebral arterial vasodilation, and heightened cerebral venodilation. We conclude, based on the present study outcomes, that decreased bioavailability of NO is apparent in the vascular beds, resulting in a downregulation of NO receptor sites, ultimately leading to blunted responses to exogenous NO., (Copyright © 2014 the American Physiological Society.)

Decreased upright cerebral blood flow (CBF) with hyperpnea and hypocapnia is seen in a minority of patients with postural tachycardia syndrome (POTS). More often, CBF is not decreased despite upright neurocognitive dysfunction. This may result from time-dependent changes in CBF. We hypothesized that increased oscillations in CBF occurs in POTS (N = 12) compared to healthy controls (N = 9), and tested by measuring CBF velocity (CBFv) by transcranial Doppler ultrasound of the middle cerebral artery, mean arterial pressure (MAP) and related parameters, supine and during 70° upright tilt. Autospectra for mean CBFv and MAP, and transfer function analysis were obtained over the frequency range of 0.0078-0.4 Hz. Upright HR was increased in POTS (125 ± 8 vs. 86 ± 2 bpm), as was diastolic BP (74 ± 3 vs. 65 ± 3 mmHg) compared to control, while peripheral resistance, cardiac output, and mean CBFv increased similarly with tilt. Upright BP variability (BPV), low frequency (LF) power (0.04-0.13 Hz), and peak frequency of BPV were increased in POTS (24.3 ± 4.1, and 18.4 ± 4.1 mmHg(2)/Hz at 0.091 Hz vs. 11.8 ± 3.3, and 8.8 ± 2 mmHg(2)/Hz c at 0.071 Hz), as was upright overall CBFv variability, low frequency power and peak frequency of CBFv variability (29.3 ± 4.7, and 22.1 ± 2.7 [cm/s](2)/Hz at.092 Hz vs. 14.7 ± 2.6, and 6.7 ± 1.2 [cm/s](2)/Hz at 0.077Hz). Autospectra were sharply peaked in POTS. LF phase was decreased in POTS (-14 ± 4 vs. -25 ± 10 degrees) while upright. LF gain was increased (1.51 ± 0.09 vs. 0.86 ± 0.12 [cm/s]/ mmHg) while coherence was increased (0.96 ± 0.01 vs. 0.80 ± 0.04). Increased oscillatory BP in upright POTS patients is closely coupled to oscillatory CBFv over a narrow bandwidth corresponding to the Mayer wave frequency. Therefore combined increased oscillatory BP and increased LF gain markedly increases CBFv oscillations in a narrow bandwidth. This close coupling of CBF to MAP indicates impaired cerebral autoregulation that may underlie upright neurocognitive dysfunction in POTS.

Hyperventilation and reduced cerebral blood flow velocity can occur in postural tachycardia syndrome (POTS). We studied orthostatically intolerant patients, with suspected POTS, with a chief complaint of upright dyspnea. On the basis of our observations of an immediate reduction of cerebral blood flow velocity with orthostasis, we hypothesize that the resulting ischemic hypoxia of the carotid body causes chemoreflex activation, hypocapnic hyperpnea, sympathetic activation, and increased heart rate and blood pressure in this subset of POTS. We compared 11 dyspneic POTS subjects with 10 healthy controls during a 70° head-up tilt. In POTS subjects during initial orthostasis before blood pressure recovery; central blood volume and mean arterial pressure were reduced (P<0.025), resulting in a significant (P<0.001) decrease in cerebral blood flow velocity, which temporally preceded (17±6 s; P<0.025) a progressive increase in minute ventilation and decrease in end tidal CO2 (P<0.05) when compared with controls. Sympathoexcitation, measured by muscle sympathetic nerve activity, was increased in POTS (P<0.01) and inversely proportional to end tidal CO2 and resulted in an increase in heart rate (P<0.001), total peripheral resistance (P<0.025), and a decrease in cardiac output (P<0.025). The decrease in cerebral blood flow velocity and mean arterial pressure during initial orthostasis was greater (P<0.025) in POTS. Our data suggest that exaggerated initial central hypovolemia during initial orthostatic hypotension in POTS results in reduced cerebral blood flow velocity and postural hypocapnic hyperpnea that perpetuates cerebral ischemia. We hypothesize that sustained hypocapnia and cerebral ischemia produce sympathoexcitation, tachycardia, and a statistically significant increase in blood pressure.

