The repeated sit-to-stand maneuver is a superior method for cardiac baroreflex assessment: a comparison with the modified Oxford method and Valsalva maneuver.

Baroreflex assessment has diagnostic and prognostic utility in the clinical and research environments, and there is a need for a reliable, simple, noninvasive method of assessment. The repeated sit-to-stand method induces oscillatory changes in blood pressure (BP) at a desired frequency and is suitable for assessing dynamic baroreflex sensitivity (BRS). However, little is known about the reliability of this method and its ability to discern fundamental properties of the baroreflex. In this study we sought to: 1) evaluate the reliability of the sit-to-stand method for assessing BRS and compare its performance against two established methods (Oxford method and Valsalva maneuver), and 2) examine whether the frequency of the sit-to-stand method influences hysteresis. Sixteen healthy participants underwent three trials of each method. For the sit-to-stand method, which was performed at 0.1 and 0.05 Hz, BRS was quantified as an integrated response (BRSINT) and in response to falling and rising BP (BRSDOWN and BRSUP, respectively). Test retest reliability was assessed using the intraclass correlation coefficient (ICC). Irrespective of frequency, the ICC for BRSINT during the sit-to-stand method was ≥0.88. The ICC for a rising BP evoked by phenylephrine (PEGAIN) in the Oxford method was 0.78 and ≤0.5 for the remaining measures. During the sit-to-stand method, hysteresis was apparent in all participants at 0.1 Hz but was absent at 0.05 Hz. These findings indicate the sit-to-stand method is a statistically reliable BRS assessment tool and suitable for the examination of baroreflex hysteresis. Using this approach we showed that baroreflex hysteresis is a frequency-dependent phenomenon.

Regional brain blood flow in man during acute changes in arterial blood gases.

Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra-cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.

Assessment of cerebral autoregulation: the quandary of quantification.

We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal P(CO2) (P(ET)(CO2) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in P(ET)(CO2) were positively related to coherence [LF: ß = 0.0065 arbitrary units (AU)/mmHg and VLF: ß = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: ß = -0.026 rad/mmHg and VLF: ß = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: ß = -0.042%/mmHg(2) and VLF: ß = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: ß = 0.0070 cm·s(-1)·mmHg(-2), P < 0.05; and VLF: ß = 0.014 cm·s(-1)·mmHg(-2), P < 0.01). Thus, during changes in P(ET)(CO2), LF phase was inversely related to LF gain (ß = -0.29 cm·s(-1)·mmHg(-1)·rad(-1), P < 0.01) but positively related to LF normalized gain (ß = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.

Influence of posture on the regulation of cerebral perfusion.

BACKGROUND: Posture has a major influence on cerebral blood flow (CBF). Unlike head-up tilt (HUT), less is known about how CBF is regulated during head-down tilt (HDT). We hypothesized that CBF would be elevated during HDT and decreased during HUT. METHODS: In 21 healthy young adults, while controlling for end-tidal Pco2, we combined concurrent measurements of middle cerebral artery velocity and posterior cerebral artery velocity (MCAv and PCAv, respectively), blood pressure (BP), and heart rate (HR). Measures were made at rest and, in a randomized order, during -90 degrees HDT and +900 HUT. Dynamic cerebral autoregulation was quantified using transfer function analysis. In a subgroup, volumetric blood flow recordings were obtained in the common carotid artery (CCA; N=11), internal and external carotid arteries (ICA; N=8 and ECA; N=6), and vertebral artery (VA; N=4). RESULTS: End-tidal Pco2, CCA, ICA, VA, MCAv(mean) and PCAv(mean) remained unchanged during -90 degrees HDT and +90 degrees HUT compared to supine. During -90 degrees HDT, mean BP (+22 mmHg) and cerebral vascular resistance (CVR) in both the MCA and PCA were elevated relative to supine, whereas HR remained unchanged. During +900 HUT, when compared to supine, HR increased (+18 bpm), and mean arterial pressure (MAP) total power and low frequency (LF) power in the MCA and PCA increased. In both the very low frequency (VLF) and LF ranges, coherence during +90 degrees HUT increased (P < 0.05 vs. supine) in both the MCA and PCA. In contrast, coherence was reduced during -90 degrees HDT. DISCUSSION: Despite marked changes in perfusion pressure with HUT or HDT, our findings indicate that cerebral perfusion is well maintained during acute severe changes in posture.

