Ventilatory Oscillations Research Articles

Ventilatory responses to independent and combined hypoxia, hypercapnia and hypobaria in healthy pre-term-born adults.

Pre-term birth is associated with physiological sequelae that persist into adulthood. In particular, modulated ventilatory responsiveness to hypoxia and hypercapnia has been observed in this population. Whether pre-term birth per se causes these effects remains unclear. Therefore, we aimed to assess pulmonary ventilation and blood gases under various environmental conditions, comparing 17 healthy prematurely born individuals (mean ± SD; gestational age, 28 ± 2weeks; age, 21 ± 4years; peak oxygen uptake, 48.1 ± 11.2mlkg-1 min-1 ) with 16 well-matched adults born at term (gestational age, 40 ± 1weeks; age, 22 ± 2years; peak oxygen uptake, 51.2 ± 7.7mlkg-1 min-1 ). Participants were exposed to seven combinations of hypoxia/hypobaria (equivalent to ∼3375m) and/or hypercapnia (3% CO2 ), at rest for 6min. Pulmonary ventilation, pulse oxygen saturation and the arterial partial pressures of O2 and CO2 were similar in pre-term and full-term individuals under all conditions. Higher ventilation in hypoxia compared to normoxia was only observed at terrestrial altitude, despite an equivalent (normobaric) hypoxic stimulus administered at sea level (0.138 ). Assessment of oscillations in key variables revealed that combined hypoxic hypercapnia induced greater underlying fluctuations in ventilation in pre-term individuals only. In general, higher pulse oxygen saturation fluctuations were observed with hypoxia, and lower fluctuations in end-tidal CO2 with hypercapnia, despite similar ventilatory oscillations observed between conditions. These findings suggest that healthy prematurely born adults display similar overall ventilation to their term-born counterparts under various environmental stressors, but that combined ventilatory stimuli could induce an irregular underlying ventilatory pattern. Moreover, barometric pressure may be an important factor when assessing ventilatory responsiveness to moderate hypoxic stimuli. KEY POINTS: Evidence exists for unique pulmonary and respiratory function under hypoxic conditions in adult survivors of pre-term birth. Whether pre-term birth per se causes these differences requires a comparison of conventionally healthy prematurely born adults with an appropriately matched sample of term-born individuals. According to the present data, there is no difference between healthy pre-term and well-matched term-born individuals in the magnitude of pulmonary ventilation or arterial blood gases during independent and combined hypobaria, hypoxia and hypercapnia. Terrestrial altitude (hypobaria) was necessary to induce differences in ventilation between normoxia and a hypoxic stimulus equivalent to ∼3375m of altitude. Furthermore, peak power in pulse oxygen saturation was similar between hypobaric normoxia and normobaric hypoxia. The observed similarities between groups suggest that ventilatory regulation under various environmental stimuli is not impaired by pre-term birth per se. Instead, an integrated combination of neonatal treatment strategies and cardiorespiratory fitness/disease status might underlie previously observed chemosensitivity impairments.

Further prognostic stratification in patients with oscillatory ventilation with exercise: is there more to it than just ups and downs?

Abstract Introduction Exercise Oscillatory Ventilation (EOV) has numerous definitions, but the common foundation is the presence of an oscillatory phenomenon of the ventilation/minute graph with a given amplitude and frequency. Recently, it was proposed that the presence of a delay in O2 consumption (VO2) peak to minute ventilation (VE) peak during ventilatory oscillation was a predictor of worse prognosis in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) <50%. The aim of this work was to assess whether these characteristics add further prognostic value to the subset of patients with HF and EOV. Methods This was a single-centre retrospective cohort of consecutive patients with HF and LVEF <50% that underwent cardiopulmonary exercise testing (CPET) from 2016–2020. EOV was defined as per Vainshelboim 2017 (≥3 consecutive cyclic fluctuations of ventilation during exercise, average amplitude over 3 ventilatory oscillations ≥5L and an average length of three oscillatory cycles 40s to 140s). The presence of EOV was evaluated by 3 independent observers after observing a VE over time plot. For the creation of this plot, data was collected as a rolling average of 5 consecutive breaths. The presence of EOV was established if at least 2 observers agreed on the classification. Afterwards, a second graph was plotted, with both VO2 and VE over time and the mean delay between VO2 peak to VE peak during EOV was manually calculated (Figure 1). The primary endpoint was a composite of time to all-cause death, heart transplantation or left ventricular assistance device (LVAD) implantation. Results Of the 285 patients, 78 (27%) were classified as having EOV. These HF patients were mostly male (75%) with a mean age of 58±12 years, mean LVEF 31±10% with 63% having ischemic etiology. During a median follow up of 27 (17 to 43) months, 4 LVAD implantations, 12 heart transplantations and 18 deaths. The rate of primary outcome was 19% and 36% at 1- and 2-years. The amplitude, frequency, and maximum number of EOV cycles were not associated with the development of the primary endpoint. Only the mean delay between VO2 peak to VE peak during EOV was predictive of time to primary endpoint, even when adjusted for peak VO2 and VE VCO2 slope (adjusted HR 1.06 95% CI 1.009–1.114) (Figure 2). The cut-off of 5 seconds for mean VO2 peak to VE peak delay seems to be the most useful to predict the primary outcome at 2 years, with a sensitivity of 48% and specificity of 84%. Conclusion This novel parameter seems to be the only EOV-related parameter to enable further stratification of prognosis in a cohort of patients with severe HF, with the best cut-off of mean delay between VO2 peak to VE peak during EOV being 5 seconds. Funding Acknowledgement Type of funding sources: None.