POTS (postural tachycardia syndrome) is a chronic form of OI (orthostatic intolerance). Neuropathic POTS is characterized by decreased adrenergic vasoconstriction, whereas hyperadrenergic POTS exhibits increased adrenergic vasoconstriction. We hypothesized that midodrine, an α1-adrenergic receptor agonist, would increase CVR (calf vascular resistance), decrease C(v) (calf venous capacitance) and decrease orthostatic tachycardia in neuropathic POTS, but not alter haemodynamics in hyperadrenergic POTS. A total of 20 POTS patients (12 neuropathic and eight hyperadrenergic), ages 12-20 years, participated in this randomized placebo-controlled double-blind cross-over study. Of these subjects, 15 were female. POTS subjects received 2 weeks of treatment with midodrine or placebo, with increased dosing from 2.5 to 10 mg three times daily. Following a 7-day drug-washout period, subjects received the cross-over treatment. HR (heart rate), MAP (mean arterial pressure), Q(calf) (calf blood flow) and CVR were measured supine and during 35° HUT (head-up tilt). C(v) was measured supine. In neuropathic POTS, midodrine decreased supine HR, Q(calf) and C(v), while increasing MAP and CVR compared with placebo. During HUT, in neuropathic POTS, midodrine decreased HR, Q(calf) and C(v), while increasing MAP and CVR. In hyperadrenergic POTS, placebo and midodrine both decreased upright HR and increased supine CVR. Placebo also increased supine C(v), compared with midodrine in hyperadrenergic POTS. Therefore midodrine improved postural tachycardia in neuropathic POTS by increasing CVR and decreasing Q(calf) and C(v), whereas these effects were not seen in hyperadrenergic POTS patients who experienced a placebo effect. This suggests that midodrine is probably an effective treatment for neuropathic POTS, but not for hyperadrenergic POTS.

Purpose: Adolescents with postural tachycardia syndrome (POTS) often experience ill-defined cognitive impairment referred to by patients as "brain fog." The objective of this study was to evaluate the symptom of brain fog as a means of gaining further insight into its etiology and potential palliative interventions., Methods: Eligible subjects who reported having been diagnosed with POTS were recruited from social media web sites. Subjects were asked to complete a 38-item questionnaire designed for this study, and the Wood mental fatigue inventory (WMFI)., Results: Responses were received from 138 subjects with POTS (88 % female), ranging in age from 14 to 29 years; 132 subjects reported brain fog. WMFI scores correlated with brain fog frequency and severity (P < 0.001). The top ranked descriptors of brain fog were "forgetful," "cloudy," and "difficulty focusing, thinking and communicating." The most frequently reported brain fog triggers were fatigue (91 %), lack of sleep (90 %), prolonged standing (87 %), dehydration (86 %), and feeling faint (85 %). Although aggravated by upright posture, brain fog was reported to persist after assuming a recumbent posture. The most frequently reported interventions for the treatment of brain fog were intravenous saline (77 %), stimulant medications (67 %), salt tablets (54 %), intra-muscular vitamin B-12 injections (48 %), and midodrine (45 %)., Conclusions: Descriptors for "brain fog" are most consistent with it being a cognitive complaint. Factors other than upright posture may play a role in the persistence of this symptom. Subjects reported a number of therapeutic interventions for brain fog not typically used in the treatment of POTS that may warrant further investigation.

Withdrawal of muscle sympathetic nerve activity (MSNA) may not be necessary for the precipitous fall of peripheral arterial resistance and arterial pressure (AP) during vasovagal syncope (VVS). We tested the hypothesis that the MSNA-AP baroreflex entrainment is disrupted before VVS regardless of MSNA withdrawal using the phase synchronization between blood pressure and MSNA during head-up tilt (HUT) to measure reflex coupling. We studied eight VVS subjects and eight healthy control subjects. Heart rate, AP, and MSNA were measured during supine baseline and at early, mid, late, and syncope stages of HUT. Phase synchronization indexes, measuring time-dependent differences between MSNA and AP phases, were computed. Directionality indexes, indicating the influence of AP on MSNA (neural arc) and MSNA on AP (peripheral arc), were computed. Heart rate was greater in VVS compared with control subjects during early, mid, and late stages of HUT and significantly declined at syncope (P = 0.04). AP significantly decreased during mid, late, and syncope stages of tilt in VVS subjects only (P = 0.001). MSNA was not significantly different between groups during HUT (P = 0.700). However, the phase synchronization index significantly decreased during mid and late stages in VVS subjects but not in control subjects (P < .001). In addition, the neural arc was significantly affected more than the peripheral arc before syncope. In conclusion, VVS is accompanied by a loss of the synchronous AP-MSNA relationship with or without a loss in MSNA at faint. This provides insight into the mechanisms behind the loss of vasoconstriction and drop in AP independent of MSNA at the time of vasovagal faint.

