Effects of Changes in Inspiratory Time on Inspiratory Flowrate and Airway Pressure during Cardiopulmonary Resuscitation: A Manikin-Based Study

Objectives: Given that cardiopulmonary resuscitation (CPR) is an aerosol-generating procedure, it is necessary to use a mechanical ventilator and reduce the number of providers involved in resuscitation for in-hospital cardiac arrest in coronavirus disease (COVID-19) patients or suspected COVID-19 patients. However, no study assessed the effect of changes in inspiratory time on flowrate and airway pressure during CPR. We herein aimed to determine changes in these parameters during CPR and identify appropriate ventilator management for adults during CPR.Methods: We measured changes in tidal volume (Vt), peak inspiratory flow rate (PIFR), peak airway pressure (Ppeak), mean airway pressure (Pmean) according to changes in inspiratory time (0.75 s, 1.0 s and 1.5 s) with or without CPR. Vt of 500 mL was supplied (flowrate: 10 times/min) using a mechanical ventilator. Chest compressions were maintained at constant compression depth (53 ± 2 mm) and speed (102 ± 2/min) using a mechanical chest compression device.Results: Median levels of respiratory physiological parameters during CPR were significantly different according to the inspiratory time (0.75 s vs. 1.5 s): PIFR (80.8 [73.3 – 87.325] vs. 70.5 [67 – 72.4] L/min, P < 0.001), Ppeak (54 [48 – 59] vs. 47 [45 – 49] cmH₂O, P < 0.001), and Pmean (3.9 [3.6 – 4.1] vs. 5.7 [5.6 – 5.8] cmH₂O, P < 0.001).Conclusions: Changes in PIFR, Ppeak, and Pmean were associated with inspiratory time. PIFR and Ppeak values tended to decrease with increase in inspiratory time, while Pmean showed a contrasting trend. Increased inspiratory time in low-compliance cardiac arrest patients will help in reducing lung injury during adult CPR.

End-Tidal Carbon Dioxide Pressure Measurement after Prolonged Inspiratory Time Gives a Good Estimation of the Arterial Carbon Dioxide Pressure in Mechanically Ventilated Patients

Background: End-tidal carbon dioxide pressure (PetCO2) is unreliable for monitoring PaCO2 in several conditions because of the unpredictable value of the PaCO2–PetCO2 gradient. We hypothesised that increasing both the end-inspiratory pause and the expiratory time would reduce this gradient in patients ventilated for COVID-19 with Acute Respiratory Distress Syndrome and in patients anaesthetised for surgery. Methods: On the occasion of an arterial blood gas sample, an extension in inspiratory pause was carried out either by recruitment manoeuvre or by extending the end-inspiratory pause to 10 s. The end-expired PCO2 was measured (expiratory time: 4 s) after this manoeuvre (PACO2) in comparison with the PetCO2 measured by the monitor. We analysed 67 Δ(a-et)CO2, Δ(a-A)CO2 pairs for 7 patients in the COVID group and for 27 patients in the anaesthesia group. Results are expressed as mean ± standard deviation. Results: Prolongation of the inspiratory pause significantly reduced PaCO2–PetCO2 gradients from 11 ± 5.7 and 5.7 ± 3.4 mm Hg (p < 0.001) to PaCO2–PACO2 gradients of −1.2 ± 3.3 (p = 0.043) and −1.9 ± 3.3 mm Hg (p < 0.003) in the COVID and anaesthesia groups, respectively. In the COVID group, PACO2 showed the lowest dispersion (−7 to +6 mm Hg) and better correlation with PaCO2 (R2 = 0.92). The PACO2 had a sensitivity of 0.81 and a specificity of 0.93 for identifying hypercapnic patients (PaCO2 > 50 mm Hg). Conclusions: Measuring end-tidal PCO2 after prolonged inspiratory time reduced the PaCO2–PetCO2 gradient to the point of obtaining values close to PaCO2. This measure identified hypercapnic patients in both intensive care and during anaesthesia.