Influence of breathing frequency on the pattern of respiratory sinus arrhythmia and blood pressure: old questions revisited.

Respiratory sinus arrhythmia (RSA) is classically described as a vagally mediated increase and decrease in heart rate concurrent with inspiration and expiration, respectively. However, although breathing frequency is known to alter this temporal relationship, the precise nature of this phase dependency and its relationship to blood pressure remains unclear. In 16 subjects we systematically examined the temporal relationships between respiration, RSA, and blood pressure by graphically portraying cardiac interval (R-R) and systolic blood pressure (SBP) variations as a function of the respiratory cycle (pattern analysis), during incremental stepwise paced breathing. The principal findings were 1) the time interval between R-R maximum and expiration onset remained the same ( approximately 2.5-3.0 s) irrespective of breathing frequency (P = 0.10), whereas R-R minimum progressively shifted from expiratory onset into midinspiration with slower breathing (P < 0.0001); 2) there is a clear qualitative distinction between pre- versus postinspiratory cardiac acceleration during slow (0.10 Hz) but not fast (0.20 Hz) breathing; 3) the time interval from inspiration onset to SBP minimum (P = 0.16) and from expiration onset to SBP maximum (P = 0.26) remained unchanged across breathing frequencies; 4) SBP maximum and R-R maximum maintained an unchanged temporal alignment of approximately 1.1 s irrespective of breathing frequency (P = 0.84), whereas the alignment between SBP minimum and R-R minimum was inconstant (P > 0.0001); and 5) beta(1)-adrenergic blockade did not influence the respiration-RSA relationships or distinct RSA patterns observed during slow breathing, suggesting that temporal dependencies associated with alterations in breathing frequency are unrelated to cardiac sympathetic modulation. Collectively, these results illustrate nonlinear respiration-RSA-blood pressure relationships that may yield new insights to the fundamental mechanism of RSA in humans.

Diurnal variation in time to presyncope and associated circulatory changes during a controlled orthostatic challenge.

Epidemiological data indicate that the risk of neurally mediated syncope is substantially higher in the morning. Syncope is precipitated by cerebral hypoperfusion, yet no chronobiological experiment has been undertaken to examine whether the major circulatory factors, which influence perfusion, show diurnal variation during a controlled orthostatic challenge. Therefore, we examined the diurnal variation in orthostatic tolerance and circulatory function measured at baseline and at presyncope. In a repeated-measures experiment, conducted at 0600 and 1600, 17 normotensive volunteers, aged 26 +/- 4 yr (mean +/- SD), rested supine at baseline and then underwent a 60 degrees head-up tilt with 5-min incremental stages of lower body negative pressure until standardized symptoms of presyncope were apparent. Pretest hydration status was similar at both times of day. Continuous beat-to-beat measurements of cerebral blood flow velocity, blood pressure, heart rate, stroke volume, cardiac output, and end-tidal Pco(2) were obtained. At baseline, mean cerebral blood flow velocity was 9 +/- 2 cm/s (15%) lower in the morning than the afternoon (P < 0.0001). The mean time to presyncope was shorter in the morning than in the afternoon (27.2 +/- 10.5 min vs. 33.1 +/- 7.9 min; 95% CI: 0.4 to 11.4 min, P = 0.01). All measurements made at presyncope did not show diurnal variation (P > 0.05), but the changes over time (from baseline to presyncope time) in arterial blood pressure, estimated peripheral vascular resistance, and alpha-index baroreflex sensitivity were greater during the morning tests (P < 0.05). These data indicate that tolerance to an incremental orthostatic challenge is markedly reduced in the morning due to diurnal variations in the time-based decline in blood pressure and the initial cerebral blood flow velocity "reserve" rather than the circulatory status at eventual presyncope. Such information may be used to help identify individuals who are particularly prone to orthostatic intolerance in the morning.

Respiratory modulation of cardiovagal baroreflex sensitivity.