The bioimpedance spectroscopic (BIS) analytical algorithm described in this report allows for the non-invasive measurement of intravascular, interstitial, and intracellular volume changes during various fluid management procedures. The purpose of this study was to test clinical use feasibility and to demonstrate the validity of the BIS algorithm in computing compartmental volume shifts in human subjects undergoing fluid management treatment. Validation was performed using volume changes recorded from 20 end stage renal disease patients. The validation procedure involved mathematically deriving post hoc hematocrit profiles from the BIS data-generated fluid redistribution time profiles. These derived hematocrit profiles were then compared to serial hematocrit values measured simultaneously by a CritLine(®) monitor during 60 routine hemodialysis sessions. Regression and Bland-Altman analyses confirm that the BIS algorithm can be used to reliably derive the continuous and real-time rates of change of the compartmental fluid volumes. Regression results yielded a R (2) > 0.99 between the two measures of hematocrit at different times during dialysis. The slopes of the regression equations at the different times were nearly identical, demonstrating an almost one-to-one correspondence between the BIS and CritLine(®) hematocrits. Bland-Altman analysis show that the BIS algorithm can be used interchangeably with the CritLine(®) monitor for the measurement of hematocrit. The present study demonstrates for the first time that BIS can provide real-time continuous measurements of compartmental intravascular, interstitial and intracellular fluid volume changes during fluid management procedures when used in conjunction with this new algorithm.

Spontaneous fluctuation indices of cardiovagal baroreflex have been suggested to be inaccurate measures of baroreflex function during orthostatic stress compared with alternate open-loop methods (e.g. neck pressure/suction, modified Oxford method). We therefore tested the hypothesis that spontaneous fluctuation measurements accurately reflect local baroreflex gain (slope) at the operating point measured by the modified Oxford method, and that apparent differences between these two techniques during orthostasis can be explained by a resetting of the baroreflex function curve. We computed the sigmoidal baroreflex function curves supine and during 70° tilt in 12 young, healthy individuals. With the use of the modified Oxford method, slopes (gains) of supine and upright curves were computed at their maxima (Gmax) and operating points. These were compared with measurements of spontaneous indices in both positions. Supine spontaneous analyses of operating point slope were similar to calculated Gmax of the modified Oxford curve. In contrast, upright operating point was distant from the centering point of the reset curve and fell on the nonlinear portion of the curve. Whereas spontaneous fluctuation measurements were commensurate with the calculated slope of the upright modified Oxford curve at the operating point, they were significantly lower than Gmax. In conclusion, spontaneous measurements of cardiovagal baroreflex function accurately estimate the slope near operating points in both supine and upright position.

The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18-24 yr old. Assuming constant O₂ consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (ΔQa) and venous outflow (ΔQv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ΔQa by 0.36 ± .03 μmol·kg(-1)·s(-1) (21.6 μmol·kg(-1)·min(-1)), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ΔQa by 0.27 ± .2 μmol·kg(-1)·s(-1) (16.2 μmol·kg(-1)·min(-1)), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE.

Local cutaneous heating causes vasodilation as an initial first peak, a nadir, and increase to plateau. Reactive oxygen species (ROS) modulate the heat plateau in healthy controls. The initial peak, due to C-fiber nociceptor-mediated axon reflexes, is blunted with local anesthetics and may serve as a surrogate for the cutaneous response to peripheral heat. Chronic fatigue syndrome (CFS) subjects report increased perception of pain. To determine the role of ROS in this neurally mediated response, we evaluated changes in cutaneous blood flow from local heat in nine CFS subjects (16-22 yr) compared with eight healthy controls (18-26 yr). We heated skin to 42°C and measured local blood flow as a percentage of maximum cutaneous vascular conductance (%CVC(max)). Although CFS subjects had significantly lower baseline flow [8.75 ± 0.56 vs. 12.27 ± 1.07 (%CVC(max), CFS vs. control)], there were no differences between groups to local heat. We then remeasured this with apocynin to inhibit NADPH oxidase, allopurinol to inhibit xanthine oxidase, tempol to inhibit superoxide, and ebselen to reduce H(2)O(2). Apocynin significantly increased baseline blood flow (before heat, 14.91 ± 2.21 vs. 8.75 ± 1.66) and the first heat peak (69.33 ± 3.36 vs. 59.75 ± 2.75). Allopurinol and ebselen only enhanced the first heat peaks (71.55 ± 2.48 vs. 61.72 ± 2.01 and 76.55 ± 5.21 vs. 58.56 ± 3.66, respectively). Tempol had no effect on local heating. None of these agents changed the response to local heat in control subjects. Thus the response to heat may be altered by local levels of ROS, particularly H(2)O(2) in CFS subjects, and may be related to their hyperesthesia/hyperalgesia.