Molecular, anatomical, and functional organization of lung interoceptors

Interoceptors, sensory neurons that monitor internal organs and states, are essential for physiological homeostasis and generating internal perceptions. Here we describe a comprehensive transcriptomic atlas of interoceptors of the mouse lung, defining 10 molecular subtypes that differ in developmental origin, myelination, receptive fields, terminal morphologies, and cell contacts. Each subtype expresses a unique but overlapping combination of sensory receptors that detect diverse physiological and pathological stimuli, and each can signal to distinct sets of lung cells including immune cells, forming a local neuroimmune interaction network. Functional interrogation of two mechanosensory subtypes reveals exquisitely-specific homeostatic roles in breathing, one regulating inspiratory time and the other inspiratory flow. The results suggest that lung interoceptors encode diverse and dynamic sensory information rivaling that of canonical exteroceptors, and this information is used to drive myriad local cellular interactions and enable precision control of breathing, while providing only vague perceptions of organ states.

Ventilatory responses during and following hypercapnic gas challenge are impaired in male but not female endothelial NOS knock-out mice

The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO2, 21% O2, 74% N2) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.

BreathTrack

Breathing biomarkers, such as breathing rate, fractional inspiratory time, and inhalation-exhalation ratio, are vital for monitoring the user's health and well-being. Accurate estimation of such biomarkers requires breathing phase detection, i.e., inhalation and exhalation. However, traditional breathing phase monitoring relies on uncomfortable equipment, e.g., chestbands. Smartphone acoustic sensors have shown promising results for passive breathing monitoring during sleep or guided breathing. However, detecting breathing phases using acoustic data can be challenging for various reasons. One of the major obstacles is the complexity of annotating breathing sounds due to inaudible parts in regular breathing and background noises. This paper assesses the potential of using smartphone acoustic sensors for passive unguided breathing phase monitoring in a natural environment. We address the annotation challenges by developing a novel variant of the teacher-student training method for transferring knowledge from an inertial sensor to an acoustic sensor, eliminating the need for manual breathing sound annotation by fusing signal processing with deep learning techniques. We train and evaluate our model on the breathing data collected from 131 subjects, including healthy individuals and respiratory patients. Experimental results show that our model can detect breathing phases with 77.33% accuracy using acoustic sensors. We further present an example use-case of breathing phase-detection by first estimating the biomarkers from the estimated breathing phases and then using these biomarkers for pulmonary patient detection. Using the detected breathing phases, we can estimate fractional inspiratory time with 92.08% accuracy, the inhalation-exhalation ratio with 86.76% accuracy, and the breathing rate with 91.74% accuracy. Moreover, we can distinguish respiratory patients from healthy individuals with up to 76% accuracy. This paper is the first to show the feasibility of detecting regular breathing phases towards passively monitoring respiratory health and well-being using acoustic data captured by a smartphone.

Coordination of Respiration, Swallowing, and Chewing in Healthy Young Adults

Examining the coordination of respiration and swallowing is important for elucidating the mechanisms underlying these functions and assessing how respiration is linked to swallowing impairment in dysphagic patients. In this study, we assessed the coordination of respiration and swallowing to clarify how voluntary swallowing is coordinated with respiration and how mastication modulates the coordination of respiration and swallowing in healthy humans. Twenty-one healthy volunteers participated in three experiments. The participants were asked to swallow 3 ml of water with or without a cue, to drink 100 ml of water using a cup without breathing between swallows, and to eat a 4-g portion of corned beef. The major coordination pattern of respiration and swallowing was expiration–swallow–expiration (EE type) while swallowing 3 ml of water either with or without a cue, swallowing 100 ml of water, and chewing. Although cueing did not affect swallowing movements, the expiratory time was lengthened with the cue. During 100-ml water swallowing, the respiratory cycle time and expiratory time immediately before swallowing were significantly shorter compared with during and after swallowing, whereas the inspiratory time did not differ throughout the recording period. During chewing, the respiratory cycle time was decreased in a time-dependent manner, probably because of metabolic demand. The coordination of the two functions is maintained not only in voluntary swallowing but also in involuntary swallowing during chewing. Understanding the mechanisms underlying respiration and swallowing is important for evaluating how coordination affects physiological swallowing in dysphagic patients.

