The effect of budesonide delivered by high-frequency oscillatory ventilation on acute inflammatory response in severe lung injury in adult rabbits.

The inflammation present in acute respiratory distress syndrome (ARDS) and thereby associated injury to the alveolar-capillary membrane and pulmonary surfactant can potentiate respiratory failure. Even considering the high mortality rate of severe ARDS, glucocorticoids appear to be a reasonable treatment option along with an appropriate route of delivery to the distal lung. This study aimed to investigate the effect of budesonide therapy delivered intratracheally by high-frequency oscillatory ventilation (HFOV) on lung function and inflammation in severe ARDS. Adult New Zealand rabbits with respiratory failure (P/F<13.3 kPa) induced by intratracheal instillation of hydrochloric acid (HCl, 3 ml/kg, pH 1.5) followed by high tidal ventilation (VT 20 ml/kg) to mimic ventilator-induced lung injury (VILI) were treated with intratracheal bolus of budesonide (0.25 mg/kg, Pulmicort) delivered by HFOV (frequency 8 Hz, MAP 1 kPa, deltaP 0.9 kPa). Saline instead of HCl without VILI with HFOV delivered air bolus instead of therapy served as healthy control. All animals were subjected to lung-protective ventilation for 4 h, and respiratory parameters were monitored regularly. Postmortem, lung injury, wet-to-dry weight ratio, leukocyte shifts, and levels of cytokines in plasma and lung were evaluated. Budesonide therapy improved the lung function (P/F ratio, oxygenation index, and compliance), decreased the cytokine levels, reduced lung edema and neutrophils influx into the lung, and improved lung architecture in interstitial congestion, hyaline membrane, and atelectasis formation compared to untreated animals. This study indicates that HFOV delivered budesonide effectively ameliorated respiratory function, and attenuated acid-induced lung injury in a rabbit model of severe ARDS.

Stroke volume variation as an index of fluid responsiveness can be impaired by mental stress.

Cardiac stroke volume variation (SVV) measurement is one of the techniques to detect fluid-responsive hypovolemia in patients under mechanical ventilation. There is an ongoing effort to apply SVV for this purpose also in conscious patients. However, the effect of mental stress often occurring in conscious patients as a potential confounding factor on SVV is not known. The aim of our study was to compare effect of simulated hypovolemia and mental stress on SVV in healthy volunteers in the context of potential confounders - breathing pattern, respiratory sinus arrhythmia magnitude and sex. We examined 102 young healthy volunteers (58 females), mean age 18.6 years. Finger arterial blood pressure was recorded by volume-clamp photoplethysmographic method (Finometer Pro, FMS, Amsterdam, Netherland). From the blood pressure curve, a built in ModelFlow algorithm calculated stroke volume values (SV) for each heartbeat. Respiratory volume was recorded using calibrated respiratory inductive plethysmography (RespiTrace, NIMS, Miami Beach, FL, USA). During four phases of examination protocol (supine rest, head-up tilt (HUT), supine recovery, mental arithmetic task (MA)) we analyzed SVV related to respiratory activity. While during HUT we found an expected increase in SVV together with mean SV decrease, SVV significantly decreased during MA. The observed changes during MA could be attributed to an increased respiratory rate and/or decreased respiratory sinus arrhythmia. Sex related differences in SVV responses to HUT and MA were observed. We conclude that mental stress together with respiratory sinus arrhythmia and respiratory pattern changes can significantly influence SVV as a potential index of fluid responsiveness in conscious patients.

Input for baroreflex analysis: which blood pressure signal should be used?

The baroreflex (BR) is an important physiological regulatory mechanism which reacts to blood pressure perturbations with reflex changes of target variables such as the heart period (electrocardiogram derived RR interval) or the peripheral vascular resistance (PVR). Evaluation of cardiac chronotropic (RR as a target variable) and vascular resistance (target PVR) BR arms was in previous studies mainly based on the use of the spontaneous variability of the systolic or diastolic blood pressure (SBP, DBP), respectively, as the input signals. The use of other blood pressure measures such as the mean blood pressure (MBP) as an input signal for BR analysis is still under investigation. Making the assumption that the strength of coupling along the BR indicates the more appropriate input signal for baroreflex analysis, we employ partial spectral decomposition to assess in the frequency domain the causal coupling from SBP, MBP or DBP to RR or PVR. Noninvasive beat-to-beat recording of RR, SBP, MBP and DBP and PVR was performed in 39 and 36 volunteers in whom orthostatic and cognitive loads were evoked respectively through head-up tilt and mental arithmetic task. At rest, the MBP was most tightly coupled with RR, in contrast to the analysis of the vascular resistance BR arm where the results showed similar importance of all blood pressure input signals. During orthostasis, the increased importance of SBP as the input signal for BR analysis along the cardiac chronotropic arm was demonstrated. In addition, the gain from MBP to RR was more sensitive to physiological state changes compared to gains with SBP or DBP signal as inputs. We conclude that the coupling strength depends not only on the analysed baroreflex arm but also on the selection of the input blood pressure signal and the physiological state. The MBP signal should be more frequently used for the cardiac baroreflex analysis.