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology., (Copyright © 2012 John Wiley & Sons, Ltd.)

CFS (chronic fatigue syndrome) is commonly co-morbid with POTS (postural tachycardia syndrome). Individuals with CFS/POTS experience unrelenting fatigue, tachycardia during orthostatic stress and ill-defined neurocognitive impairment, often described as 'mental fog'. We hypothesized that orthostatic stress causes neurocognitive impairment in CFS/POTS related to decreased CBFV (cerebral blood flow velocity). A total of 16 CFS/POTS and 20 control subjects underwent graded tilt table testing (at 0, 15, 30, 45, 60 and 75°) with continuous cardiovascular, cerebrovascular, and respiratory monitoring and neurocognitive testing using an n-back task at each angle. The n-back task tests working memory, concentration, attention and information processing. The n-back task imposes increasing cognitive challenge with escalating (0-, 1-, 2-, 3- and 4-back) difficulty levels. Subject dropout due to orthostatic presyncope at each angle was similar between groups. There were no n-back accuracy or RT (reaction time) differences between groups while supine. CFS/POTS subjects responded less correctly during the n-back task test and had greater nRT (normalized RT) at 45, 60 and 75°. Furthermore, at 75° CFS/POTS subjects responded less correctly and had greater nRT than controls during the 2-, 3- and 4-back tests. Changes in CBFV were not different between the groups and were not associated with n-back task test scores. Thus we conclude that increasing orthostatic stress combined with a cognitive challenge impairs the neurocognitive abilities of working memory, accuracy and information processing in CFS/POTS, but that this is not related to changes in CBFV. Individuals with CFS/POTS should be aware that orthostatic stress may impair their neurocognitive abilities.

Neurocognition is impaired in chronic fatigue syndrome (CFS). We propose that the impairment relates to postural cerebral hemodynamics. Twenty-five CFS subjects and twenty control subjects underwent incremental upright tilt at 0, 15, 30, 45, 60, and 75° with continuous measurement of arterial blood pressure and cerebral blood flow velocity (CBFV). We used an n-back task with n ranging from 0 to 4 (increased n = increased task difficulty) to test working memory and information processing. We measured n-back outcomes by the number of correct answers and by reaction time. We measured CBFV, critical closing pressure (CCP), and CBFV altered by neuronal activity (activated CBFV) during each n value and every tilt angle using transcranial Doppler ultrasound. N-back outcome in control subjects decreased with n valve but was independent of tilt angle. N-back outcome in CFS subjects decreased with n value but deteriorated as orthostasis progressed. Absolute mean CBFV was slightly less than in control subjects in CFS subject at each angle. Activated CBFV in control subjects was independent of tilt angle and increased with n value. In contrast, activated CBFV averaged 0 in CFS subjects, decreased with angle, and was less than in control subjects. CCP was increased in CFS subjects, suggesting increased vasomotor tone and decreased metabolic control of CBFV. CCP did not change with orthostasis in CFS subjects but decreased monotonically in control subjects, consistent with vasodilation as compensation for the orthostatic reduction of cerebral perfusion pressure. Increasing orthostatic stress impairs neurocognition in CFS subjects. CBFV activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased CCP and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.

