P088 Presence versus absence of flow limitation during stable breathing in patients with obstructive sleep apnoea

Introduction Flow limitation is the distinguishing characteristic of obstructive sleep apnoea. Critically, periods of flow limitation can occur without overt reductions in airflow (e.g. disproportionate increase in ventilatory drive vs. achieved ventilation), however, such periods are ignored by clinical scoring. Here we investigate flow limitation during so-called “stable breathing”, i.e. periods of sleep without scored events, by applying our recently-validated model to estimate flow limitation from the airflow signal. Methods Flow limitation was visually-scored (N=117,871 breaths) from N=40 participants attending an overnight sleep study for suspected sleep apnoea. Scoring was aided by physiological signals (e.g. intra-oesophageal diaphragm EMG). Model flow limitation classification used features extracted from the pneumotach signal (cross-validated accuracy=92.4%). We applied this method to investigate the occurrence of flow limitation during stable breathing, defined as periods of sleep >3 min duration without scored arousals or respiratory events. Results Model predicted flow limitation frequency was strongly correlated with visual scoring (R²=0.84 p<0.001). The median flow limitation frequency during stable breathing ranged from 8–91%, with an overall median of 59% (IQR 37%-75%). Flow limitation frequency during stable breathing was only modestly associated with the apnoea-hypopnea index (R²=0.12 p<0.05). Discussion Flow limitation occurs surprisingly frequently during stable breathing. While some individuals achieve stable breathing with minimal flow limitation, others demonstrate substantial flow limitation. Heterogeneity in frequency of flow limitation (within and between individuals) may provide further insights into emergent phenotypic variability within sleep disordered breathing. Finally, this model performed similarly in nasal pressure (88.2% accuracy), indicating potential application to clinical studies.

Quantification of Airway Conductance from Non-invasive Ventilatory Drive in Patients with Sleep Apnea

Upper airway conductance, the ratio of inspiratory airflow to inspiratory effort, quantifies the degree of airway obstruction in hypopneas observed in sleep apnea. We evaluated the ratio of ventilation to non-invasive ventilatory drive as a surrogate of conductance. Further, we developed and tested a refinement of non-invasive drive to incorporate the interactions of inspiratory flow, pressure, and drive in order to better estimate conductance. Hypopneas were compiled from existing polysomnography studies with esophageal catheterization in 18 patients with known or suspected sleep apnea, totaling 1517 hypopneas during NREM sleep. For each hypopnea, reference-standard conductance was calculated as the ratio of peak inspiratory flow to esophageal pressure change during inspiration. Ventilatory drive was calculated using the algorithm developed by Terrill et al and then mathematically modified according to the presence or absence of flow limitation in order to non-invasively estimate esophageal pressure. The ratio of ventilation to ventilatory drive and the ratio of peak inspiratory flow to estimated esophageal pressure were each compared to the reference standard for all hypopneas and for median values from individual patients. Hypopnea ventilation:drive ratios were of limited correlation with the reference standard (R2 = 0.17, individual hypopneas; R2 = 0.03, median patient values). Modification of drive to estimated pressure yielded estimated conductance, which strongly correlated with reference standard conductance (R2 = 0.49, individual hypopneas; R2 = 0.77, median patient values­). We conclude that the severity of airway obstruction during hypopneas may be estimated from non-invasive drive by accounting for mechanical effects of flow on pressure.

Frequency of flow limitation using airflow shape

Study Objectives The presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep. Methods A library of 117,871 breaths (N=40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen’s ƙ) and overnight flow limitation frequency (R 2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive. Results The model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ=0.572, p<0.001) and minimal error (overnight flow limitation frequency R 2=0.86, error=7.2%). Flow limitation frequency was largely independent of AHI (R 2=0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI>15/hr, N=22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R 2=0.26-0.29; R 2<0.01 AHI v. drive). Conclusions Our method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive.

d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of d-cystine diethyl ester (d-cystine diEE) or d-cystine dimethyl ester (d-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of d-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by d-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by d-cystine diEE. d-cystine diEE and d-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the d-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.

