Cerebral blood flow response to cardiorespiratory oscillations in healthy humans.

Dynamic cerebral autoregulation (CA) characterizes the cerebral blood flow (CBF) response to abrupt changes in arterial blood pressure (ABP). CA operates at frequencies below 0.15 Hz. ABP regulation and probably CA are modified by autonomic nervous activity. We investigated the CBF response and CA dynamics to mild increase in sympathetic activity. Twelve healthy volunteers underwent oscillatory lower body negative pressure (oLBNP), which induced respiratory-related ABP oscillations at an average of 0.22 Hz. We recorded blood velocity in the internal carotid artery (ICA) by Doppler ultrasound and ABP. We quantified variability and peak wavelet power of ABP and ICA blood velocity by wavelet analysis at low frequency (LF, 0.05-0.15 Hz) and Mayer waves (0.08-0.12 Hz), respectively. CA was quantified by calculation of the wavelet synchronization gamma index for the pair ABP-ICA blood velocity in the LF and Mayer wave band. oLBNP increased ABP peak wavelet power at the Mayer wave frequency. At the Mayer wave, ABP peak wavelet power increased by >70 % from rest to oLBNP (p < 0.05), while ICA blood flow velocity peak wavelet power was unchanged, and gamma index increased (from 0.49 to 0.69, p < 0.05). At LF, variability in both ABP and ICA blood velocity and gamma index were unchanged from rest to oLBNP. Despite an increased gamma index at Mayer wave, ICA blood flow variability was unchanged during increased ABP variability. The increased synchronization during oLBNP did not cause less stable CBF or less active CA. Sympathetic activation seems to improve the mechanisms of CA.

Respiratory Sinus Arrhythmia is Mainly Driven by Central Feedforward Mechanisms in Healthy Humans.

Heart rate variability (HRV) has prognostic and diagnostic potential, however, the mechanisms behind respiratory sinus arrhythmia (RSA), a main short-term HRV, are still not well understood. We investigated if the central feedforward mechanism or pulmonary stretch reflex contributed most to RSA in healthy humans. Ventilatory support reduces the centrally mediated respiratory effort but remains the inspiratory stretch of the pulmonary receptors. We aimed to quantify the difference in RSA between spontaneous breathing and ventilatory support. Nineteen healthy, young subjects underwent spontaneous breathing and non-invasive intermittent positive pressure ventilation (NIV) while we recorded heart rate (HR, from ECG), mean arterial pressure (MAP) and stroke volume (SV) estimated from the non-invasive finger arterial pressure curve, end-tidal CO2 (capnograph), and respiratory frequency (RF) with a stretch band. Variability was quantified by an integral between 0.15-0.4 Hz calculated from the power spectra. Median and 95% confidence intervals (95%CI) were calculated as Hodges-Lehmann's one-sample estimator. Statistical difference was calculated by the Wilcoxon matched-pairs signed-rank test. RF and end-tidal CO2 were unchanged by NIV. NIV reduced HR by 2 bpm, while MAP and SV were unchanged in comparison to spontaneous breathing. Variability in both HR and SV was reduced by 60% and 75%, respectively, during NIV as compared to spontaneous breathing, but their interrelationship with respiration was maintained. NIV reduced RSA through a less central respiratory drive, and pulmonary stretch reflex contributed little to RSA. RSA is mainly driven by a central feedforward mechanism in healthy humans. Peripheral reflexes may contribute as modifiers of RSA.

Internal Carotid Artery Blood Flow Response to Anesthesia, Pneumoperitoneum, and Head-up Tilt during Laparoscopic Cholecystectomy.