Objective: We hypothesize that, after a sudden decrease in cerebral blood flow velocity (CBFV) in adolescents, a faint, rapid hyperemic pulsatile CBFV occurs upon the patient's return to the supine position and is associated with postsyncopal headache., Study Design: This case-control study involved 16 adolescent subjects with a history of fainting and headaches. We induced fainting during 70° tilt-table testing and measured mean arterial pressure, heart rate, end-tidal CO(2), and CBFV. Fifteen control subjects were similarly evaluated with a tilt but did not faint, and comparisons with fainters were made at equivalent defined time points., Results: Baseline values were similar between the groups. Upon fainting, mean arterial pressure decreased 49% in the patients who fainted vs 6% in controls (P < .001). The heart rate decreased 15% in fainters and increased 35% in controls (P < .001). In patients who fainted, cerebrovascular critical closing pressure increased markedly, which resulted in reduced diastolic (-66%) and mean CBFV (-46%) at faint; systolic CBFV was similar to controls. Pulsatile CBFV (systolic-diastolic CBFV) increased 38% in fainters, which caused flow-mediated dilatation of cerebral vessels. When the fainters returned to the supine position, CBFV exhibited increased systolic and decreased diastolic flows compared with controls (P < .02)., Conclusion: Increased pulsatile CBFV during and after faint may cause postsyncopal cerebral vasodilation and headache., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Models of microgravity are linked to excessive constitutive nitric oxide (NO) synthase (NOS), splanchnic vasodilation, and orthostatic intolerance. Normal-flow postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance associated with splanchnic hyperemia. To test the hypothesis that there is excessive constitutive NOS in POTS, we determined whether cutaneous microvascular neuronal NO and endothelial NO are increased. We performed two sets of experiments in POTS and control subjects aged 21.4 ± 2 yr. We used laser-Doppler flowmetry to measure the cutaneous response to local heating as an indicator of bioavailable neuronal NO. To test for bioavailable endothelial NO, we infused intradermal acetylcholine through intradermal microdialysis catheters and used the selective neuronal NOS inhibitor l-N(ω)-nitroarginine-2,4-L-diamino-butyric amide (N(ω), 10 mM), the selective inducible NOS inhibitor aminoguanidine (10 mM), the nonspecific NOS inhibitor nitro-l-arginine (NLA, 10 mM), or Ringer solution. The acetylcholine dose response and the NO-dependent plateau of the local heating response were increased in POTS compared with those in control subjects. The local heating plateau was significantly higher, 98 ± 1%maximum cutaneous vascular conductance (%CVC(max)) in POTS compared with 88 ± 2%CVC(max) in control subjects but decreased to the same level with N(ω) (46 ± 5%CVC(max) in POTS compared with 49 ± 4%CVC(max) in control) or with NLA (45 ± 3%CVC(max) in POTS compared with 47 ± 4%CVC(max) in control). Only NLA blunted the acetylcholine dose response, indicating that NO produced by endothelial NOS was released by acetylcholine. Aminoguanidine was without effect. This is consistent with increased endothelial and neuronal NOS activity in normal-flow POTS.

Low flow postural tachycardia syndrome (LFP) is associated with vasoconstriction, reduced cardiac output, increased plasma angiotensin II, reduced bioavailable nitric oxide (NO), and oxidative stress. We tested whether ascorbate would improve cutaneous NO and reduce vasoconstriction when delivered systemically. We used local cutaneous heating to 42°C and laser Doppler flowmetry to assess NO-dependent conductance (%CVC(max)) to sodium ascorbate and the systemic hemodynamic response to ascorbic acid in 11 LFP patients and in 8 control subjects (aged 23 ± 2 yr). We perfused intradermal microdialysis catheters with sodium ascorbate (10 mM) or Ringer solution. Predrug heat response was reduced in LFP, particularly the NO-dependent plateau phase (56 ± 6 vs. 88 ± 7%CVC(max)). Ascorbate increased baseline skin flow in LFP and control subjects and increased the LFP plateau response (82 ± 6 vs. 92 ± 6 control). Systemic infusion experiments used Finometer and ModelFlow to estimate relative cardiac index (CI) and forearm and calf venous occlusion plethysmography to estimate blood flows, peripheral arterial and venous resistances, and capacitance before and after infusing ascorbic acid. CI increased 40% after ascorbate as did peripheral flows. Peripheral resistances were increased (nearly double control) and decreased by nearly 50% after ascorbate. Calf capacitance and venous resistance were decreased compared with control but normalized with ascorbate. These data provide experimental support for the concept that oxidative stress and reduced NO possibly contribute to vasoconstriction and venoconstriction of LFP.