Nocturnal hypoxaemia in interstitial lung disease: a systematic review

BackgroundPatients with interstitial lung disease (ILD) are at risk of developing nocturnal hypoxaemia due to ventilatory restriction and impaired gas exchange that worsen with supine posture and reduced ventilatory drive during sleep. This systematic review synthesised literature on the diagnostic evaluation, epidemiology, associations, management and prognosis of nocturnal hypoxaemia in ILD.MethodsOvid MEDLINE, Embase and CENTRAL databases were searched for eligible studies. Meta-analyses with subgroup analyses were conducted, where possible.ResultsFifty-three studies were included (total participant number=2590). The most common definition for clinically significant nocturnal hypoxaemia was ≥10% of total sleep time with oxyhaemoglobin saturation <90%, with pooled prevalence of 37%. There were no significant differences in pooled prevalence according to ILD subtype and comorbid obstructive sleep apnoea status. Study heterogeneity precluded meta-analysis of associations and prognosis. Diffusing capacity for carbon monoxide (DLCO) and echocardiographic features for pulmonary hypertension were consistently associated with nocturnal hypoxaemia. There were inconsistent associations between nocturnal hypoxaemia with ILD subtype and severity. Multivariable analyses in most studies demonstrated significant associations of nocturnal hypoxaemia with survival. Two small short-term intervention studies demonstrated that supplemental oxygen of 1–3 L/min corrected nocturnal hypoxaemia, with improved heart rate control during in-laboratory observation and increased serum antioxidant levels after 1 month of therapy.ConclusionNocturnal hypoxaemia is common, associated with DLCO impairment and markers suggestive of pulmonary hypertension, and a potential prognostic factor in patients in ILD. There is a need to establish a consensus definition of nocturnal hypoxaemia and evaluate long-term effects of nocturnal supplemental oxygen in ILD.

D-Cystine di(m)ethyl Ester Reverses the Deleterious Effects of Morphine on Ventilation and Arterial Blood Gas Chemistry While Promoting Analgesia

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising analgesia. Here we report the effects of D-cystine diethyl ester (D-cystine diEE) or D-cystine dimethyl ester (D-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and analgesia in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of D-cystine diEE (500 mmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by D-cystine diME (500 mmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) analgesia was augmented by D-cystine diEE. D-cystine diEE and D-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting analgesia.

Impaired hypoxic ventilatory drive induced by diabetic autonomic neuropathy, a cause of misdiagnosed severe cardiac events: brief report of two cases

Background Sudden cardiac deaths are twice more frequent in diabetic patients with cardiac autonomic neuropathy. Sudden cardiac death etiologies remain unclear and no recommendations are made to identify factors associated with cardiorespiratory arrest in diabetic patients. We hypothesized, from two clinical cases, that impaired hypoxic ventilatory drive, induced by diabetic autonomic neuropathy, is a cause of misdiagnosed severe cardiac events. Case presentation We describe the cases of two patients with isolated low blood saturation on pulse oximeter during the systematic nurse check-up (77% and 85% respectively) contrasting with the absence of any complaint such as dyspnea, polypnea or other respiratory insufficiency signs observed during the clinical examination. Arterial blood gas measurements subsequently confirmed that blood oxygen saturation was low and both patients were indeed hypoxemic. Patient 1 suffered from vascular overload complicated by cardiac arrest caused by hypoxemia in light of the quick recovery observed after ventilation. Pulmonary edema was diagnosed in patient 2. The common denominator of these 2 cases described in this brief report is the absence of respiratory failure clinical signs contrasting with the presence of confirmed hypoxemia. Also, in both cases, such absence of precursory signs seems to be induced by an impaired ventilatory drive to hypoxemia. This appears to be related to the autonomic diabetic neuropathy encountered in those 2 patients. Conclusions Therefore, we describe, in this brief report, cardiac autonomic neuropathy as a cause of impaired hypoxic ventilatory drive involved in severe acute cardiorespiratory events in two type 1 diabetic patients. We assume that altered response to hypoxemia due to cardiac autonomic neuropathy and non-functional central neurological breathing command could play a key role in sudden deaths among diabetic patients. An important point is that hypoxemia can be easily missed since no clinical signs of respiratory failure are reported in these two clinical cases. Systematic screening of cardiac autonomic neuropathy in diabetic patients and proactive detection of impaired hypoxic ventilatory drive for early management (e.g. treatment of hypoxemia) should be systematically undertaken in diabetic patients to prevent its dramatic consequences such as cardiorespiratory arrest and death.