Beta-adrenergic receptors gene polymorphisms are associated with cardiac contractility and blood pressure variability.

Beta-adrenergic receptors (beta-ARs) play a pivotal role in the cardiovascular regulation. In the human heart beta1- and beta2-ARs dominate in atria as well as in ventricle influencing heart rate and myocardial contractility. Some single nucleotide polymorphisms (SNPs) of beta-ARs might influence cardiovascular function. However, the influence of beta-AR genes SNPs on hemodynamic parameters at rest and their reactivity under stress is still not well known. We aimed to explore the associations between four selected beta-ARs gene polymorphisms and selected cardiovascular measures in eighty-seven young healthy subjects. While in beta1-AR polymorphism rs1801252 no significant association was observed, second beta1-AR polymorphism rs1801253 was associated with decreased cardiac output and cardiac index during all phases and with decreased flow time corrected and ejection time index at rest and during mental arithmetics. Polymorphism rs1042713 in beta2-AR was associated with alterations in blood pressure variability at rest and during head-up-tilt, while rs1042714 was associated predominantly with decreased parameters of cardiac contractility at rest and during mental arithmetics. We conclude that complex analysis of various cardiovascular characteristics related to the strength of cardiac contraction and blood pressure variability can reveal subtle differences in cardiovascular sympathetic nervous control associated with beta-ARs polymorphisms.

Short-term arterial compliance changes in the context of systolic blood pressure influence.

Arterial compliance (C) is a complex parameter influencing ventricular-arterial coupling depending on structural (arterial wall remodeling) and functional (blood pressure, smooth muscles tone) changes. Based on Windkessel model, C can be calculated as the ratio of a time constant Tau characterizing diastolic blood pressure decay and total peripheral resistance (TPR). The aim of this study was to assess changes of C in the context of systolic arterial pressure (SAP) perturbations during four physiological states (supine rest, head-up tilt, supine recovery, mental arithmetic). In order to compare pressure independent changes of C a new index of C120 was proposed predicting C value at 120 mm Hg of SAP. Eighty-one healthy young subjects (48 f, average age 18.6 years) were examined. Hemodynamic parameters were measured beat-to-beat using volume-clamp photoplethysmographic method and impedance cardiography. We observed that C was strongly related to SAP values on the beat-to-beat time scale. Interestingly, C120 decreased significantly during stress phases. In conclusion, potential changes of SAP should be considered when measuring C. Arterial compliance changes in the opposite direction to TPR pointing towards influence of vascular tone changes on its value.

Vascular resistance arm of the baroreflex: methodology and comparison with the cardiac chronotropic arm.

Baroreflex response consists of cardiac chronotropic (effect on heart rate), cardiac inotropic (on contractility), venous (on venous return) and vascular (on vascular resistance) arms. Because of the simplicity of its measurement, the cardiac chronotropic arm is most often analyzed. The aim was to introduce a method to assess the vascular baroreflex arm and to characterize its changes during stress. We evaluated the effect of orthostasis and mental arithmetics (MA) in 39 (22 women, 17 men; median age: 18.7 yr) and 36 (21 women, 15 men; 19.2 yr) healthy volunteers, respectively. We recorded systolic (SBP) and mean (MBP) blood pressure by volume-clamp method and R-R interval (RR) by ECG. Cardiac output (CO) was recorded by impedance cardiography. From MBP and CO, peripheral vascular resistance (PVR) was calculated. The directional spectral coupling and gain of cardiac chronotropic (SBP to RR) and vascular (SBP to PVR) arms were quantified. The strength of the causal coupling from SBP to PVR was significantly higher than that of SBP to RR coupling over the whole protocol (P < 0.001). Along both arms, the coupling was higher during orthostasis compared with the supine position (P < 0.001 and P = 0.006); no MA effect was observed. No significant changes in the spectral gain (ratio of RR or PVR change to a unit SBP change) across all phases were found (0.111 ≤ P ≤ 0.907). We conclude that changes in PVR are tightly coupled with SBP oscillations via the baroreflex, providing an approach for baroreflex vascular arm analysis with the potential to reveal new aspects of blood pressure dysregulation.NEW & NOTEWORTHY Baroreflex response consists of several arms, but the cardiac chronotropic arm (blood pressure changes evoking heart rate response) is usually analyzed. This study introduces a method to assess the vascular baroreflex arm with the continuous noninvasive measurement of peripheral vascular resistance as an output considering causality in the interaction between oscillations and slower dynamics of vascular tone changes. We conclude that although vascular baroreflex arm involvement becomes dominant during orthostasis, gain of this interaction is relatively stable.