Local cutaneous heating produces vasodilation that is largely nitric oxide (NO) dependent. We showed that angiotensin II (ANG II) attenuates this by an ANG II receptor, type 1 (AT1R)-dependent mechanism that is reversible with the antioxidant ascorbate, indicating oxidative stress. Reactive oxygen species (ROS) produced by ANG II employ NADPH and xanthine oxidase pathways. To determine whether these mechanisms pertain to skin, we measured cutaneous local heating with 10 μM ANG II, using apocynin to inhibit NADPH oxidase and allopurinol to inhibit xanthine oxidase. We also inhibited superoxide with tempol, and H(2)O(2) with ebselen. We heated the skin of the calf in 8 healthy volunteers (24.5-29.9 yr old) to 42°C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance. We remeasured while perfusing allopurinol, apocynin, ebselen, and tempol through individual microdialysis catheters. This was then repeated with ANG II combined with antioxidant drugs. tempol and apocynin alone had no effect on the heat response. Allopurinol enhanced the entire response (125% of heat alone), while ebselen suppressed the heat plateau (76% of heat alone). ANG II alone caused significant attenuation of the entire heat response (52%). When added to ANG II, Allopurinol partially reversed the ANG II attenuation. Heat with ebselen and ANG II were similar to heat and ANG II; ebselen only partially reversed the ANG II attenuation. Apocynin and tempol each partially reversed the attenuation caused by ANG II. This suggests that ROS, produced by ANG II via NADPH and xanthine oxidase pathways, modulates the response of skin to the application of heat, and thus contributes to the control of local cutaneous blood flow.

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.

Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18-26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V(E)), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V(E) increased from 8.8 ± 1.3 l/min in room air to 14.6 ± 0.8 l/min during hypoxia and to 20.1 ± 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V(E) doubled during SNP. CO increased from 4.9 ± .3 l/min in room air to 6.1 ± .6 l/min during hypoxia and 6.4 ± .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V(E) versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia.

Objective: To evaluate the response to rectal distension in children with chronic constipation and children with chronic constipation and encopresis., Study Design: We studied 27 children, aged 3 to 16 years, with chronic constipation; 12 had encopresis. Anorectal motility was measured with a solid state catheter. When the catheter was located in the internal sphincter, the balloon was inflated to 60 mL with air., Results: There were no differences in age, sex distribution, and duration of constipation in the two groups. Comparing groups, anorectal manometry showed no differences in the resting sphincter pressure, recovery pressure, the lowest relaxation pressure, and percent relaxation. However, time to maximum relaxation, time to recovery to baseline pressure, and duration of relaxation were significantly higher in patients with constipation and encopresis, compared with patients who had constipation alone., Conclusions: There may be an imbalance in neuromuscular control of defecation in constipated patients with encopresis that results in incontinence as a consequence of the increased time to recovery and duration of relaxation of the internal anal sphincter., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Loss of the cardiovagal baroreflex (CVB), thoracic hypovolemia, and hyperpnea contribute to the nonlinear time-dependent hemodynamic instability of vasovagal syncope. We used a nonlinear phase synchronization index (PhSI) to describe the extent of coupling between cardiorespiratory parameters, systolic blood pressure (SBP) or arterial pressure (AP), RR interval (RR), and ventilation, and a directional index (DI) measuring the direction of coupling. We also examined phase differences directly. We hypothesized that AP-RR interval PhSI would be normal during early upright tilt, indicating intact CVB, but would progressively decrease as faint approached and CVB failed. Continuous measurements of AP, RR interval, respiratory plethysomography, and end-tidal CO2 were recorded supine and during 70-degree head-up tilt in 15 control subjects and 15 fainters. Data were evaluated during five distinct times: baseline, early tilt, late tilt, faint, and recovery. During late tilt to faint, fainters exhibited a biphasic change in SBP-RR interval PhSI. Initially in fainters during late tilt, SBP-RR interval PhSI decreased (fainters, from 0.65±0.04 to 0.24±0.03 vs. control subjects, from 0.51±0.03 to 0.48±0.03; P<0.01) but then increased at the time of faint (fainters=0.80±0.03 vs. control subjects=0.42±0.04; P<0.001) coinciding with a change in phase difference from positive to negative. Starting in late tilt and continuing through faint, fainters exhibited increasing phase coupling between respiration and AP PhSI (fainters=0.54±0.06 vs. control subjects=0.27±0.03; P<0.001) and between respiration and RR interval (fainters=0.54±0.05 vs. control subjects=0.37±0.04; P<0.01). DI indicated respiratory driven AP (fainters=0.84±0.04 vs. control subjects=0.39±0.09; P<0.01) and RR interval (fainters=0.73±0.10 vs. control subjects=0.23±0.11; P<0.001) in fainters. The initial drop in the SBP-RR interval PhSI and directional change of phase difference at late tilt indicates loss of cardiovagal baroreflex. The subsequent increase in SBP-RR interval PhSI is due to a respiratory synchronization and drive on both AP and RR interval. Cardiovagal baroreflex is lost before syncope and supplanted by respiratory reflexes, producing hypotension and bradycardia.