Emerging evidence has suggested that with minimal prerequisite training, slow deep breathing around 0.10 Hz can acutely enhance cardiovagal baroreflex sensitivity (BRS) in humans. Such reports have led to the speculation that behavioral interventions designed to reduce breathing frequency may serve a therapeutic role in ameliorating depressed baroreflex function in conditions such as chronic heart failure, essential hypertension, and obstructive airway disease. This study sought to test the hypothesis that slow controlled breathing acutely enhances cardiovagal baroreflex function in young healthy volunteers. Distinct from earlier studies, however, baroreflex function was examined (n = 30) using the classical pharmacological modified Oxford method, which enabled the assessment of cardiovagal BRS through experimentally driven baroreceptor stimulation across a wide range of blood pressures. For a comparison against existing evidence, spontaneous cardiovagal BRS was also assessed using the alpha-index and sequence method. Compared with fast breathing (0.25 Hz), slow breathing (0.10 Hz) was associated with an increase in the alpha-index (8.1 +/- 14 ms/mmHg, P < 0.01) and spontaneous up-sequence BRS (10 +/- 11 ms/mmHg, P < 0.01). In contrast, BRS derived from spontaneous down sequences and the modified Oxford method were unaltered by slow breathing. The lack of change in BRS derived from the modified Oxford method challenges the concept that slow breathing acutely augments arterial baroreflex function in otherwise healthy humans. Our results also provide further evidence that spontaneous BRS may not reflect the BRS determined by experimentally driven baroreceptor stimulation.

A randomized controlled trial to assess the central hemodynamic response to exercise in patients with transient ischaemic attack and minor stroke.

Early exercise engagement elicits meaningful changes in peripheral blood pressure in patients diagnosed with transient ischaemic attack (TIA) or minor stroke. However, central hemodynamic markers may provide clinicians with important diagnostic and prognostic information beyond that provided by peripheral blood pressure readings. The purpose of this single-centre, randomized, parallel-group clinical trial was to determine the effect of a 12-week aerobic exercise intervention on central and peripheral hemodynamic variables in patients with TIA or minor stroke. In this study, 47 participants (66±10 years) completed a baseline assessment, which involved the measurement of central and peripheral hemodynamic parameters, undertaken in the morning, in a fasted state. Participants were randomized to either a 12-week exercise or control group on completion of the baseline assessment. An identical follow-up assessment was completed post intervention. Central hemodynamic variables were assessed using an oscillometric device at both assessments. Analysis of covariance demonstrated a significant interaction for central and peripheral blood pressure and augmentation index (all P<0.05; ηp2.09-.11), with the exercise group presenting lower values than the control group post intervention (118±17 vs 132±28 mm Hg for central blood pressure; 125±19 vs 138±28 mm Hg for peripheral blood pressure; 104±49 vs 115±67% for augmentation index). The present study demonstrates that participation in an exercise program soon after stroke/TIA diagnosis may elicit significant beneficial changes to a patient's central systolic blood pressure and augmentation index. This may positively impact upon the treatment strategies implemented by clinicians in the care of patients with TIA and minor stroke.

Effect of automatic external defibrillator audio prompts on cardiopulmonary resuscitation performance.

OBJECTIVES: To determine the effectiveness of the cardiopulmonary resuscitation (CPR) audio prompts in an automatic external defibrillator in 24 lay subjects, before and after CPR training. METHODS: Untrained subjects were asked to perform CPR on a manikin with and without the assistance of audio prompts. All subjects were then trained in CPR, and retested them eight weeks later. RESULTS: Untrained subjects who performed CPR first without audio prompts performed poorly, with only (mean (SD)) 24.5% (32%) of compressions at the correct site and depth, a mean compression rate of 52 (31) per minute, and with 15% (32%) of ventilatory attempts adequate. Repeat performance by this group with audio prompts resulted in significant improvements in compression rate (91(12), p = 0.0002, paired t test), and percentage of correct ventilations (47% (40%), p = 0.01 paired t test), but not in the percentage correct compressions (23% (29%)). Those who performed CPR first with audio prompts performed significantly better in compression rate (87 (19), p = 003, unpaired t test), and the percentage of correct ventilations (51 (34), p = 0.003 unpaired t test), but not in the percentage of correct compressions (18 (27)) than those without audio prompts. After training, CPR performance was significantly better than before training, but there was no difference in performance with or without audio prompts, although 73% of subjects commented that they felt more comfortable performing CPR with audio prompts. CONCLUSIONS: For untrained subjects, the quality of CPR may be improved by using this device, while for trained subjects the willingness to perform CPR may be increased.