BACKGROUND: Little is known about how implementation of pneumoperitoneum and head-up tilt position contributes to general anesthesia-induced decrease in cerebral blood flow in humans. We investigated this question in patients undergoing laparoscopic cholecystectomy, hypothesizing that cardiorespiratory changes during this procedure would reduce cerebral perfusion. METHODS: In a nonrandomized, observational study of 16 patients (American Society of Anesthesiologists physical status I or II) undergoing laparoscopic cholecystectomy, internal carotid artery blood velocity was measured by Doppler ultrasound at four time points: awake, after anesthesia induction, after induction of pneumoperitoneum, and after head-up tilt. Vessel diameter was obtained each time, and internal carotid artery blood flow, the main outcome variable, was calculated. The authors recorded pulse contour estimated mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV) index, cardiac index, end-tidal carbon dioxide (ETCO2), bispectral index, and ventilator settings. Results are medians (95% CI). RESULTS: Internal carotid artery blood flow decreased upon anesthesia induction from 350 ml/min (273 to 410) to 213 ml/min (175 to 249; -37%, P < 0.001), and tended to decrease further with pneumoperitoneum (178 ml/min [127 to 208], -15%, P = 0.026). Tilt induced no further change (171 ml/min [134 to 205]). ETCO2 and bispectral index were unchanged after induction. MAP decreased with anesthesia, from 102 (91 to 108) to 72 (65 to 76) mmHg, and then remained unchanged (Pneumoperitoneum: 70 [63 to 75]; Tilt: 74 [66 to 78]). Cardiac index decreased with anesthesia and with pneumoperitoneum (overall from 3.2 [2.7 to 3.5] to 2.3 [1.9 to 2.5] l · min · m); tilt induced no further change (2.1 [1.8 to 2.3]). Multiple regression analysis attributed the fall in internal carotid artery blood flow to reduced cardiac index (both HR and SV index contributing) and MAP (P < 0.001). Vessel diameter also declined (P < 0.01). CONCLUSIONS: During laparoscopic cholecystectomy, internal carotid artery blood flow declined with anesthesia and with pneumoperitoneum, in close association with reductions in cardiac index and MAP. Head-up tilt caused no further reduction. Cardiac output independently affects human cerebral blood flow.

Respiratory pump maintains cardiac stroke volume during hypovolemia in young, healthy volunteers.

Spontaneous breathing has beneficial effects on the circulation, since negative intrathoracic pressure enhances venous return and increases cardiac stroke volume. We quantified the contribution of the respiratory pump to preserve stroke volume during hypovolemia in awake, young, healthy subjects. Noninvasive stroke volume, cardiac output, heart rate, and mean arterial pressure (Finometer) were recorded in 31 volunteers (19 women), 19-30 yr old, during normovolemia and hypovolemia (approximating 450- to 500-ml reduction in central blood volume) induced by lower-body negative pressure. Control-mode noninvasive positive-pressure ventilation was employed to reduce the effect of the respiratory pump. The ventilator settings were matched to each subject's spontaneous respiratory pattern. Stroke volume estimates during positive-pressure ventilation and spontaneous breathing were compared with Wilcoxon matched-pairs signed-rank test. Values are overall medians. During normovolemia, positive-pressure ventilation did not affect stroke volume or cardiac output. Hypovolemia resulted in an 18% decrease in stroke volume and a 9% decrease in cardiac output ( P < 0.001). Employing positive-pressure ventilation during hypovolemia decreased stroke volume further by 8% ( P < 0.001). Overall, hypovolemia and positive-pressure ventilation resulted in a reduction of 26% in stroke volume ( P < 0.001) and 13% in cardiac output ( P < 0.001) compared with baseline. Compared with the situation with control-mode positive-pressure ventilation, spontaneous breathing attenuated the reduction in stroke volume induced by moderate hypovolemia by 30% (i.e., -26 vs. -18%). In the patient who is critically ill with hypovolemia or uncontrolled hemorrhage, spontaneous breathing may contribute to hemodynamic stability, whereas controlled positive-pressure ventilation may result in circulatory decompensation. NEW & NOTEWORTHY Maintaining spontaneous respiration has beneficial effects on hemodynamic compensation, which is clinically relevant for patients in intensive care. We have quantified the contribution of the respiratory pump to cardiac stroke volume and cardiac output in healthy volunteers during normovolemia and central hypovolemia. The positive hemodynamic effect of the respiratory pump was abolished by noninvasive, low-level positive-pressure ventilation. Compared with control-mode positive-pressure ventilation, spontaneous negative-pressure ventilation attenuated the fall in stroke volume by 30%.