Initial orthostatic hypotension is common in children. Isometric handgrip increases arterial pressure, central blood volume, cardiac output, and total peripheral resistance. We show that in 14 subjects with initial orthostatic hypotension, isometric handgrip coupled with standing abolished symptoms of initial orthostatic hypotension and minimized decreases in blood pressure and cardiac output with standing., (Copyright 2010 Mosby, Inc. All rights reserved.)

Objective: We used breath-holding during inspiration as a model to study the effect of pulmonary stretch on sympathetic nerve activity., Methods: Twelve healthy subjects (7 females, 5 males; 19-27 years) were tested while they performed an inspiratory breath-hold, both supine and during a 60 degrees head-up tilt (HUT 60). Heart rate (HR), mean arterial blood pressure (MAP), respiration, muscle sympathetic nerve activity (MSNA), oxygen saturation (SaO(2)) and end tidal carbon dioxide (ETCO(2)) were recorded. Cardiac output (CO) and total peripheral resistance (TPR) were calculated., Results: While breath-holding, ETCO(2) increased significantly from 41 +/- 2 to 60 +/- 2 Torr during supine (p < 0.05) and 38 +/- 2 Torr to 58 +/- 2 during HUT60 (p < 0.05); SaO(2) decreased from 98 +/- 1.5% to 95 +/- 1.4% supine, and from 97 +/- 1.5% to 94 +/- 1.7% during HUT60 (p = NS). MSNA showed three distinctive phases, a quiescent phase due to pulmonary stretch associated with decreased MAP, HR, CO, and TPR; a second phase of baroreflex-mediated elevated MSNA which was associated with recovery of MAP and HR only during HUT60; CO and peripheral resistance returned to baseline while supine and HUT60; a third phase of further increased MSNA activity related to hypercapnia and associated with increased TPR., Interpretation: Breath-holding results in initial reductions of MSNA, MAP, and HR by the pulmonary stretch reflex followed by increased sympathetic activity related to the arterial baroreflex and chemoreflex.

Vasovagal syncope may be due to a transient cerebral hypoperfusion that accompanies frequency entrainment between arterial pressure (AP) and cerebral blood flow velocity (CBFV). We hypothesized that cerebral autoregulation fails during fainting; a phase synchronization index (PhSI) between AP and CBFV was used as a nonlinear, nonstationary, time-dependent measurement of cerebral autoregulation. Twelve healthy control subjects and twelve subjects with a history of vasovagal syncope underwent 10-min tilt table testing with the continuous measurement of AP, CBFV, heart rate (HR), end-tidal CO2 (ETCO2), and respiratory frequency. Time intervals were defined to compare physiologically equivalent periods in fainters and control subjects. A PhSI value of 0 corresponds to an absence of phase synchronization and efficient cerebral autoregulation, whereas a PhSI value of 1 corresponds to complete phase synchronization and inefficient cerebral autoregulation. During supine baseline conditions, both control and syncope groups demonstrated similar oscillatory changes in phase, with mean PhSI values of 0.58+/-0.04 and 0.54+/-0.02, respectively. Throughout tilt, control subjects demonstrated similar PhSI values compared with supine conditions. Approximately 2 min before fainting, syncopal subjects demonstrated a sharp decrease in PhSI (0.23+/-0.06), representing efficient cerebral autoregulation. Immediately after this period, PhSI increased sharply, suggesting inefficient cerebral autoregulation, and remained elevated at the time of faint (0.92+/-0.02) and during the early recovery period (0.79+/-0.04) immediately after the return to the supine position. Our data demonstrate rapid, biphasic changes in cerebral autoregulation, which are temporally related to vasovagal syncope. Thus, a sudden period of highly efficient cerebral autoregulation precedes the virtual loss of autoregulation, which continued during and after the faint.