Sleep-disordered breathing and ventilatory chemosensitivity in first ischaemic stroke patients: a prospective cohort study

RationaleSleep-disordered breathing (SDB) is highly prevalent after stroke. The clinical and ventilatory chemosensitivity characteristics of SDB, namely obstructive, central and coexisting obstructive and central sleep apnoea (coexisting sleep apnoea) following stroke are poorly described.ObjectiveTo determine the respective clinical and ventilatory chemosensitivity characteristics of SDB at least 3 months after a first ischaemic stroke.MethodsCross-sectional analysis of a prospective, monocentric cohort conducted in a university hospital. 380 consecutive stroke or transient ischaemic attack patients were screened between December 2016 and December 2019.Measurements and main resultsFull-night polysomnography, and hypercapnic ventilatory response were performed at a median (Q1; Q3) time from stroke onset of 134.5 (97.0; 227.3) days. 185 first-time stroke patients were included in the analysis. 94 (50.8%) patients presented no or mild SDB (Apnoea-Hypopnoea Index <15 events/hour of sleep) and 91 (49.2%) moderate to severe SDB, of which 52 (57.1%) presented obstructive sleep apnoea and 39 (42.9%) coexisting or central sleep apnoea. Obstructive sleep apnoea patients significantly differed regarding their clinical presentation from patients with no or mild SDB, whereas there was no difference with coexisting and central sleep apnoea patients. The latter presented a higher frequency of cerebellar lesions along with a heightened hypercapnic ventilatory response compared with no or mild SDB patients.ConclusionSDB in first-time stroke patients differ in their presentation by their respective clinical traits and ventilatory chemosensitivity characteristics. The heightened hypercapnic ventilatory response in coexisting and central sleep apnoea stroke patients may orientate them to specific ventilatory support.

Carotid body chemosensitivity is not attenuated during cold water diving

Introduction: Tonic carotid body (CB) activity is reduced during exposure to cold and hyperoxia. We tested the hypotheses that cold water diving lowers CB chemosensitivity and augments CO2 retention more than thermoneutral diving. Methods: Thirteen subjects (age: 26±4 y; BMI: 26±2 kg/m2) completed two, four-hour head out water immersion protocols in a hyperbaric chamber (1.6 ATA) in cold (15°C) and thermoneutral (25°C) water. CB chemosensitivity was assessed using brief hypercapnic ventilatory response (CBCO2) and hypoxic ventilatory response (CBO2) tests pre-dive, 80 and 160 min into the dives (D80 and D160, respectively), immediately following and 60 min post-dive. Data are reported as an absolute mean (SD) change from pre-dive. Results: End-tidal CO2 pressure increased during both the thermoneutral water dive (D160: +2(3) mmHg; p=0.02) and cold water dive (D160: +1(2) mmHg; p=0.03). Ventilationincreased during the cold water dive (D80: 4.13(4.38) and D160: 7.75(5.23) L·min-1; both p<0.01) and was greater than the thermoneutral water dive at both time points (both p<0.01). CBCO2 was unchanged during the dive (p=0.24) and was not different between conditions (p=0.23). CBO2 decreased during the thermonutral water dive (D80: -3.45(3.61) and D160: -2.76(4.04) L·min·mmHg-1; p<0.01 and p=0.03, respectively), but not the cold water dive. However, CBO2 was not different between conditions (p=0.17). Conclusion: CB chemosensitivity was not attenuated during the cold stress diving condition and does not appear to contribute to changes in ventilation or CO2 retention.

Hypercapnic ventilatory response in heart failure patients with central sleep-disordered breathing

Background Sleep-disordered breathing (SDB) is a highly common comorbidity in heart failure (HF) patients and appears mainly as obstructive SDB, or central SDB. SDB has been shown to deteriorate quality of life in HF patients, but its presence is also associated with worse prognosis. SDB severity has been shown to mirror HF level and hereby hypercapnic ventilatory response (HCVR) depicts ventilation instability which furthermore expresses HF severity. But HCVR direct correlation with HF to predict HF severity has not been sufficiently studied yet. Methods and results We included 501 HF patients that received multichannel cardiorespiratory polygraphy, clinical workup for HF and HCVR in our center. The degree of SDB was graded with apnea-hypopnea-index (AHI) with guideline recommendation for treatment at an AHI &gt;15/h. NT-Pro-BNP was obtained for HF quantification. Mean age was 66.4±11 years, body mass index (BMI) 30.7±5 kg/m2 and mean HCVR was 2.56±1.18. 136 (27.2%) patients had central SDB with a proportion of 124 (24.8%) having moderate to severe SDB (AHI &gt;15/h). 345 (68.9%) had obstructive SDB with moderate to severe SDB in 296 (59.1%) patients. Differences were detected for HCVR and HF in the central SDB group with a HCVR of 2.78±1.4 and NT-Pro-BNP of 2835.88±10536.4 pg/ml, while the OSA group shows a HCVR of 2.5±1 and NT-Pro-BNP of 929.9±1781. Linear regression identified HCVR (p=0.045) and NT-Pro-BNP (p=0.034) to independently correlate with central SDB and in addition HCVR was also significantly associated with NT-Pro-BNP (p=0.007). Conclusion HF severity is closely linked to both NT-Pro-BNP and central SDB. HCVR seems to have the potential to predict manifestation of central SDB and increased NT-Pro-BNP values in HF. HCVR may be an easily obtainable parameter to identify both HF severity and presence of central SDB in HF patients. Funding Acknowledgement Type of funding source: None

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

Background To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. Methods Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic–pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) – P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. Results The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P &lt; 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. Conclusions These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%–10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40–400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%–10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a “normal” HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.