Supine Parasympathetic Withdrawal and Upright Sympathetic Activation Underly Abnormalities of the Baroreflex in Postural Tachycardia Syndrome: Effects of Pyridostigmine and Digoxin.

[Figure: see text].

The preponderance of initial orthostatic hypotension in postural tachycardia syndrome.

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.

The Benefits of Oral Rehydration on Orthostatic Intolerance in Children with Postural Tachycardia Syndrome.

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 (CBFv) 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 CBFv 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.

Mechanisms of tilt-induced vasovagal syncope in healthy volunteers and postural tachycardia syndrome patients without past history of syncope.

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.

Hemodynamic characteristics of postural hyperventilation: POTS with hyperventilation versus panic versus voluntary hyperventilation.

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.

Postural Hyperventilation as a Cause of Postural Tachycardia Syndrome: Increased Systemic Vascular Resistance and Decreased Cardiac Output When Upright in All Postural Tachycardia Syndrome Variants.

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 CO2. 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 CO2 <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 CO2 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 CO2 in hyperventilation by addition of exogenous CO2 into a rebreathing apparatus. With added CO2, 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.

Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope.

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 (CMRO2), 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 CMRO2 was unchanged in POTS and controls during tilt while OEF increased by 19 ± 3% and 15 ± 3%, respectively. CMRO2 decreased by 31 ± 3% in VVS during tilt while OEF only increased by 7 ± 3%. Oxyhemoglobin decreased by 1.1 ± 1.3 µmol/kg brain tissue in controls, by 1.1 ± 1.3 µmol/kg in POTS, and 11.1 ± 1.3 µmol/kg in VVS CBFv and CMRO2 fell steadily in VVS during upright tilt. The deficit in CMRO2 in VVS results from inadequate OEF in the face of greatly reduced CBF.

Postural Heart Rate Changes in Young Patients With Vasovagal Syncope.

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.

Oscillatory lower body negative pressure impairs working memory task-related functional hyperemia in healthy volunteers.

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.

Postsynaptic α1-Adrenergic Vasoconstriction Is Impaired in Young Patients With Vasovagal Syncope and Is Corrected by Nitric Oxide Synthase Inhibition.

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.

Oscillatory lower body negative pressure impairs task related functional hyperemia in healthy volunteers.

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.

Oscillatory cerebral blood flow is associated with impaired neurocognition and functional hyperemia in postural tachycardia syndrome during graded tilt.

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.

Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome.

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.

Altered oscillatory cerebral blood flow velocity and autoregulation in postural tachycardia syndrome.

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.

Middle cerebral O2 delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine.

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.

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome.

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.

Cutaneous constitutive nitric oxide synthase activation in postural tachycardia syndrome with splanchnic hyperemia.

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.

Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation.

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.

Enteral feeding and caloric intake in neonates after cardiac surgery.

BACKGROUND: Adequate enteral nutrition may be difficult to achieve early in neonates after cardiac surgery, but it is essential for growth, wound healing, and immune function. OBJECTIVE: To assess caloric intake in neonates receiving enteral nutrition after surgery. METHODS: A retrospective chart review was conducted of daily enteral caloric intake in the cardiac intensive care unit of a tertiary children's hospital. Data on the institution of enteral feeding and the discontinuation of parenteral nutrition were assessed for full-term neonates who had undergone cardiac surgery. RESULTS: Caloric intake was assessed in 100 patients, 52 with biventricular cardiac defects and 48 with a functional single ventricle. The median duration of stay in the cardiac intensive care unit was 13 days (range, 4-69), and patients received enteral feeding exclusively for a median of 5 days (range, 1-43). In total, 705 patient days were evaluated. The median caloric intake per day was 93 kcal/kg (range, 43-142). A goal of 100 kcal/kg was achieved for 48.4% of patient days and 120 kcal/kg for only 19.7% of patient days. Median weight change for the period of enteral feeding was -20 g (range, -775 to 1485 g). CONCLUSIONS: Enteral feeding alone is often suboptimal after neonatal cardiac surgery. New strategies to improve caloric intake may enhance postoperative recovery.