Dynamic cerebral autoregulation is preserved during isometric handgrip and head-down tilt in healthy volunteers.

In healthy humans, cerebral blood flow (CBF) is autoregulated against changes in arterial blood pressure. Spontaneous fluctuations in mean arterial pressure (MAP) and CBF can be used to assess cerebral autoregulation. We hypothesized that dynamic cerebral autoregulation is affected by changes in autonomic activity, MAP, and cardiac output (CO) induced by handgrip (HG), head-down tilt (HDT), and their combination. In thirteen healthy volunteers, we recorded blood velocity by ultrasound in the internal carotid artery (ICA), HR, MAP and CO-estimates from continuous finger blood pressure, and end-tidal CO2 . Instantaneous ICA beat volume (ICABV, mL) and ICA blood flow (ICABF, mL/min) were calculated. Wavelet synchronization index γ (0-1) was calculated for the pairs: MAP-ICABF, CO-ICABF and HR-ICABV in the low (0.05-0.15 Hz; LF) and high (0.15-0.4 Hz; HF) frequency bands. ICABF did not change between experimental states. MAP and CO were increased during HG (+16% and +15%, respectively, P < 0.001) and during HDT + HG (+12% and +23%, respectively, P < 0.001). In the LF interval, median γ for the MAP-ICABF pair (baseline: 0.23 [0.12-0.28]) and the CO-ICABF pair (baseline: 0.22 [0.15-0.28]) did not change with HG, HDT, or their combination. High γ was observed for the HR-ICABV pair at the respiratory frequency, the oscillations in these variables being in inverse phase. The unaltered ICABF and the low synchronization between MAP and ICABF in the LF interval suggest intact dynamic cerebral autoregulation during HG, HDT, and their combination.

Respiration-related cerebral blood flow variability increases during control-mode non-invasive ventilation in normovolemia and hypovolemia.

PURPOSE: Increased variability in cerebral blood flow (CBF) predisposes to adverse cerebrovascular events. Oscillations in arterial blood pressure and PaCO2 induce CBF variability. Less is known about how heart rate (HR) variability affects CBF. We experimentally reduced respiration-induced HR variability in healthy subjects, hypothesizing that CBF variability would increase. METHODS: Internal carotid artery (ICA) blood velocity was recorded by Doppler ultrasound in ten healthy subjects during baseline, control-mode, non-invasive mechanical ventilation (NIV), i.e., with fixed respiratory rate, hypovolemia induced by lower body negative pressure, and combinations of these. ICA beat volume (ICABV) and ICA blood flow (ICABF) were calculated. HR, mean arterial blood pressure (MAP), respiratory frequency (RF), and end-tidal CO2 were recorded. Integrals of power spectra at each subject's RF ± 0.03 Hz were used to measure variability. Phase angle/coherence measured coupling between cardiovascular variables. RESULTS: Control-mode NIV reduced HR variability (-56%, p = 0.002) and ICABV variability (-64%, p = 0.006) and increased ICABF variability (+140%, p = 0.002) around RF. NIV + hypovolemia reduced variability in HR and ICABV by 70-80% (p = 0.002) and doubled ICABF variability (p = 0.03). MAP variability was unchanged in either condition. Respiration-induced HR and ICABV oscillations were in inverse phase and highly coherent (coherence >0.9) during baseline, but this coherence decreased during NIV, in normovolemia and hypovolemia (p = 0.01). CONCLUSION: Controlling respiration in awake healthy humans reduced HR variability and increased CBF variability in hypovolemia and normovolemia. We suggest respiration-induced HR variability to be a mechanism in CBF regulation. Maintaining spontaneous respiration in patients receiving ventilatory support may be beneficial also for cerebral circulatory purposes.

Cold-induced sympathetic tone modifies the impact of endothelium-dependent vasodilation in the finger pulp.

