Philip J. Berger

Loop Gain As a Means to Predict a Positive Airway Pressure Suppression of Cheyne-Stokes Respiration in Patients with Heart Failure

RATIONALE Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2π/(2πDR - sin2πDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy.

Supine position related obstructive sleep apnea in adults: pathogenesis and treatment.

The most striking feature of obstructive respiratory events is that they are at their most severe and frequent in the supine sleeping position: indeed, more than half of all obstructive sleep apnea (OSA) patients can be classified as supine related OSA. Existing evidence points to supine related OSA being attributable to unfavorable airway geometry, reduced lung volume, and an inability of airway dilator muscles to adequately compensate as the airway collapses. The role of arousal threshold and ventilatory control instability in the supine position has however yet to be defined. Crucially, few physiological studies have examined patients in the lateral and supine positions, so there is little information to elucidate how breathing stability is affected by sleep posture. The mechanisms of supine related OSA can be overcome by the use of continuous positive airway pressure. There are conflicting data on the utility of oral appliances, while the effectiveness of weight loss and nasal expiratory resistance remains unclear. Avoidance of the supine posture is efficacious, but long term compliance data and well powered randomized controlled trials are lacking. The treatment of supine related OSA remains largely ignored in major clinical guidelines. Supine OSA is the dominant phenotype of the OSA syndrome. This review explains why the supine position so favors upper airway collapse and presents the available data on the management of patients with supine related OSA.

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O2. Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL-1α and IL-1β on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1α/β in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.

Phenotypes of patients with mild to moderate obstructive sleep apnoea as confirmed by cluster analysis

Background and objective:  Patients with OSA manifest different patterns of disease. However, this heterogeneity is more evident in patients with mild‐moderate OSA than in those with severe disease and a high total AHI. We hypothesized that mild‐moderate OSA can be categorized into discreet disease phenotypes, and the aim of this study was to comprehensively describe the pattern of OSA phenotypes through the use of cluster analysis techniques.

Continuous positive airway pressure reduces loop gain and resolves periodic central apneas in the lamb

Continous positive airway pressure (CPAP) is used to treat infant respiratory distress syndrome and apnea of prematurity, but its mode of action is not fully understood. We hypothesised that CPAP increases lung volume and stabilises respiratory control by decreasing loop gain (LG). Experimentally induced periodic breathing (PB) in the lamb was terminated early by CPAP in a dose-dependent manner, with a control epoch of 45.4+/-5.1s at zero CPAP falling to 32.9+/-5.4, 13.2+/-4.2 and 9.8+/-3.1s at 2.5, 5 and 10 cmH(2)O, respectively (p<0.001); corresponding duty ratios (duration of the ventilatory phase of PB divided by its cycle duration) increased from 0.50+/-0.02 to 0.62+/-0.05, 0.76+/-0.06 and 0.68+/-0.08, respectively (p<0.001). Since epoch duration and duty ratio are surrogate measures of LG, we conclude that CPAP ameliorates the effects of recurrent central apneas, and perhaps mixed and obstructive apneas, by decreasing LG via increases in lung volume.

A Model Analysis of Arterial Oxygen Desaturation during Apnea in Preterm Infants

Rapid arterial O2 desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O2 desaturation during apnea () is complicated by the non-linear O2 dissociation curve, falling pulmonary O2 uptake, and by the fact that O2 desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O2 consumption accelerates throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates during stage 1, and finally, total blood O2 capacity (blood volume and hemoglobin content) alone determines during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.