Utilization of Airway Pressure Release Ventilation as a Rescue Strategy in COVID-19 Patients: A Retrospective Analysis

Background: Airway Pressure Release Ventilation (APRV) is a pressure controlled intermittent mandatory mode of ventilation characterized by prolonged inspiratory time and high mean airway pressure. Several studies have demonstrated that APRV can improve oxygenation and lung recruitment in patients with Acute Respiratory Distress Syndrome (ARDS). Although most patients with COVID-19 meet the Berlin criteria for ARDS, hypoxic respiratory failure due to COVID-19 may differ from traditional ARDS as patients often present with severe, refractory hypoxemia and significant variation in respiratory system compliance. To date, no studies investigating APRV in this patient population have been published. The aim of this study was to evaluate the effectiveness of APRV as a rescue mode of ventilation in critically ill patients diagnosed with COVID-19 and refractory hypoxemia. Methods: We conducted a retrospective analysis of patients admitted with COVID-19 requiring invasive mechanical ventilation who were treated with a trial of APRV for refractory hypoxemia. PaO2/FIO2 (P/F ratio), ventilatory ratio and ventilation outputs before and during APRV were compared. Results: APRV significantly improved the P/F ratio and decreased FIO2 requirements. PaCO2 and ventilatory ratio were also improved. There was an increase in tidal volume per predicted body weight during APRV and a decrease in total minute ventilation. On multivariate analysis, higher inspiratory to expiratory ratio (I: E) and airway pressure were associated with greater improvement in P/F ratio. Conclusions: APRV may improve oxygenation, alveolar ventilation and CO2 clearance in patients with COVID-19 and refractory hypoxemia. These effects are more pronounced with higher airway pressure and inspiratory time.

Reference equations for tidal breathing parameters using structured light plethysmography

Tidal breathing measurements can be used to identify changes in respiratory status. Structured light plethysmography (SLP) is a non-contact tidal breathing measurement technique. Lack of reference equations for SLP parameters makes clinical decision-making difficult. We have developed a set of growth adjusted reference equations for seven clinically pertinent parameters of respiratory rate (RR), inspiratory time (Ti), expiratory time (Te), duty cycle (Ti/Total-breath-time), phase (thoraco-abdominal asynchrony or TAA), relative thoracic contribution (RTC) and IE50 (tidal inspiratory/expiratory flow at 50% volume).Reference equations were developed based on a cohort of 198 seated healthy subjects (age 2–75 years, height 82 cm–194 cm, 108 Male). We adopted the same methodological approach as the global lung function initiative (GLI) report on spirometric reference equations [1]. Five minutes of tidal breathing was recorded per subject. Parameters were summarised with their medians. The online supplement provided is an integral part of this work and a reference range calculator is also provided therein.We found predicted RR to decrease with age and height rapidly in the first 20 years and slowly thereafter. Expected Ti, Te and RTC followed the opposite trend. RTC was 6.7% higher in females. Duty cycle increased with age, peaked at 13 and decreased after. TAA was high and variable in early life and declined rapidly with age. Predicted IE50 was constant as it did not correlate with growth.These reference ranges for seven key measures ensure clinicians and researchers can identify tidal breathing patterns in disease and better understand and interpret SLP and tidal breathing data.

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration

Purpose Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. Methods An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration (“pulsed delivery”), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5–40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. Results Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 ± 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. Conclusion Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes.

Ventilatory Responses During and Following Hypercapnic Gas Challenge are Impaired in Male but Not Female Endothelial NOS Knock-out Mice

The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO2, 21% O2, 74% N2) were assessed in freely moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was equal in male and female WT mice. However, the post-HCC increases in frequency of breathing (and decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory and expiratory drives, and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.