Impaired Hypoxic Ventilatory Drive Induced by Diabetic Autonomic Neuropathy, A Cause of Misdiagnosed Severe Cardiac Events. Brief Report of Two Cases.

Background: Sudden cardiac death are twice more frequent in diabetic patients with cardiac autonomic neuropathy. Sudden cardiac death etiologies remain unclear and no recommendation are made to identify factor associated with cardiorespiratory arrest in diabetic patients. We hypothesized, from two clinical cases, that impaired hypoxic ventilatory drive, induced by diabetic autonomic neuropathy, is a cause of misdiagnosed severe cardiac events.Case presentation: We describe the cases of two patients with isolated low blood saturation on pulse oximeter during the systematic nurse check-up (77% and 85% respectively) contrasting with the absence of any complaint as well as any dyspnea, polypnea or other respiratory insufficiency signs observed during the clinical examination. Arterial blood gas measurements subsequently confirmed that blood saturation was low and that both patients were indeed hypoxemic. Patient 1 suffered of vascular overload complicated by cardiac arrest caused by hypoxemia in light of the quick recovery observed after ventilation. Pulmonary edema was diagnosed in patient 2. The common denominator of these 2 cases described in this brief report is the absence of respiratory failure clinical signs contrasting with the presence of confirmed hypoxemia. Also, in both cases, such absence of precursory signs seems to be induced by an impaired ventilatory drive to hypoxemia. This appears to be related to the autonomic diabetic neuropathy encountered in those 2 patients.Conclusions: Therefore, we describe, in this brief report, cardiac autonomic neuropathy as a cause of impaired hypoxic ventilatory drive involved in severe acute cardiorespiratory events in two type 1 diabetic patients. We assume that altered response to hypoxemia due to cardiac autonomic neuropathy and non-functional central neurological breathing command could play a key role in sudden deaths among diabetic patients. A point to emphasize is that hypoxemia can be easily missed since no clinical signs of respiratory failure are reported in these two clinical cases. Systematic screening of cardiac autonomic neuropathy in diabetic patients and proactive detection of impaired hypoxic ventilatory drive for early management (e.g. treatment of hypoxemia) should be systematically undertaken in diabetic patients to prevent its dramatic consequences such as cardiorespiratory arrest and death.

Continuous assessment of neuro-ventilatory drive during 12 h of pressure support ventilation in critically ill patients

Introduction Pressure support ventilation (PSV) should allow spontaneous breathing with a “normal” neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of “Low” and/or “High” neuro-ventilatory drive during clinical application of PSV. Method In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with “Normal” (EAdiPEAK 5–15 μV), “Low” (EAdiPEAK < 5 μV) and “High” (EAdiPEAK > 15 μV) neuro-ventilatory drive. Results Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was “Low” in 50.116 breath (28%), “Normal” in 88.419 breaths (50%) and “High” in 38.582 breaths (22%). The average times spent in “Low”, “Normal” and “High” class were 1.37, 3.67 and 0.55 h, respectively (p < 0.0001), with wide variations among patients. Eleven patients remained in the “Low” neuro-ventilatory drive class for more than 1 h, median 6.1 [3.9–8.5] h and 6 in the “High” neuro-ventilatory drive class, median 3.4 [2.2–7.8] h. The asynchrony index was significantly higher in the “Low” neuro-ventilatory class, mainly because of a higher number of missed efforts. Conclusions We observed wide variations in EAdi amplitude and unevenly distributed “Low” and “High” neuro ventilatory drive periods during 12 h of PSV in critically ill patients. Further studies are needed to assess the possible clinical implications of our physiological findings.