Christian Straus

Neurally Adjusted Ventilatory Assist Increases Respiratory Variability and Complexity in Acute Respiratory Failure

Background:Neurally adjusted ventilatory assist (NAVA) is a partial ventilatory support mode where positive pressure is provided in relation to diaphragmatic electrical activity (EAdi). Central inspiratory activity is normally not monotonous, but it demonstrates short-term variability and complexity. The authors reasoned that NAVA should produce a more “natural” or variable breathing pattern than other modes. This study compared respiratory variability and complexity during pressure support ventilation (PSV) and NAVA. Methods:Flow and EAdi were recorded during routine PSV (tidal volume ∼6–8 ml/kg) and four NAVA levels (1–4 cm H2O/&mgr;VEAdi) in 12 intubated patients. Breath-by-breath variability of flow and EAdi-related variables was quantified by the coefficient of variation (CV) and autocorrelation analysis. Complexity of flow and EAdi was described using noise titration, largest Lyapunov exponent, Kolmogorov-Sinai entropy, and three-dimensional phase portraits. Results:Switching from PSV to NAVA increased the CV and decreased the autocorrelation for most flow-related variables in a dose-dependent manner (P < 0.05, partial &eegr;2 for the CV of mean inspiratory flow 0.642). The changes were less marked for EAdi. A positive noise limit was consistently found for flow and EAdi. Largest Lyapunov exponent and Kolmogorov-Sinai entropy for flow were greater during NAVA than PSV and increased with NAVA level (P < 0.05, partial &eegr;2 0.334 and 0.312, respectively). Largest Lyapunov exponent and Kolmogorov-Sinai entropy for EAdi were not influenced by ventilator mode. Conclusions:Compared with PSV, NAVA increases the breathing pattern variability and complexity of flow, whereas the complexity of EAdi is unchanged. Whether this improves clinical outcomes remains to be determined.

Evidence that ventilatory rhythmogenesis in the frog involves two distinct neuronal oscillators

In Rana catesbeiana the upper airways are used for two distinct yet highly coordinated ventilatory behaviours: buccal ventilation and lung inflation cycles. How these behaviours are generated and coordinated is unknown. The purpose of this study was to identify putative rhythmogenic brainstem loci involved in these ventilatory behaviours. We surveyed the isolated postmetamorphic brainstem to determine sites where local depolarization, produced by microinjecting the non‐NMDA glutamate receptor agonist, AMPA, augmented the ventilatory motor patterns. Two sites were identified: a caudal site, at the level of cranial nerve (CN) X, where AMPA injections caused increased buccal burst frequency but abolished lung bursts, and a rostral site, between the levels of CN VIII and IX, where injections increased the frequency of both types of ventilatory bursts. These two sites were further examined using GABA microinjections to locally inhibit cells. GABA injected into the caudal site suppressed the buccal rhythm but the lung rhythm continued, albeit at a different frequency. When GABA was injected into the rostral site the lung bursts were abolished but the buccal rhythm continued. When the two sites were physically separated by transection, both rostral and caudal brainstem sections were capable of rhythmogenesis. The results suggest the respiratory network within the amphibian brainstem is composed of at least two distinct but interacting oscillators, the buccal and lung oscillators. These putative oscillators may provide a promising experimental model for studying coupled oscillators in vertebrates.

Electroencephalographic evidence for pre-motor cortex activation during inspiratory loading in humans

Faced with mechanical inspiratory loading, awake animals and anaesthetized humans develop alveolar hypoventilation, whereas awake humans do defend ventilation. This points to a suprapontine compensatory mechanism instead of or in addition to the ‘traditional’ brainstem respiratory regulation. This study assesses the role of the cortical pre‐motor representation of inspiratory muscles in this behaviour. Ten healthy subjects (age 19–34 years, three men) were studied during quiet breathing, CO2‐stimulated breathing, inspiratory resistive loading, inspiratory threshold loading, and during self‐paced voluntary sniffs. Pre‐triggered ensemble averaging of Cz EEG epochs starting 2.5 s before the onset of inspiration was used to look for pre‐motor activity. Pre‐motor potentials were present during voluntary sniffs in all subjects (average latency (±s.d.): 1325 ± 521 ms), but also during inspiratory threshold loading (1427 ± 537 ms) and during inspiratory resistive loading (1109 ± 465 ms). Pre‐motor potentials were systematically followed by motor potentials during inspiratory loading. Pre‐motor potentials were lacking during quiet breathing (except in one case) and during CO2‐stimulated breathing (except in two cases). The same pattern was observed during repeated experiments at an interval of several weeks in a subset of three subjects. The behavioural component of inspiratory loading compensation in awake humans could thus depend on higher cortical motor areas. Demonstrating a similar role of the cerebral cortex in the compensation of disease‐related inspiratory loads (e.g. asthma attacks) would have important pathophysiological implications: it could for example contribute to explain why sleep is both altered and deleterious in such situations.