Volume and secretion rate of lung liquid in the final days of gestation and labour in the fetal sheep

1 Most of the liquid that fills the lung of the fetal sheep in late gestation is cleared by the end of labour. Clearance of this liquid has a beneficial effect on postnatal gas exchange and therefore represents an important adaptation for postnatal life. Despite its importance, there is disagreement about whether clearance begins prior to labour, or occurs entirely within labour. 2 To address this issue, we made serial determinations of lung liquid volume by indicator dilution during late gestation and labour in the fetal sheep. 3 Regression analysis demonstrated that lung liquid volume exhibited a plateau level in the near‐term fetus before it began to decline. Two models provided a fit to the decline in volume. In one, lung liquid clearance occurred in two linear phases, the first beginning 70 h before the study was terminated when the ewe was in advanced labour, the second occupying the last 8 h of the study period. In the initial phase, average lung liquid volume fell from 38.3 to 26.4 ml kg−1 before a rapid decline in the second phase reduced the volume to 13.8 ml kg−1. An exponential decay model was also found to fit the data; this showed a gradual decline in lung liquid volume in the 2 days preceding onset of labour, followed by a much more rapid decline within labour. 4 The rate of lung liquid secretion also declined in two linear phases, both of which commenced earlier than the changes in lung liquid volume. An exponential decay model also gave a significant fit to the data, but the fit was significantly weaker than that achieved with the two‐slope model. 5 We conclude that clearance of lung liquid begins well before commencement of labour in the full term fetal sheep, and then accelerates once labour is established. In our study, lung liquid volume fell even in the absence of reabsorption of liquid across the pulmonary epithelium, indicating that outflow of liquid through the trachea must have occurred at a rate in excess of the secretion rate.

Postnatal maturation of breathing stability and loop gain: The role of carotid chemoreceptor development

Any general model of respiratory control must explain a puzzling array of breathing patterns that are observed during the course of a lifetime. Particular challenges are to understand why periodic breathing is rarely seen in the first few days after birth, reaches a peak at 2-4 weeks postnatal age, and disappears by 6 months, why it is prevalent in preterm infants, and why it reappears in adults at altitude or with heart failure. In this review we use the concept of loop gain to obtain quantitative insight into the genesis of unstable breathing patterns with a particular focus on how changes in carotid body function could underlie the age-related dependence of periodic breathing.

Increased peripheral chemosensitivity via dopaminergic manipulation promotes respiratory instability in lambs.

Periodic breathing (PB) is an instability of the respiratory control system believed to be mediated principally by the peripheral chemoreceptors. We hypothesised that domperidone, a dopamine D(2)-receptor antagonist that increases carotid body sensitivity to O(2) and CO(2), would promote PB through an increase in the loop gain (LG) of the respiratory control system. Domperidone significantly increased controller gain for oxygen (p<0.05) and gave rise, following post-hyperventilation apnea, to an increased incidence of PB (14% vs. 86%), an increased PB epoch duration, and a decrease in duty ratio of PB (p<0.001); these changes are consistent with domperidone increasing LG. Although domperidone increased controller gain for CO(2) (p<0.05), the contribution of Pa(CO)(2) oscillations to the genesis of PB in the lamb remained small. We conclude that domperidone increases LG in the lamb via an increase in controller gain for oxygen. Our study demonstrates that a quantitative understanding of the factors that determine LG provides insight into the cause of PB.

Phasic respiratory activity in the fetal lamb during late gestation and labour.

We quantified the respiratory activity of 9 fetal lambs using computer-analysis of the diaphragmatic electromyogram (EMG) obtained during 2 h recording sessions interspersed over the last 13 days of gestation. The fetuses delivered unassisted at an average gestational age of 145 days (term = 147 days). During the last 2 h of labour the number of phasic EMG bursts (breaths) averaged 3% of the peak recorded earlier in the study. This decline in breathing began at least 2 days before labour and resulted predominantly from the fetus spending an increasing proportion of time in apnoea. Respiratory rate within epochs of breathing also fell significantly 1 day before labour, and the proportion of time spent in the low voltage electrocortical state declined once labour commenced. No significant change occurred in arterial PO2, PCO2 or pH over the study period. We conclude that fetal respiratory activity falls well before the onset of labour, largely as a result of increased apnoea, and that the decline does not result from the development of a progressive hypoxaemia associated with labour.