Computer-Assisted Assessment of the Interaction Between Arousals, Breath-by-Breath Ventilation, and Chemical Drive During Cheyne-Stokes Respiration in Heart Failure Patients.

Transient increases in ventilation induced by arousal from sleep during Cheyne-Stokes respiration in heart failure patients are thought to contribute to sustaining and exacerbating the ventilatory oscillation. The only possibility to investigate the validity of this notion is to use observational data. This entails some significant challenges: (i) accurate identification of both arousal onset and offset; (ii) detection of short arousals (<3 s); (iii) breath-by-breath analysis of the interaction between arousals and ventilation; (iv) careful control for important confounding factors. In this paper we report how we have tackled these challenges by developing innovative computer-assisted methodologies. The identification of arousal onset and offset is performed by a hybrid approach that integrates visual scoring with computer-based automated analysis. We use a statistical detector to automatically discriminate between dominant theta–delta and dominant alpha activity at each instant of time. Moreover, a statistical detector is used to validate visual scoring of K complexes, delta waves or artifacts associated with an EEG frequency shift, as well as frequency shifts to beta activity. A high-resolution (250 ms) state-transition diagram providing continuous information on the sleep-wake state of the subject is finally obtained. Based on this information, arousals are automatically identified as any state change from sleep to wakefulness lasting ≥2 s. The assessment of the interaction between arousals and ventilation is performed using a breath-by-breath, case-control approach. The arousal-associated change in ventilation is measured as the normalized difference between minute ventilation in the case breath (i.e., with arousal) and that in the control breath (i.e., without arousal), controlling for sleep stage and chemical drive. The latter is estimated by using information from pulse oximetry at the finger. In the last part of the paper, we discuss main potential sources of error inherent in the described methodologies.

Effect of cardiac rehabilitation on exercise ventilatory oscillations in patients with chronic heart failure

Cardiovascular rehabilitation (CVR) is recommended in patients with heart failure (HF) to reduce mortality and new hospitalizations. A cardiopulmonary exercise testing (CPX) presents prognostic criteria such as the presence of exercise oscillatory ventilation (EOV). The aim of our study was to analyse the impact of CVR on EOV and the prognostic value of an evolution of EVO after CVR in a population of chronic heart failure patients. Retrospective, monocentric study including HF patients with reduced/intermediate left ventricular ejection fraction (i.e. < 50%) who participated to a CVR programme in our institution from July 2013 to November 2020, consisting of 21 sessions with a CPX at the first and last sessions. The presence of EOV at the CPX priori to CVR defined the EOV+ and EOV- groups. The main outcome of the study was the resolution of EOV after CVR. The secondary outcome was the occurrence of rehospitalisation for HF and/or death during follow-up, and according to the EOV status. Among the 142 patients included, 24 (17%) had EOV (EOV+ group). The VE/VCO2 slope before CVR was significantly increased in the EOV+ vs. EOV- patients (39.6 ± 5.9 vs. 36.8 ± 6.1 P = 0.05). Regarding the main outcome, EOV resolution was noted after CVR in 14 patients (58.3%, P < 0.01). The 10 patients (7%) with maintained EOV had a significant decrease of the length of the EOV cycle (40.2 ± 12.8 vs. 49.5 ± 15.3 sec, P = 0.005). After a mean follow-up of 31 ± 22 months, we found no difference in the rates of occurrence of the secondary outcome according to the post-CVR EOV status. Cardiovascular rehabilitation is associated with a substantial resolution of EOV (or EOV cycle length) in patients with chronic heart failure. However, the prognostic value of this phenomenon is uncertain.

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations.

Periodic breathing is a respiratory phenomenon frequently observed in patients with heart failure and in normal subjects sleeping at high altitude. However, until recently, periodic breathing has not been studied in wakefulness and during exercise. This review relates the latest findings describing this ventilatory disorder when a healthy subject is submitted to simultaneous physiological (exercise) and environmental (hypoxia, hyperoxia, hypercapnia) or pharmacological (acetazolamide) stimuli. Preliminary studies have unveiled fundamental physiological mechanisms related to the genesis of periodic breathing characterized by a shorter period than those observed in patients (11~12 vs. 30~60 s). A mathematical model of the respiratory system functioning under the aforementioned stressors corroborated these data and pointed out other parameters, such as dead space, later confirmed in further research protocols. Finally, a cardiorespiratory interdependence between ventilatory oscillations and heart rate variability in the low frequency band may partly explain the origin of the augmented sympathetic activation at exercise in hypoxia. These nonlinear instabilities highlight the intrinsic “homeodynamic” system that allows any living organism to adapt, to a certain extent, to permanent environmental and internal perturbations.

Low-frequency ventilatory oscillations in hypoxia are a major contributor to the low-frequency component of heart rate variability

Heart rate variability (HRV) may be influenced by several factors, such as environment (hypoxia, hyperoxia, hypercapnia) or physiological demand (exercise). In this retrospective study, we tested the hypothesis that inter-beat (RR) intervals in healthy subjects exercising under various environmental stresses exhibit oscillations at the same frequency than ventilatory oscillations. Spectra from RR intervals and ventilation ([Formula: see text]E) were collected from 37 healthy young male subjects who participated in 5 previous studies focused on ventilatory oscillations (or periodic breathing) during exercise in hypoxia, hyperoxia and hypercapnia. Bland and Altman test and multivariate regressions were then performed to compare respective frequencies and changes in peak powers of the two signals. Fast Fourier analysis of RR and [Formula: see text]E signals showed that RR was oscillating at the same frequency than periodic breathing, i.e., ~ 0.09Hz (11s). During exercise, in these various conditions, the difference between minimum and maximum HRV peak power was positively correlated to the same change in ventilation peak power (P < 0.05). Low-frequency (LF) peak power was correlated to tidal volume (P < 0.01) and breathing frequency (P < 0.001). This study suggests that low-frequency ventilatory oscillations in hypoxia are a major contributor to the LF band power of heart rate variability. CLINICAL TRIAL REG. NO.: NCT02201875.

Assessing ventilatory instability using the response to spontaneous sighs during sleep in preterm infants.

Periodic breathing (PB) is common in newborns and is an obvious manifestation of ventilatory control instability. However, many infants without PB may still have important underlying ventilatory control instabilities that go unnoticed using standard clinical monitoring. Methods to detect infants with "subclinical" ventilatory control instability are therefore required. The current study aimed to assess the degree of ventilatory control instability using simple bedside recordings in preterm infants. Respiratory inductance plethysmography (RIP) recordings were analyzed from ~20 minutes of quiet sleep in 20 preterm infants at 36 weeks post-menstrual age (median [range]: 36 [34-40]). The percentage time spent in PB was also calculated for each infant (%PB). Spontaneous sighs were identified and breath-by-breath measurements of (uncalibrated) ventilation were derived from RIP traces. Loop gain (LG, a measure of ventilatory control instability) was calculated by fitting a simple ventilatory control model (gain, time-constant, delay) to the post-sigh ventilatory pattern. For comparison, periodic inter-breath variability was also quantified using power spectral analysis (ventilatory oscillation magnitude index [VOMI]). %PB was strongly associated with LG (r2 = 0.77, p < 0.001) and moderately with the VOMI (r2 = 0.21, p = 0.047). LG (0.52 ± 0.05 vs. 0.30 ± 0.03; p = 0.0025) and the VOMI (-8.2 ± 1.1 dB vs. -11.8 ± 0.9 dB; p = 0.026) were both significantly higher in infants that displayed PB vs. those without. LG and VOMI determined from the ventilatory responses to spontaneous sighs can provide a practical approach to assessing ventilatory control instability in preterm infants. Such simple techniques may help identify infants at particular risk for ventilatory instabilities with concomitant hypoxemia and its associated consequences.

A method for determining exercise oscillatory ventilation in heart failure: Prognostic value and practical implications

BackgroundExercise oscillatory ventilation (EOV) has been shown to be a powerful prognostic marker in chronic heart failure (CHF). However, EOV is poorly defined, its measurement lacks standardization and it is underutilized in clinical practice. The purpose of this pilot study was to investigate the prognostic value of a modified definition of EOV in patients with CHF. MethodsEighty-nine CHF patients (56.5±8.4years) (64% NYHA class III-IV) underwent cardiopulmonary exercise testing. EOV was defined as meeting all the following criteria: (1) ≥3 consecutive cyclic fluctuations of ventilation during exercise; (2) average amplitude over 3 ventilatory oscillations ≥5L; and (3) an average length of three oscillatory cycles 40s to 140s. Adverse cardiac events were tracked during 28±19months follow up. Cox proportional hazard analysis was used to determine the association between cardiac events and EOV. ResultsForty-eight patients (54%) met all three criteria and were determined to have EOV. These patients exhibited significantly increased risk for adverse cardiac events [hazard ratio=2.2, 95% CI (1.2 to 4.1), p=0.011] compared to patients without EOV. After adjusting for age and established prognostic covariates (peak VO2 and VE/VCO2 slope), the modified EOV definition was the only significant variable in the multivariate model [hazard ratio=2.0, 95% CI (1.1 to 3.7), p=0.035]. ConclusionsThe proposed method for determining EOV was independently associated with increased risk for adverse cardiac events in CHF patients. While larger prospective studies are needed, this definition provides a relatively simple and more objective characterization of EOV, suggesting its potential application in clinical practice.

Effect of dead space on breathing stability at exercise in hypoxia

Recent studies have shown that normal subjects exhibit periodic breathing when submitted to concomitant environmental (hypoxia) and physiological (exercise) stresses. A mathematical model including mass balance equations confirmed the short period of ventilatory oscillations and pointed out an important role of dead space in the genesis of these phenomena. Ten healthy subjects performed mild exercise on a cycloergometer in different conditions: rest/exercise, normoxia/hypoxia and no added dead space/added dead space (aDS). Ventilatory oscillations (V˙E peak power) were augmented by exercise, hypoxia and aDS (P<0.001, P<0.001 and P<0.01, respectively) whereas V˙E period was only shortened by exercise (P<0.001), with an 11-s period. aDS also increased V˙E (P<0.001), tidal volume (VT, P<0.001), and slightly augmented PETCO2 (P<0.05) and the respiratory frequency (P<0.05). These results confirmed our previous model, showing an exacerbation of breathing instability by increasing dead space. This underlines opposite effects observed in heart failure patients and normal subjects, in which added dead space drastically reduced periodic breathing and sleep apneas. It also points out that alveolar ventilation remains very close to metabolic needs and is not affected by an added dead space.Clinical Trial reg. n°: NCT02201875

Increased circadian variations in chemoreflex sensitivity in chronic heart failure

Respiratory function follows a circadian pattern, and rhythmic changes in carotid body sensitivity to blood gases may contribute to these oscillations in ventilation. Recent studies have demonstrated that the isolated rat carotid body shows enhanced responses to hypoxic and hypercapnic stimulation in the presence of melatonin, a nocturnally released hormone. Carotid body dysfunction is known to occur in several pathological conditions, including chronic heart failure (CHF). CHF is characterized by tonic hyperactivity and exaggerated reactivity of the carotid bodies to hypoxia and hypercapnia. Thus, we've begun to examine circadian rhythms in chemoreflex breathing in CHF to determine if the already heightened hypoxic and hypercapnic responses in CHF are further augmented during the night. Male Sprague‐Dawley rats were divided into either control or CHF groups. Heart failure was induced via coronary ligation. Chemoreflex breathing was assessed during the day and then again 12 hours later during the night. Animals were exposed to room air (baseline), hypoxia (10 % O2) and hypercapnia (5 % CO2). Percent change in respiratory rate from day to night were similar between CHF (17.1 % increase) and control (16.9 % increase) rats when exposed to room air, but hypoxic and hypercapnic challenges induced large circadian differences in CHF (hypoxia: 20.9 % increase; hypercapnia: 23.9 % increase) but not in control (hypoxia: 8.2 % increase; hypercapnia: 13.9 % increase) rats. CHF rats also showed robust night time circadian differences in tidal volume when exposed to room air (31.6 % increase), hypoxia (27.9 % increase), and hypercapnia (43.8 %). In contrast, circadian variations in tidal volume were attenuated in control rats (room air: 11 % increase; hypoxia: 15.6 % increase; hypercapnia: 11.0 % increase). Minute ventilation showed similar differences between CHF and control rats with CHF significantly augmenting circadian variations. CHF rats showed a 53.1 % increase in minute ventilation during the night, and a 52.9 % increase and a 78.2 % increase in response to hypoxia and hypercapnia, respectively. Control rats, in contrast, showed only a 27.7 % increase in minute ventilation to room air, a 25.1 % increase in response to hypoxia, and a 26.9 % increase in response to hypercapnia. Therefore, the data suggest that circadian rhythms in ventilatory responses are amplified in CHF. Future research may directly assess the contribution of the carotid bodies to this phenomenon.

Development of a clinical applicable graphical user interface to automatically detect exercise oscillatory ventilation: The VOdEX-tool

BackgroundCardiopulmonary exercise testing (CPET) gained importance in the prognostic assessment of especially patients with heart failure (HF). A meaningful prognostic parameter for early mortality in HF is exercise oscillatory ventilation (EOV). This abnormal respiratory pattern is recognized by hypo- and hyperventilation during CPET. Up until now, assessment of EOV is mainly done upon visual agreement or manual calculation. The purpose of this research was to automate the interpretation of EOV so this prognostic parameter could be readily investigated during CPET. Methods and resultsPreliminary, four definitions describing the original characteristics of EOV, were selected and integrated in the “Ventilatory Oscillations during Exercise-tool” (VOdEX-tool), a graphical user interface that allows automate calculation of EOV. A Discrete Meyer Level 2 wavelet transformation appeared to be the optimal filter to apply on the collected breath-by-breath minute ventilation CPET data. Divers aspects of the definitions i.e. cycle length, amplitude, regularity and total duration of EOV were combined and calculated. The oscillations meeting the criteria were visualised. Filter methods and cut-off criteria were made adjustable for clinical application and research. The VOdEX-tool was connected to a database. ConclusionsThe VOdEX-tool provides the possibility to calculate EOV automatically and to present the clinician an overview of the presence of EOV at a glance. The computerized analysis of EOV can be made readily available in clinical practice by integrating the tool in the manufactures existing CPET software. The VOdEX-tool enhances assessment of EOV and therefore contributes to the estimation of prognosis in especially patients with HF.

Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = -0.68) oscillations (P < 0.001 for all, both groups combined). Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.

Pathogenesis of central and complex sleep apnoea.

Central sleep apnoea (CSA) - the temporary absence or diminution of ventilatory effort during sleep - is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne-Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep-wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar-inspired PCO2 difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.

Ventilatory oscillations at exercise in hypoxia: A mathematical model

We evaluated the mechanisms responsible for the instability of ventilation control system under simultaneous metabolic (exercise) and environmental (hypoxia) stresses, promoting the genesis of periodic breathing. A model following the main concepts of ventilatory control has been tested, including cardiovascular and respiratory parameters, characteristics of peripheral and central chemoreceptors, at mild exercise in hypoxia (FIO2=0.145). Interaction between O2 and CO2 sensing was introduced following three different modalities. A sensitivity and multivariate regression analyses closely matched with physiological data for magnitude and period of oscillations. Low FIO2 and long circulatory delay from lungs to peripheral chemoreceptors (DeltaTp) lengthen the period of oscillations, while high peripheral and central chemoresponses to O2 and CO2, low FIO2 and high DeltaTp increased their magnitude. Peripheral and central O2/CO2 interactions highlight the role of CO2 on peripheral gain to O2 and the contribution of peripheral afferences on central gain to CO2. Our model supports the key role of peripheral chemoreceptors in the genesis of ventilatory oscillations. Differences in the dynamics of central and peripheral components might be determinant for the system stability.

Effect of a cardiac rehabilitation program on exercise oscillatory ventilation in Japanese patients with heart failure.

Although exercise oscillatory ventilation has emerged as a potent independent risk factor for adverse prognosis in heart failure, it is not well known whether cardiac rehabilitation can improve oscillatory ventilation. In this study, we investigated the magnitude of oscillations in ventilation before and after cardiac rehabilitation in chronic heart failure patients with exercise oscillatory ventilation. Cardiac rehabilitation (5-month program) was performed in 26 patients with chronic heart failure who showed an oscillatory ventilation pattern during cardiopulmonary exercise testing (CPX). After the 5-month rehabilitation program was completed, the patients again underwent CPX. To determine the magnitude of oscillations in ventilation, the amplitude and cycle length of the oscillations were calculated and compared with several other parameters, including biomarkers that have established prognostic value in heart failure. At baseline before cardiac rehabilitation, both oscillation amplitude (R=0.625, P<0.01) and cycle length (R=0.469, P<0.05) were positively correlated with the slope of minute ventilation vs. carbon dioxide production. Plasma BNP levels were positively correlated with amplitude (R=0.615, P<0.01) but not cycle length (R=0.371). Cardiac rehabilitation decreased oscillation amplitude (P<0.01) but failed to change cycle length. The change in amplitude was positively correlated with the change in BNP levels (R=0.760, P<0.01). Multiple regression analysis showed that only the change in amplitude was an independent predictor of the change in BNP levels (R=0.717, P<0.01). A 5-month cardiac rehabilitation program improves exercise oscillatory ventilation in chronic heart failure patients by reducing the oscillation amplitude. This effect is associated with a reduction of plasma BNP levels, potentially contributing to an improvement of heart failure.

Heart rate variability during sleep at high altitude: effect of periodic breathing.

Heart rate variability (HRV) during sleep in normal subjects at high altitude shows a decrease in parasympathetic tone associated with an increase in the sympathetic one, which tends to be reversed with acclimatization. However, periodic breathing (PB) during sleep may influence this effect detected by HRV spectral analysis. The aim of our study was to investigate HRV during sleep periodic breathing (PB) at high altitude in normal subjects at two different times of acclimatization, i.e., two different levels of hypoxemia. Recordings of six healthy climbers (aged between 33 and 40 years), at sea level (SL) and at Everest North Base Camp (5180 m), during the first (BC1) and the tenth (BC2) overnight unattended polygraphy, were analyzed. PB was commonplace in all subjects at high altitude to a variable extent. At SL and at BC1 and BC2, HRV was evaluated overnight and separately during clear regular breathing (RB) and PB. A mean overnight beat-by-beat series interval (RR) reduction at acute environmental hypoxic exposure that resumed to SL values after 10-day sojourn was observed. This reduction was mostly due to RR during RB, while during PB, RR values were not different from SL. Higher peaks of tidal volume were associated with higher HRV. The present study shows that in healthy subjects, PB with central apneas increases the amplitude of RR oscillations, and these oscillations are tightly related to respiratory amplitude. Oxygenation does not influence this phenomenon. Therefore, oscillations in ventilation itself should be taken into account when investigating HRV.

Ventilatory oscillations at exercise: effects of hyperoxia, hypercapnia, and acetazolamide.

Periodic breathing has been found in patients with heart failure and sleep apneas, and in healthy subjects in hypoxia, during sleep and wakefulness, at rest and, recently, at exercise. To unravel the cardiorespiratory parameters liable to modulate the amplitude and period of ventilatory oscillations, 26 healthy subjects were tested under physiological (exercise) and environmental (hypoxia, hyperoxia, hyperoxic hypercapnia) stresses, and under acetazolamide (ACZ) treatment. A fast Fourier transform spectral analysis of breath-by-breath ventilation evidenced an increase in peak power under hypercapnia (vs. normoxia and hyperoxia, P < 0.001) and a decrease under ACZ (vs. placebo, P < 0.001), whereas it was not modified in hyperoxia. period was shortened by exercise in all conditions (vs. rest, P < 0.01) and by hypercapnia (vs. normoxia, P < 0.05) but remained unchanged under ACZ (vs. placebo). peak power was positively related to cardiac output () and in hyperoxia (P < 0.01), in hypercapnia (P < 0.001) and under ACZ (P < 0.001). period was negatively related to and in hyperoxia (P < 0.01 and P < 0.001, respectively), in hypercapnia (P < 0.05 and P < 0.01, respectively) and under ACZ (P < 0.05 and P < 0.01, respectively). Total respiratory cycle time was the main factor responsible for changes in period. In conclusion, exercise, hypoxia, and hypercapnia increase ventilatory oscillations by increasing and , whereas ACZ decreases ventilatory instability in part by a contrasting action on O2 and CO2 sensing. An intrinsic oscillator might modulate ventilation through a complex system where peripheral chemoreflex would play a key role.

Effect of Low Dose Dopamine on Ventilatory Stability in Healthy Adults

BackgroundIn models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV Vt) and breathing frequency (%CV Fb)] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine.MethodsHealthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR.ResultsDopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV Vt: saline = 21±2, dopamine = 30±4, p=0.01; %CV Fb: saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (Vt: r=0.15, p=0.54; Fb: r=0.33, p=0.16).ConclusionContrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease.Funding: NIH DK090541

Central and Peripheral Hemodynamic Adaptations During Cardiopulmonary Exercise Test in Heart Failure Patients With Exercise Periodic Breathing.

Some heart failure (HF) patients develop ventilatory oscillation which is composed of exercise periodic breathing (EPB) and sleep apnea. The ventilatory oscillation is associated with exercise intolerance. This study employed an integrated monitoring system to elucidate the way of central and peripheral hemodynamic adaption responding to exercise. This study recruited 157 HF patients to perform exercise testing using a bicycle ergometer. A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy (NIRS) was used to assess perfusion and O2 extraction in the frontal cerebral lobe (FC) and vastus lateralis muscle (VL) during exercise respectively. Furthermore, quality of life (QoL) was measured with the Short Form-36 (SF-36) and the Minnesota Living with Heart Failure questionnaires (MLHFQ). The patients were divided into an EPB group (n = 65) and a non-EPB group (n = 92) according to their ventilation patterns during testing. Compared to their non-EPB counterparts, the patients with EPB exhibited 1) impaired aerobic capacity with a smaller peak oxygen consumption (VO2peak) and oxygen uptake efficiency slopes; 2) impaired circulatory and ventilatory efficiency with relatively high cardiac output and ventilation per unit workload; 3) impaired ventilatory/hemodynamic adaptation in response to exercise with elevated deoxyhemoglobin levels in the FC region; and 4) impaired QoL with lower physical component scores on the SF-36 and higher scores on the MLHFQ. In conclusion, EPB may reduce circulatory-ventilatory-hemodynamic efficiency during exercise, thereby impairing functional capacity in patients with HF.

Traumatic brain injury: Increasing ICP attenuates respiratory modulations of cerebral blood flow velocity

In vitro experiments have suggested that respiratory oscillations (R waves) in cerebral blood flow velocity are reduced as soon as the intracranial pressure–volume reserve is exhausted. Could R waves hence, provide indication for increasing ICP after traumatic brain injury (TBI)? On days 1 to 4 after TBI, 22 sedated and ventilated patients were monitored for intracranial pressure (ICP) in brain parenchyma, Doppler flow velocity (FV) in the middle cerebral arteries (MCA), and arterial blood pressure (ABP). The analysis included the transfer function gains of R waves (respiratory rate of 9–20 cpm) between ABP and FV (GainFv) as well as between ABP and ICP (GainICP). Also, the index of the intracranial pressure–volume reserve (RAP) was calculated. The rise of ICP (day 1: 14.10 ± 6.22 mmHg; to day 4: 29.69 ± 12.35 mmHg) and increase of RAP (day 1: 0.72 ± 0.22; to day 4: 0.85 ± 0.18) were accompanied by a decrease of GainFv (right MCA; day 1: 1.78 ± 1.0; day 4: 0.84 ± 0.47; left MCA day 1: 1.74 ± 1.10; day 4: 0.86 ± 0.46; p < 0.01) but no significant change in GainICP day 1: 1.50 ± 0.77; day 4: 1.15 ± 0.47; p = 0.07). The transfer of ventilatory oscillations to the intracerebral arteries after TBI appears to be dampened by increasing ICP and exhausted intracranial pressure–volume reserves. Results warrant prospective studies of whether respiratory waves in cerebral blood flow velocity may anticipate intracranial hypertension non-invasively.