Chaotic dynamics of resting ventilatory flow in humans assessed through noise titration

The mammalian ventilatory behaviour exhibits nonlinear dynamics as reflected by certain nonlinearity or complexity indicators (e.g. correlation dimension, approximate entropy, Lyapunov exponents, etc.) but this is not sufficient to determine its possible chaotic nature. To address this, we applied the noise titration technique, previously shown to discern and quantify chaos in short and noisy time series, to ventilatory flow recordings obtained in quietly breathing normal humans. Nine subjects (8 men and 1 woman, 24-42 years) were studied during 15-min epochs of ventilatory steady-state (10.1+/-3.0 breaths/min, tidal volume 0.63+/-0.2 L). Noise titration applied to the unfiltered signals subsampled at 5 Hz detected nonlinearity in all cases (noise limit 20.2+/-12.5%). Noise limit values were weakly correlated to the correlation dimension and the largest Lyapunov exponent of the signals. This study shows that the noise titration approach evidences a chaotic dimension to the behavior of ventilatory flow over time in normal humans during tidal breathing.

Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies

Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.

Assessment of the voluntary activation of the diaphragm using cervical and cortical magnetic stimulation.

The twitch occlusion technique is a promising tool for use in accessing central drive to the diaphragm and determining maximal transdiaphragmatic pressure (Pdi) from submaximal efforts. It clinical use is limited by difficulties inherent to bilateral electrical stimulation (BES) of the phrenic nerves. This study was designed to revisit the technique using cervical magnetic stimulation (CMS). In addition, the effects of a voluntary contraction on diaphragm response to magnetic stimulation of the cortex (CxMS) were studied. Seven volunteers aged 23-33 yrs were studied. Pdi was determined at relaxed functional residual capacity (FRC) in response to BES (Pdi,P-ES) and CMS (Pdi,p-CMS), and the effects of an increasing voluntary contraction (Pdi, vol) were assessed, The same procedure was applied to CxMS. Pdi,p-CMS at relaxed FRC was 27.5 +/- 2.2 cmH2O (mean+/-SEM), about 20% higher than Pdi,p-ES, and reported previously. Pd,p-CMS linearly decreased with Pdi, vol, and six out of seven subjects were capable of producing voluntary contractions sufficient to extinguish the twitch. More complex patterns were observed with CxMS. Cervical magnetic stimulation provides diaphragmatic twitch occlusion data very similar to bilateral electrical phrenic stimulation. Magnetic stimulation, be it cervical or cortical, could probably be helpful for the assessment of central and peripheral mechanisms of diaphragmatic dysfunction in the clinical setting.

Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome.

Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms.

Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis

Abstract In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning (n = 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p = 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes.

Source of human ventilatory chaos: lessons from switching controlled mechanical ventilation to inspiratory pressure support in critically ill patients.

Ventilatory flow measured at the airway opening in humans exhibits a complex dynamics that has the features of chaos. Currently available data point to a neural origin of this feature, but the role of respiratory mechanics has not been specifically assessed. In this aim, we studied 17 critically ill mechanically ventilated patients during a switch form an entirely machine-controlled assistance mode (assist-controlled ventilation ACV) to a patient-driven mode (inspiratory pressure support IPS). Breath-by-breath respiratory variability was assessed with the coefficient of variation of tidal volume, total cycle time, inspiratory time, expiratory time, mean inspiratory flow, duty cycle. The detection of chaos was performed with the noise titration technique. When present, chaos was characterized with numerical indexes (correlation dimension, irregularity; largest Lyapunov exponent, sensitivity to initial conditions). Expectedly, the coefficients of variations of the respiratory variables were higher during IPS than during ACV. During ACV, noise titration failed to detect nonlinearities in 12 patients who did not exhibit signs of spontaneous respiratory activity. This indicates that the mechanical properties of the respiratory system were not sufficient to produce ventilatory chaos in the presence of a nonlinear command (ventilator clock). A positive noise limit was found in the remaining 5 cases, but these patients exhibited signs of active expiratory control (highly variable expiratory time, respiratory frequency higher than the set frequency). A positive noise limit was also observed in 16/17 patients during IPS (p<0.001). These observations suggest that ventilatory chaos predominantly has a neural origin (intrinsic to the respiratory central pattern generators, resulting from their perturbation by respiratory afferents, or both), with little contribution of respiratory mechanics, if any.

Chemosensitivity recovery in Ondine's curse syndrome under treatment with desogestrel

Congenital central hypoventilation syndrome (CCHS), or Ondines curse syndrome, is a rare genetic disorder associated with mutations of the PHOX2B gene. It is characterized by sleep-related life-threatening hypoventilation that requires mechanical ventilation. The ventilatory response to hypercapnia and hypoxia is absent or dramatically reduced. Spontaneous or pharmacologically induced recovery has never been reported. We have fortuitously observed a case of CO(2)-chemosensitivity recovery in a woman with CCHS who took a progestin contraceptive - desogestrel. We hypothesized that the desogestrel could be responsible for this effect. We tested this hypothesis in a second adult patient. Her lack of CO(2)-chemosensitivity was documented 5 months before she was prescribed desogestrel. Three weeks after initiation of the treatment she exhibited a ventilatory and sensory response to hypercapnia. This response persisted 3 weeks later. This is the first documented case of pharmacologically restored chemosensitivity in CCHS. It suggests that a very potent progestin such as desogestrel could unveil latent chemosensitive neural circuits.