Information domain analysis of respiratory sinus arrhythmia mechanisms.

Ventilation related heart rate oscillations - respiratory sinus arrhythmia (RSA) - originate in human from several mechanisms. Two most important of them - the central mechanism (direct communication between respiratory and cardiomotor centers), and the peripheral mechanism (ventilation-associated blood pressure changes transferred to heart rate via baroreflex) have been described in previous studies. The major aim of this study was to compare the importance of these mechanisms in the generation of RSA non-invasively during various states by quantifying the strength of the directed interactions between heart rate, systolic blood pressure and respiratory volume signals. Seventy-eight healthy volunteers (32 male, age range: 16.02-25.77 years, median age: 18.57 years) participated in this study. The strength of mutual interconnections among the spontaneous beat-to-beat oscillations of systolic blood pressure (SBP), R-R interval (RR signal) and respiration (volume changes - RESP signal) was quantified during supine rest, orthostatic challenge (head-up tilt, HUT) and cognitive load (mental arithmetics, MA) using bivariate and trivariate measures of cardio-respiratory information transfer to separate baroreflex and nonbaroreflex (central) mechanisms. Our results indicate that both basic mechanisms take part in RSA generation in the intact cardiorespiratory control of human subjects. During orthostatic and mental challenges baroreflex based peripheral mechanism becomes more important.

Univariate and multivariate conditional entropy measures for the characterization of short-term cardiovascular complexity under physiological stress.

OBJECTIVE: A defining feature of physiological systems under the neuroautonomic regulation is their dynamical complexity. The most common approach to assess physiological complexity from short-term recordings, i.e. to compute the rate of entropy generation of an individual system by means of measures of conditional entropy (CE), does not consider that complexity may change when the investigated system is part of a network of physiological interactions. This study aims at extending the concept of short-term complexity towards the perspective of network physiology, defining multivariate CE measures whereby multiple physiological processes are accounted for in the computation of entropy rates. APPROACH: Univariate and multivariate CE measures are computed using state-of-the-art methods for entropy estimation and applied to time series of heart period (H), systolic (S) and diastolic (D) arterial pressure, and respiration (R) variability measured in healthy subjects monitored in a resting state and during conditions of postural and mental stress. MAIN RESULTS: Compared with the traditional univariate metric of short-term complexity, multivariate measures provide additional information with plausible physiological interpretation, such as (i) the dampening of respiratory sinus arrhythmia and activation of the baroreflex control during postural stress; (ii) the increased complexity of heart period and blood pressure variability during mental stress, reflecting the effect of respiratory influences and upper cortical centers; (iii) the strong influence of D on S, mediated by left ventricular ejection fraction and vascular properties; (iv) the role of H in reducing the complexity of D, related to cardiac run-off effects; and (v) the unidirectional role of R in influencing cardiovascular variability. SIGNIFICANCE: Our results document the importance of employing a network perspective in the evaluation of the short-term complexity of cardiovascular and respiratory dynamics across different physiological states.

Preejection period as a sympathetic activity index: a role of confounding factors.