OBJECTIVE: In thermoneutral and cold subjects, the sympathetic nervous system regulates skin blood flow by adjusting frequency of the tonic vasoconstrictor impulses. However, the way these thermoregulatory impulses influence the vascular endothelium is not well known. We studied how the sympathetic nervous system influences endothelium-dependent vasodilation (EDV) caused by shear stress in skin containing arteriovenous anastomoses (AVAs) and arterioles in healthy subjects. METHODS: Thirteen healthy subjects were exposed to thermoneutral (29°C) and cold (22°C) ambient temperatures on separate days. EDV was induced by releasing suprasystolic pressure cuff applied to the forearm or third finger after 4min. Bilateral laser Doppler flux from the finger pulp, dorsal finger and dorsal wrist was measured together with ultrasound Doppler from the right radial artery. Absolute EDV response (EDV peak minus baseline) and normalized relative EDV response (ratio EDV peak/baseline) were calculated (median, 95% confidence interval). The relative EDV response reflect the size of EDV response independent of the baseline level and is thus used to compare the EDV responses in the finger pulp and wrist skin in the two temperature conditions. RESULTS: In finger pulp (dominated by AVAs), the absolute EDV response (flux, au) in thermoneutral (137.8 (67.5, 168.8)) and cold (130.3 (97.2, 154.9)) was the same (p=0.85), whereas the relative EDV response was significantly higher in cold (3.6 (2.5, 5.9)) than in thermoneutral (1.4 (1.1, 1.6), p=0.002). The same patterns were found in the radial artery. In the dorsal wrist (dominated by arterioles) the absolute EDV response (flux, au) was smaller in cold (30.9 (15.91, 38.0)) than in thermoneutral (52.1 (38.4, 57.8), p=0.04), whereas the relative EDV responses in cold (3.5 (2.3, 4.2)), and thermoneutral (2.3 (1.6, 2.7)) were equal (p=0.16). CONCLUSIONS: The relative EDV responses show that the impact of EDV on skin perfusion in cold conditions is significantly greater in the finger pulp than in wrist skin. However, the absolute EDV responses indicate that vascular smooth muscle relaxation during EDV is probably not affected by higher mild cold-induced sympathetic activity either in AVAs or in arterioles.

Internal carotid artery blood flow in healthy awake subjects is reduced by simulated hypovolemia and noninvasive mechanical ventilation.

Intact cerebral blood flow (CBF) is essential for cerebral metabolism and function, whereas hypoperfusion in relation to hypovolemia and hypocapnia can lead to severe cerebral damage. This study was designed to assess internal carotid artery blood flow (ICA-BF) during simulated hypovolemia and noninvasive positive pressure ventilation (PPV) in young healthy humans. Beat-by-beat blood velocity (ICA and aorta) were measured by Doppler ultrasound during normovolemia and simulated hypovolemia (lower body negative pressure), with or without PPV in 15 awake subjects. Heart rate, plethysmographic finger arterial pressure, respiratory frequency, and end-tidal CO2 (ETCO2) were also recorded. Cardiac index (CI) and ICA-BF were calculated beat-by-beat. Medians and 95% confidence intervals and Wilcoxon signed rank test for paired samples were used to test the difference between conditions. Effects on ICA-BF were modeled by linear mixed-effects regression analysis. During spontaneous breathing, ICA-BF was reduced from normovolemia (247, 202-284 mL/min) to hypovolemia (218, 194-271 mL/min). During combined PPV and hypovolemia, ICA-BF decreased by 15% (200, 152-231 mL/min, P = 0.001). Regression analysis attributed this fall to concurrent reductions in CI (ß: 43.2, SE: 17.1, P = 0.013) and ETCO2 (ß: 32.8, SE: 9.3, P = 0.001). Mean arterial pressure was maintained and did not contribute to ICA-BF variance. In healthy awake subjects, ICA-BF was significantly reduced during simulated hypovolemia combined with noninvasive PPV Reductions in CI and ETCO2 had additive effects on ICA-BF reduction. In hypovolemic patients, even low-pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure.