Respiratory Entrainment Research Articles

Respiratory entrainment related reverse triggering in mechanically ventilated children

BackgroundThe underlying pathophysiological pathways how reverse triggering is being caused are not fully understood. Respiratory entrainment may be one of these mechanisms, but both terms are used interchangeably. We sought to characterize reverse triggering and the relationship with respiratory entrainment among mechanically ventilated children with and without acute lung injury.MethodsWe performed a secondary phyiology analysis of two previously published data sets of invasively mechanically ventilated children < 18 years with and without lung injury mechanically ventilated in a continuous or intermittent mandatory ventilation mode. Ventilator waveforms, electrical activity of the diaphragm measured with surface electromyography and oesophageal tracings were analyzed for entrained and non-entrained reverse triggered breaths.ResultsIn total 102 measurements (3110 min) from 67 patients (median age 4.9 [1.8 ; 19,1] months) were analyzed. Entrained RT was identified in 12 (12%) and non-entrained RT in 39 (38%) recordings. Breathing variability for entrained RT breaths was lower compared to non-entrained RT breaths. We did not observe breath stacking during entrained RT. Double triggering often occurred during non-entrained RT and led to an increased tidal volume. Patients with respiratory entrainment related RT had a shorter duration of MV and length of PICU stay.ConclusionsReverse triggering is not one entity but a clinical spectrum with different mechanisms and consequences.Trial registrationNot applicable.

Respiratory entrainment of the locus coeruleus modulates arousal level to avoid physical risks from external vibration

Slow rocking chairs can easily put people to sleep, while violent shaking, such as during earthquakes, may lead to rapid awakening. However, the influence of external body vibrations on arousal remains unclear. Herein, a computational model of a locus coeruleus (LC)-norepinephrine (NE) system and cardio-respiratory system were used to show that respiratory entrainment of the LC modulates arousal levels, which is an adaptation to avoid physical risks from external vibration. External vibrations of sinusoidal waves with different frequencies ranging from 0.1 to 20 [Hz] were applied to the LC based on the results of previous studies. We found that respiratory entrainment of the LC decreased the breathing rate (BR) and heart rate (HR) to maintain the HR within its normal range. Furthermore, 1:1 phase locking enhanced arousal level while phase-amplitude coupling decreased it for larger vibration stimuli. These findings suggest that respiratory entrainment of the LC might automatically modulate cardio-respiratory system homeostasis and arousal levels for performance readiness (fight/flight or freeze) to avoid physical risks from larger external vibrations.

Locomotor-Respiratory Entrainment upon Phonated Compared to Spontaneous Breathing during Submaximal Exercise.

Recently, increased attention to breathing techniques during exercise has addressed the need for more in-depth study of the ergogenic effects of breathing manipulation. The physiological effects of phonation, as a potential breathing tool, have not yet been studied. Thus, the aim of this study was to investigate the respiratory, metabolic and hemodynamic responses of phonated exhalation and its impact on locomotor-respiratory entrainment in young healthy adults during moderate exercise. Twenty-six young, healthy participants were subjected to peak expiratory flow (PEF) measurements and a moderate steady cycling protocol based on three different breathing patterns (BrP): spontaneous breathing (BrP1), phonated breathing pronouncing "h" (BrP2) and phonated breathing pronouncing "ss" (BrP3). The heart rate, arterial blood pressure, oxygen consumption, CO2 production, respiratory rate (RR), tidal volume (VT), respiratory exchange ratio and ventilatory equivalents for both important respiratory gasses (eqO2 and eqCO2) were measured (Cosmed, Italy) simultaneously during a short period of moderate stationary cycling at a predefined cadence. To evaluate the psychological outcomes, the rate of perceived exertion (RPE) was recorded after each cycling protocol. The locomotor-respiratory frequency coupling was calculated at each BrP, and dominant coupling was determined. Phonation gradually decreased the PEF (388 ± 54 L/min at BrP2 and 234 ± 54 L/min at BrP3 compared to 455 ± 42 L/min upon spontaneous breathing) and affected the RR (18.8 ± 5.0 min-1 at BrP2 compared to 22.6 ± 5.5 min-1 at BrP1 and 21.3 ± 7.2 min-1 at BrP3), VT (2.33 ± 0.53 L at BrP2 compared to 1.86 ± 0.46 L at BrP1 and 2.00 ± 0.45 L at BrP3), dominant locomotor-respiratory coupling (1:4 at BrP2 compared to 1:3 at BrP1 and BrP2) and RPE (10.27 ± 2.00 at BrP1 compared to 11.95 ± 1.79 at BrP1 and 11.95 ± 1.01 at BrP3) but not any other respiratory, metabolic or hemodynamic measures of the healthy adults during moderate cycling. The ventilatory efficiency was shown to improve upon dominant locomotor-respiratory coupling, regardless of BrP (eqO2 = 21.8 ± 2.2 and eqCO2 = 24.0 ± 1.9), compared to the other entrainment coupling regimes (25.3 ± 1.9, 27.3 ± 1.7) and no entrainment (24.8 ± 1.5, 26.5 ± 1.3), respectively. No interaction between phonated breathing and entrainment was observed during moderate cycling. We showed, for the first time, that phonation can be used as a simple tool to manipulate expiratory flow. Furthermore, our results indicated that in young healthy adults, entrainment, rather than expiratory resistance, preferentially affected ergogenic enhancement upon moderate stationary cycling. It can only be speculated that phonation would be a good strategy to increase exercise tolerance among COPD patients or to boost the respiratory efficiency of healthy people at higher exercise loads.

Effects of breathing pathway and musical features on the processing of music induced emotions

The effects of the breathing pathway (nasal vs. oral) on the processing of emotions are not yet well-understood although there is evidence of respiratory entrainment of local field potential activity in human limbic networks and the importance of nasal airflow in shaping this entrainment. In this study, we compared the degree of various emotions triggered by different pieces of music during oral breathing (OB) and nasal breathing (NB). In addition, correlation of different musical features with emotions was investigated. Our results showed that during NB, subjects found songs more relaxing (p = 0.00013) and happier (p = 0.069), and they felt more arousal states from songs (p = 0.036) when compared to the same songs during OB, while during OB subjects' average rating for more negative emotions was higher when compared to NB (NS). During both OB and NB, we observed that the consonance degree of songs had significantly high positive correlations with positive emotions (valence: p < 0.01, happy: p < 0.05, relaxed: NB: p < 0.05, OB: NS) and significantly high negative correlations with negative emotions (angry: p < 0.001, fear: p < 0.05, frustrated: NB: p < 0.001, OB: NS), while the higher complexity rate of songs had a positive correlation with negative emotions (fear: p < 0.01, sad < 0.05, frustrated: p < 0.05, angry: OB: p < 0.05, NB: NS) and negative correlations with positive emotions (happy: p < 0.05, relaxed: p < 0.05, valence: p < 0.05).

Respiratory entrainment of units in the mouse parietal cortex depends on vigilance state

Synchronous oscillations are essential for coordinated activity in neuronal networks and, hence, for behavior and cognition. While most network oscillations are generated within the central nervous system, recent evidence shows that rhythmic body processes strongly influence activity patterns throughout the brain. A major factor is respiration (Resp), which entrains multiple brain regions at the mesoscopic (local field potential) and single-cell levels. However, it is largely unknown how such Resp-driven rhythms interact or compete with internal brain oscillations, especially those with similar frequency domains. In mice, Resp and theta (θ) oscillations have overlapping frequencies and co-occur in various brain regions. Here, we investigated the effects of Resp and θ on neuronal discharges in the mouse parietal cortex during four behavioral states which either show prominent θ (REM sleep and active waking (AW)) or lack significant θ (NREM sleep and waking immobility (WI)). We report a pronounced state-dependence of spike modulation by both rhythms. During REM sleep, θ effects on unit discharges dominate, while during AW, Resp has a larger influence, despite the concomitant presence of θ oscillations. In most states, unit modulation by θ or Resp increases with mean firing rate. The preferred timing of Resp-entrained discharges (inspiration versus expiration) varies between states, indicating state-specific and different underlying mechanisms. Our findings show that neurons in an associative cortex area are differentially and state-dependently modulated by two fundamentally different processes: brain-endogenous θ oscillations and rhythmic somatic feedback signals from Resp.

Identifying asynchronies: Reverse trigger

A variety of asynchronies between the patient’s respiratory efforts and the programed ventilatory settings have been categorized. Reverse trigger is described as an inspiratory effort occurring after a ventilator-initiated breath and may represent a form of respiratory entrainment. In other words, the ventilator triggers muscular efforts. It often appears in a repetitive, stereotyped pattern. It occurs often in mechanically ventilated patients at risk of injury, might be underrecognized at the bedside and may has adverse effects on oxygenation and ventilation, as well as potentially increasing lung injury. We can phenotype these events using the Campbell diagram (pressure–volume loop) by differentiating their occurrence during inspiration and expiration. Reverse trigger with sufficient inspiratory effort and duration can result in an additional ventilator-delivered stacked breath, which can cause large tidal volumes and increased transpulmonary pressure. Keywords: Asynchrony, ventilator, reverse trigger, entrainment, lung injury, phenotype.

Reverse Trigger Phenotypes in Acute Respiratory Distress Syndrome.

Rationale: Reverse triggering is an underexplored form of dyssynchrony with important clinical implications in patients with acute respiratory distress syndrome.Objectives: This retrospective study identified reverse trigger phenotypes and characterized their impacts on Vt and transpulmonary pressure.Methods: Fifty-five patients with acute respiratory distress syndrome on pressure-regulated ventilator modes were included. Four phenotypes of reverse triggering with and without breath stacking and their impact on lung inflation and deflation were investigated.Measurements and Main Results: Inflation volumes, respiratory muscle pressure generation, and transpulmonary pressures were determined and phenotypes differentiated using Campbell diagrams of respiratory activity. Reverse triggering was detected in 25 patients, 15 with associated breath stacking, and 13 with stable reverse triggering consistent with respiratory entrainment. Phenotypes were associated with variable levels of inspiratory effort (mean 4-10 cm H2O per phenotype). Early reverse triggering with early expiratory relaxation increased Vts (88 [64-113] ml) and inspiratory transpulmonary pressures (3 [2-3] cm H2O) compared with passive breaths. Early reverse triggering with delayed expiratory relaxation increased Vts (128 [86-170] ml) and increased inspiratory and mean-expiratory transpulmonary pressure (7 [5-9] cm H2O and 5 [4-6] cm H2O). Mid-cycle reverse triggering (initiation during inflation and maximal effort during deflation) increased Vt (51 [38-64] ml), increased inspiratory and mean-expiratory transpulmonary pressure (3 [2-4] cm H2O and 3 [2-3] cm H2O), and caused incomplete exhalation. Late reverse triggering (occurring exclusively during exhalation) increased mean expiratory transpulmonary pressure (2 [1-2] cm H2O) and caused incomplete exhalation. Breath stacking resulted in large delivered volumes (176 [155-197] ml).Conclusions: Reverse triggering causes variable physiological effects, depending on the phenotype. Differentiation of phenotype effects may be important to understand the clinical impacts of these events.

PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate.

Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitation in vivo and in situ in rats, as well as neuronal tracing, we demonstrate that preBötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity whilst excitatory preBötC neurons modulate sympathetic vasomotor neuron activity, generating heart rate and blood pressure oscillations in phase with respiration. Our data reveal yet more functions entrained to the activity of the preBötC, with a role in generating cardiorespiratory oscillations. The findings have implications for cardiovascular pathologies, such as hypertension and heart failure, where respiratory entrainment of heart rate is diminished and respiratory entrainment of blood pressure exaggerated.

Electrocortical high frequency activity and respiratory entrainment in 6-hydroxydopamine model of Parkinson’s disease

Parkinson’s disease is characterized by motor symptoms (akinesia, rigidity, etc.), which are associated with the degeneration of the dopaminergic neurons of the midbrain. In addition, olfactory impairment that usually develops before the detection of motor deficits, is detected in 90% of Parkinsonian patients.Recent studies in mammals, have shown that slow cortical potentials phase-lock with nasal respiration. In several cortical areas, gamma synchronization of the electrographic activity is also coupled to respiration, suggesting than nasal respiratory entrainment could have a role in the processing of olfactory information.In the present study, we evaluate the role of midbrain dopaminergic neurons, in the modulation of the electrocorticogram activity and its respiratory entrainment during wakefulness and sleep. For this purpose, we performed a unilateral lesion of dopaminergic neurons of the substantia nigra pars compacta of the rat, with 6-hydroxydopamine.An increase in beta (20–35 Hz) together with a decrease in gamma power (60–95 Hz) in the motor cortex ipsilateral to the lesion was observed during wakefulness. These results correlated with the degree of motor alterations and dopamine measured at the striatum. Moreover, we found a decline in gamma coherence between the ipsilateral olfactory bulb and motor cortex. Also, at the olfactory bulb we noticed an increase in respiratory-gamma cross-frequency coupling after the lesion, while at the motor cortex, a decrease in respiratory potential entrainment of gamma activity was observed. Interestingly, we did not observe any significant modification either during Non-REM or REM sleep. These waking dysrhythmias may play a role both in the anosmia and motor deficits present in Parkinson disease.

Breathing Coordinates Limbic Network Dynamics Underlying Memory Consolidation

The coordinated activity between remote brain regions underlies cognition and memory function. Althoughneuronal oscillations have been proposed as a mechanistic substrate for the coordination of information trans-fer and memory consolidation during sleep, little is known about the mechanisms that support the widespreadsynchronization of brain regions and the relationship of neuronal dynamics with other bodily rhythms, such asbreathing. Here we address this question using large-scale recordings from a number of structures, includingthe medial prefrontal cortex, hippocampus, thalamus, amygdala and nucleus accumbens in mice. We identifya dual mechanism of respiratory entrainment, in the form of an intracerebral corollary discharge that actsjointly with an olfactory reafference to coordinate limbic network dynamics, such as hippocampal ripplesand cortical UP and DOWN states, involved in memory consolidation. These results highlight breathing, aperennial rhythmic input to the brain, as an oscillatory scaffold for the functional coordination of the limbiccircuit, enabling the segregation and integration of information flow across neuronal network

Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment of local field potential activity in human piriform cortex, amygdala, and hippocampus. These effects diminished when breathing was diverted to the mouth, highlighting the importance of nasal airflow for generating respiratory oscillations. Finally, behavioral data in healthy subjects suggest that breathing phase systematically influences cognitive tasks related to amygdala and hippocampal functions.

Neuromechanical coupling during mechanical ventilation: reverse-triggering vs others forms of asynchrony

The term “respiratory entrainment” refers to of coupling patterns between the rhythm neuronal and mechanical of ventilator to achieve satisfactory synchrony. Respiratory effort stimulated by the mechanical inspiratory flow or reverse trigger (RT), has been recently demonstrated [1]. This asynchrony is difficult to showed without additional signals as esophageal pressure or electrodiaphragmatic signal.

Lack of respiratory coupling with neocortical and hippocampal slow oscillations.

Previous work has demonstrated an influence of the respiratory cycle and, more specifically, rhythmic nasal inspiration for the entrainment of slow oscillations in olfactory cortex during ketamine-xylazine anesthesia. This respiratory entrainment has been suggested to occur more broadly during slow-wave states (including sleep) throughout the forebrain, in particular in the frontal and parahippocampal and hippocampal cortices. Using multisite local field potential recording methods and spectral coherence analysis in the rat, we show here that no such broad forebrain coupling takes place during slow-wave activity patterns under either ketamine-xylazine or urethane anesthesia and, furthermore, that it also does not arise during natural slow-wave sleep. Therefore, respiratory-related oscillatory neural activities are likely limited to primary olfactory structures during slow-wave forebrain states.

Mechanical Ventilation-Induced Reverse-Triggered Breaths: A Frequently Unrecognized Form of Neuromechanical Coupling

Diaphragmatic muscle contractions triggered by ventilator insuffl ations constitute a form of patient-ventilator interaction referred to as “entrainment,” which is usually unrecognized in critically ill patients. Our objective was to review tracings, which also included muscular activity, obtained in sedated patients who were mechanically ventilated to describe the entrainment events and their characteristics. The term “reverse triggering” was adopted to describe the ventilator-triggered muscular efforts. Over a 3-month period, recordings containing fl ow, airway pressure, and esophageal pressure or electrical activity of the diaphragm were reviewed. Recordings were obtained from a series of consecutive heavily sedated patients ventilated with an assist-control mode of ventilation for ARDS. The duration of entrainment, the entrainment ratio, and the phase difference elapsing between the commencement of the ventilator and neural breaths were evaluated. The tracings of eight consecutive patients with ARDS were reviewed; they all showed different forms of entrainment. Reverse triggering occurred over a portion varying from 12% to 100% of the total recording period. Seven patients had a 1:1 mechanical insuffl ation to diaphragmatic contractions ratio; this coexisted with a 1:2 ratio in one patient and 1:2 and 1:3 ratios in another. One patient exhibited only a 1:2 ratio. The frequency of reverse-triggered breaths had a mean coeffi cient of variability of , 5%, very close to the variability of mechanical breaths. To our knowledge, this is the fi rst time that the presence of respiratory entrainment in sedated, critically ill adult patients who are mechanically ventilated has been documented. The “reverse-triggered” breaths illustrate a new form of neuromechanical coupling with potentially important clinical consequences.

Decreased Hering-Breuer input-output entrainment in a mouse model of Rett syndrome.

Rett syndrome, a severe X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (Mecp2), is associated with a highly irregular respiratory pattern including severe upper-airway dysfunction. Recent work suggests that hyperexcitability of the Hering–Breuer reflex (HBR) pathway contributes to respiratory dysrhythmia in Mecp2 mutant mice. To assess how enhanced HBR input impacts respiratory entrainment by sensory afferents in closed-loop in vivo-like conditions, we investigated the input (vagal stimulus trains) – output (phrenic bursting) entrainment via the HBR in wild-type and MeCP2-deficient mice. Using the in situ perfused brainstem preparation, which maintains an intact pontomedullary axis capable of generating an in vivo-like respiratory rhythm in the absence of the HBR, we mimicked the HBR feedback input by stimulating the vagus nerve (at threshold current, 0.5 ms pulse duration, 75 Hz pulse frequency, 100 ms train duration) at an inter-burst frequency matching that of the intrinsic oscillation of the inspiratory motor output of each preparation. Using this approach, we observed significant input-output entrainment in wild-type mice as measured by the maximum of the cross-correlation function, the peak of the instantaneous relative phase distribution, and the mutual information of the instantaneous phases. This entrainment was associated with a reduction in inspiratory duration during feedback stimulation. In contrast, the strength of input-output entrainment was significantly weaker in Mecp2−/+ mice. However, Mecp2−/+ mice also had a reduced inspiratory duration during stimulation, indicating that reflex behavior in the HBR pathway was intact. Together, these observations suggest that the respiratory network compensates for enhanced sensitivity of HBR inputs by reducing HBR input-output entrainment.

Auto-Entrainment Risk Assessment in Heart Failure

Risk assessment studies use a suite of nominally independent noninvasive heart rate metrics, often brought together in a statistical model to compute a risk score. The ongoing need to noninvasively identify the higher risk patients requiring more invasive investigations/interventions drives the search for better noninvasive predictive metrics, with increased sensitivity. Many varieties of autoregulatory malfunction occur within the cardiovascular system; thus, it seems a daunting challenge to build predictive models that account for all potential modes of failure. Auto-entrainment (AE) methodology was developed to help address this challenge. AE methodology tests intrinsic capacity to maintain a stable and coherent oscillatory dynamic of autoregulatory control via respiratory entrainment of the blood pressure and heart period. Using cardiovascular death (n=18) at follow-up (1.5 years) as the end point, analysis of AE measurements from 148 patients with heart failure revealed 2 parameters significantly predictive of death. Using logistic regression, the magnitude of systolic pulsus alternans measured during AE had predictive sensitivity of 90% (confidence interval, 62%-100% and specificity of 62% (confidence interval, 49%-74%). The capacity to maintain a stable oscillatory dynamic was measured by the fraction of the total RR-interval spectral power contained within the AE-band. This capacity had predictive sensitivity of 73% (confidence interval, 47%-99%) and specificity of 55% (confidence interval, 43%-66%). AE methodology provides a noninvasive platform to assess the integrity of cardiovascular autoregulatory control systems for risk assessment in heart failure patients.

Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats.

The retrotrapezoid nucleus contains Phox2b-expressing glutamatergic neurons (RTN-Phox2b neurons) that regulate breathing in a CO₂-dependent manner. Here we use channelrhodopsin-based optogenetics to explore how these neurons control breathing in conscious and anesthetized adult rats. Respiratory entrainment (pacing) of breathing frequency (fR) was produced over 57% (anesthetized) and 28% (conscious) of the natural frequency range by burst activation of RTN-Phox2b neurons (3-8 × 0.5-20 ms pulses at 20 Hz). In conscious rats, pacing under normocapnic conditions increased tidal volume (V(T)) and each inspiration was preceded by active expiration, denoting abdominal muscle contraction. During long-term pacing V(T) returned to prestimulation levels, suggesting that central chemoreceptors such as RTN-Phox2b neurons regulate V(T) partly independently of their effect on fR. Randomly applied light trains reset the respiratory rhythm and shortened the expiratory phase when the stimulus coincided with late-inspiration or early-expiration. Importantly, continuous (20 Hz) photostimulation of the RTN-Phox2b neurons and a saturating CO₂ concentration produced similar effects on breathing that were much larger than those elicited by phasic RTN stimulation. In sum, consistent with their anatomical projections, RTN-Phox2b neurons regulate lung ventilation by controlling breathing frequency, inspiration, and active expiration. Adult RTN-Phox2b neurons can entrain the respiratory rhythm if their discharge is artificially synchronized, but continuous activation of these neurons is much more effective at increasing lung ventilation. These results suggest that RTN-Phox2b neurons are no longer rhythmogenic in adulthood and that their average discharge rate may be far more important than their discharge pattern in driving lung ventilation.

The Reliability of VO2peakDetermination in Healthy Females during an Incremental Arm Ergometry Test

This study examined the reliability of an incremental arm ergometry (AE) protocol during peak aerobic power (VO2(peak)) determination in healthy females. Fifteen females completed two incremental AE tests to exhaustion, seven to eleven days apart, using a mechanically braked arm ergometer. The initial work rate was 16W and increased by 16W every two minutes until exhaustion. Significant differences between tests were determined by repeated measures ANOVA, and paired t-tests or Wilcoxon signed-rank tests, where appropriate. Reliability was determined by intraclass correlation coefficients (ICC), typical error, coefficient of variation (CV) and measurement bias/ratio and 95% limits of agreement (LOA). Peak cardio-respiratory responses were similar between tests, except for tidal volume (1.95 +/-0.47 vs. 1.81 +/- 0.41 L, P<0.05). Reliability for peak variables was moderate to high (ICC=0.659-0.941; CV< or =10%) while LOA were considerable for most variables including VO2(peak) (LOA=0.57 L.min(-1)). Similar peak cardio-respiratory responses, low CV and moderate-high ICC confirmed the reliability of the current incremental AE protocol to be similar to that of prior reported protocols for VO2(peak) determination. Substantial within-participant variability (LOA) for respiratory rate and tidal volume was common during the AE protocol and possibly reflects the influence of respiratory entrainment on reliability that requires further investigation.

Passive Motion of the Extremities Modifies Alveolar Ventilation during Sleep in Patients with Congenital Central Hypoventilation Syndrome

Passive motion of lower extremities (PMLE) elicits significant increases in alveolar ventilation (V A) in awake children with congenital central hypoventilation syndrome (CCHS), who have absent or near absent ventilatory responses to hypercapnia. We hypothesized that PMLE would improve V A during non-rapid eye movement (NREM) sleep. To study this, six patients with CCHS (0.2 to 7 yr of age) were disconnected from mechanical ventilatory support during Stage III-IV NREM, and their feet were passively moved at the ankle, either manually or with a motorized device strapped to their feet at 40 to 50 strokes/min. Holding of the feet without motion served as control (C). From a total of 74 successful trials not associated with sleep state changes, PET(CO(2)) decreased from 58.9 +/- 3.5 to 40.9 +/- 2.6 mm Hg with PMLE (n = 58; p < 0.001), whereas end-tidal carbon dioxide (PET(CO(2))) increased in C (n = 16; 58.8 +/- 3.1 to 60.3 +/- 3.7 mm Hg; PMLE versus C: p < 0.001). PMLE increased respiratory frequency from 10.2 +/- 1.9 to 21.2 +/- 2.7 breaths/min (p < 0.0001). We conclude that PMLE during NREM increases V A possibly via activation of mechanoreceptor-afferent pathways rather than by respiratory entrainment. We speculate that such effect may provide future noninvasive ventilatory support strategies in patients with CCHS and mild phenotypic expression of their disease.

Use of the frequency-tracking locus in estimating the degree of respiratory entrainment in preterm infants

In order to define the complex interactions between external stimuli and nonlinear physiological systems, a technique (the frequency-tracking locus, FTL) was devised that describes the cycle-by-cycle changes in phase angle and amplitude between 2 signals. Qualitative assessment of the nature of interactions between the signals can be made by examining the FTL Quantitation of the extent of entrainment of the spontaneous physiological rhythm is possible after deriving a numerical index (the path-length index, PLI) describing the departure of the system from a fully entrained state. The FTL was applied to the study of interactions between spontaneous respiratory effort and mechanical inflation in preterm newborn babies undergoing mechanical ventilation. Stable and unstable states of 1:1 interaction were noted while integer-ratio relationships were seen at low rates of mechanical ventilation. Stable states of entrainment corresponded to a PLI value near unity, and the value of PLI increased rapidly as interaction became unstable. The FTL may be used to describe complex interactions in physiological systems, and may be used as a guide to baby-ventilator matching during mechanical ventilation of the newborn.