In previous studies, one of the systolic time intervals - preejection period (PEP) - was used as an index of sympathetic activity reflecting the cardiac contractility. However, PEP could be also influenced by several other cardiovascular variables including preload, afterload and diastolic blood pressure (DBP). The aim of this study was to assess the behavior of the PEP together with other potentially confounding cardiovascular system characteristics in healthy humans during mental and orthostatic stress (head-up tilt test - HUT). Forty-nine healthy volunteers (28 females, 21 males, mean age 18.6 years (SD=1.8 years)) participated in the study. We recorded finger arterial blood pressure by volume-clamp method (Finometer Pro, FMS, Netherlands), PEP, thoracic fluid content (TFC) - a measure of preload, and cardiac output (CO) by impedance cardiography (CardioScreen® 2000, Medis, Germany). Systemic vascular resistance (SVR) - a measure of afterload - was calculated as a ratio of mean arterial pressure and CO. We observed that during HUT, an expected decrease in TFC was accompanied by an increase of PEP, an increase of SVR and no significant change in DBP. During mental stress, we observed a decrease of PEP and an increase of TFC, SVR and DBP. Correlating a change in assessed measures (delta values) between mental stress and previous supine rest, we found that deltaPEP correlated negatively with deltaCO and positively with deltaSVR. In orthostasis, no significant correlation between deltaPEP and deltaDBP, deltaTFC, deltaCO, deltaMBP or deltaSVR was found. We conclude that despite an expected increase of sympathetic activity during both challenges, PEP behaved differently indicating an effect of other confounding factors. To interpret PEP values properly, we recommend simultaneously to measure other variables influencing this cardiovascular measure.

Multiscale time irreversibility of heart rate and blood pressure variability during orthostasis.

Time irreversibility is a characteristic feature of non-equilibrium, complex systems such as the cardiovascular control mediated by the autonomic nervous system (ANS). Time irreversibility analysis of heart rate variability (HRV) and blood pressure variability (BPV) represents a new approach to assess cardiovascular regulatory mechanisms. The aim of this paper was to assess the changes in HRV and BPV irreversibility during the active orthostatic test (a balance of ANS shifted towards sympathetic predominance) in 28 healthy young subjects. We used three different time irreversibility indices-Porta's, Guzik's and Ehler's indices (P%, G% and E, respectively) derived from data segments containing 1000 beat-to-beat intervals on four timescales. We observed an increase in the HRV and a decrease in the BPV irreversibility during standing compared to the supine position. The postural change in irreversibility was confirmed by surrogate data analysis. The differences were more evident in G% and E than P% and for higher scale factors. Statistical analysis showed a close relationship between G% and E. Contrary to this, the association between P% and G% and P% and E was not proven. We conclude that time irreversibility of beat-to-beat HRV and BPV is significantly altered during orthostasis, implicating involvement of the autonomous nervous system in its generation.

Respiratory sinus arrhythmia is reduced in adolescent major depressive disorder.

OBJECTIVE: Although the emotion regulatory difficulties in patients with major depressive disorder (MDD) are predicted to associate with impaired cardiovascular autonomic regulation, the changes of cardiac vagal regulation MDD are incompletely understood. The aim of the study was to evaluate the respiratory sinus arrhythmia (as an index of cardiac vagal regulation) using the spectral analysis in high frequency band of the heart rate variability and the indices of deep breathing test in adolescent patients with major depressive disorder. MATERIAL AND METHOD: Twenty-eight adolescent girls were examined - 14 patients with major depressive disorder without pharmacological treatment (average age: 16.4 +/- 0.2 yr) and 14 healthy probands (control group) matched for age and gender. The respiratory sinus arrhythmia was evaluated using the spectral analysis in high frequency band of the heart rate variability (HF-HRV) and the parameters of deep breathing test (I-E, I/E). In addition, mean R-R interval was calculated. RESULTS: The adolescent patients with MDD has significantly reduced spectral activity in the HF-HRV and lower I/E, I-E parameters compared to marched health subjects (P<0.05). CONCLUSIONS: We conclude that the adolescents girls with MDD have reduced respiratory sinus arrhythmia indicating cardiac vagal dysregulation. Since impaired cardiac vagal regulation is associated with increased risk of cardiovascular morbidity, this finding underscores the importance of impaired autonomic neuro-cardiac integrity already in adolescents with major depressive disorder without pharmacological treatment.

The effect of orthostasis on recurrence quantification analysis of heart rate and blood pressure dynamics.

The purpose of this paper is to investigate the effect of orthostatic challenge on recurrence plot based complexity measures of heart rate and blood pressure variability (HRV and BPV). HRV and BPV complexities were assessed in 28 healthy subjects over 15 min in the supine and standing positions. The complexity of HRV and BPV was assessed based on recurrence quantification analysis. HRV complexity was reduced along with the HRV magnitude after changing from the supine to the standing position. In contrast, the BPV magnitude increased and BPV complexity decreased upon standing. Recurrence quantification analysis (RQA) of HRV and BPV is sensitive to orthostatic challenge and might therefore be suited to assess changes in autonomic neural outflow to the cardiovascular system.