Interactions between breathing rate and low-frequency fluctuations in blood pressure and cardiac intervals.

Evidence derived from spontaneous measures of cardiovagal baroreflex sensitivity (BRS) suggests that slow breathing at 6 breaths/min augments BRS. However, increases in BRS associated with slow breathing may simply reflect the frequency-dependent nature of the baroreflex rather than the modulation of baroreflex function by changes in breathing rate per se. To test this hypothesis we employed a crossover study design (n = 14) wherein breathing rate and systolic arterial blood pressure (SAP) oscillation induced via the application of oscillating lower body negative pressure (OLBNP) were independently varied at fixed frequencies. Breathing rate was controlled at 6 or 10 breaths/min with the aid of a metronome, and SAP oscillations were driven at 0.06 Hz and 0.1 Hz using OLBNP. The magnitudes of SAP and R-R interval (cardiac period) oscillations were quantified using power spectral analysis, and the transfer function gain between SAP and R-R interval was used to estimate BRS. Linear mixed-effects models were used to examine the main effects and interactions between breathing rate and OLBNP frequency. There was no statistical interaction between breathing and OLBNP frequency (P = 0.59), indicating that the effect of breathing rate on BRS did not differ according to OLBNP frequency (and vice versa). Additionally, there was no main effect for breathing rate (P = 0.28). However, we observed a significant main effect for OLBNP frequency (P = 0.01) consistent with the frequency-dependent nature of baroreflex. These findings suggest that increases in spectral indices of BRS reflect the frequency dependence of the baroreflex and are not due to slow breathing per se.

Fractal characteristics of breath to breath timing in sleeping infants.

We examined interbreath interval (IBI) time series of 19 term infants during active and quiet sleep for fractal properties using Fano factor analysis. For each time series we calculated the fractal exponent (alpha), comparing alpha for the original time series with two forms of surrogate data, a temporally independent surrogate set and an autoregressive surrogate set. alpha values were normally distributed between 0.79 and -0.22, and did not differ with sleep state. The fractal characteristics of the original time series were not retained in the temporally independent surrogate time series indicating that the distribution of intervals alone was not fractal, but were retained using autoregressive surrogates with an order of 10, suggesting that the fractal properties of the IBI time series were related to correlations between successive breaths. These observations suggest that some of the respiratory variability that occurs during sleep in infants, which in the past has been regarded as stochastic noise, may be the product of deterministic processes.

Inspiratory coupling to cardiac activity and to somatic afferent nerve stimulation in the anaesthetised rat.

We examined the ability of somatic afferent nerve stimulation to entrain inspiratory onset in the anaesthetized spontaneously breathing rat, and compared features of this stimulus-ventilatory coupling to entrainment of inspiratory onset by cardiac activity. In 14 rats prior to stimulation, we commonly observed a constant temporal alignment between ECG R waves and inspiratory onset (cardioventilatory coupling). Stimulation of a hamstring nerve at rates close to the heart rate also caused coupling (a constant stimulus to inspiratory onset interval), although this was highly dependent upon frequency of stimulation, with small changes in frequency causing a loss of coupling. In experiments where stimuli were given at constant intervals after ECG R waves, we observed no augmentation of coupling. Our results indicate that both cardiac and somatic afferent nerve activity is able to entrain inspiratory onset. We have suggested that coupling causes respiratory frequency to increase, and it is possible that this is a general mechanism whereby non-respiratory afferents act as stimulants or pacemakers to respiratory rhythm. The role of non-respiratory activity in initiating inspiration needs to be more fully recognised and studied.

Fundamental relationships between blood pressure and cerebral blood flow in humans.

Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R(2) values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04-0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.