Intra-tidal PaO2 oscillations associated with mechanical ventilation: a pilot study to identify discrete morphologies in a porcine model.

BACKGROUND: Within-breath oscillations in arterial oxygen tension (PaO2) can be detected using fast responding intra-arterial oxygen sensors in animal models. These PaO2 signals, which rise in inspiration and fall in expiration, may represent cyclical recruitment/derecruitment and, therefore, a potential clinical monitor to allow titration of ventilator settings in lung injury. However, in hypovolaemia models, these oscillations have the potential to become inverted, such that they decline, rather than rise, in inspiration. This inversion suggests multiple aetiologies may underlie these oscillations. A correct interpretation of the various PaO2 oscillation morphologies is essential to translate this signal into a monitoring tool for clinical practice. We present a pilot study to demonstrate the feasibility of a new analysis method to identify these morphologies. METHODS: Seven domestic pigs (average weight 31.1 kg) were studied under general anaesthesia with muscle relaxation and mechanical ventilation. Three underwent saline-lavage lung injury and four were uninjured. Variations in PEEP, tidal volume and presence/absence of lung injury were used to induce different morphologies of PaO2 oscillation. Functional principal component analysis and k-means clustering were employed to separate PaO2 oscillations into distinct morphologies, and the cardiorespiratory physiology associated with these PaO2 morphologies was compared. RESULTS: PaO2 oscillations from 73 ventilatory conditions were included. Five functional principal components were sufficient to explain ≥ 95% of the variance of the recorded PaO2 signals. From these, five unique morphologies of PaO2 oscillation were identified, ranging from those which increased in inspiration and decreased in expiration, through to those which decreased in inspiration and increased in expiration. This progression was associated with the estimates of the first functional principal component (P < 0.001, R2 = 0.88). Intermediate morphologies demonstrated waveforms with two peaks and troughs per breath. The progression towards inverted oscillations was associated with increased pulse pressure variation (P = 0.03). CONCLUSIONS: Functional principal component analysis and k-means clustering are appropriate to identify unique morphologies of PaO2 waveform associated with distinct cardiorespiratory physiology. We demonstrated novel intermediate morphologies of PaO2 waveform, which may represent a development of zone 2 physiologies within the lung. Future studies of PaO2 oscillations and modelling should aim to understand the aetiologies of these morphologies.

Experimental asynchrony to study self-inflicted lung injury.

Patient self-inflicted lung injury may be associated with worse clinical outcomes and higher mortality. Patient-ventilator asynchrony is associated with increased ventilator days and mortality, and it has been hypothesised as one of the important mechanisms leading to patient self-inflicted lung injury. However, given the observational nature of the key studies in the field so far, the hypothesis that patient-ventilator asynchrony causes patient self-inflicted lung injury has not been supported by evidence yet. Wittenstein and colleagues present a novel approach that enables controlling patient-ventilator asynchrony in a pig model of acute lung injury, to investigate the patient-ventilator asynchrony and patient self-inflicted lung injury causality. Their results suggest that increased patient-ventilator asynchrony associated with poor clinical outcomes reported in observational trials could be a marker, rather than a cause of patient self-inflicted lung injury. These findings on their own are not sufficient to justify a greater tolerance of patient-ventilator asynchrony amongst clinicians, a change for which further experimental work and clinical evidence is needed.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Mechanical ventilation in COVID-19: A physiological perspective.

NEW FINDINGS: What is the topic of this review? This review presents the fundamental concepts of respiratory physiology and pathophysiology, with particular reference to lung mechanics and the pulmonary phenotype associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent coronavirus disease 2019 (COVID-19) pneumonia. What advances does it highlight? The review provides a critical summary of the main physiological aspects to be considered for safe and effective mechanical ventilation in patients with severe COVID-19 in the intensive care unit. ABSTRACT: Severe respiratory failure from coronavirus disease 2019 (COVID-19) pneumonia not responding to non-invasive respiratory support requires mechanical ventilation. Although ventilation can be a life-saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a pattern of lung injury in patients with severe COVID-19 pneumonia typically associated with two distinct phenotypes, along a temporal and pathophysiological continuum, characterized by different levels of elastance, ventilation-to-perfusion ratio, right-to-left shunt, lung weight and recruitability. Understanding the underlying pathophysiology, duration of symptoms, radiological characteristics and lung mechanics at the individual patient level is crucial for the appropriate choice of mechanical ventilation settings to optimize gas exchange and prevent further lung injury. By critical analysis of the literature, we propose fundamental physiological and mechanical criteria for the selection of ventilation settings for COVID-19 patients in intensive care units. In particular, the choice of tidal volume should be based on obtaining a driving pressure < 14 cmH2 O, ensuring the avoidance of hypoventilation in patients with preserved compliance and of excessive strain in patients with smaller lung volumes and lower lung compliance. The level of positive end-expiratory pressure (PEEP) should be informed by the measurement of the potential for lung recruitability, where patients with greater recruitability potential may benefit from higher PEEP levels. Prone positioning is often beneficial and should be considered early. The rationale for the proposed mechanical ventilation settings criteria is presented and discussed.

Pathophysiology of coronavirus-19 disease acute lung injury.

PURPOSE OF REVIEW: More than 230 million people have tested positive for severe acute respiratory syndrome-coronavirus-2 infection globally by September 2021. The infection affects primarily the function of the respiratory system, where ∼20% of infected individuals develop coronavirus-19 disease (COVID-19) pneumonia. This review provides an update on the pathophysiology of the COVID-19 acute lung injury. RECENT FINDINGS: In patients with COVID-19 pneumonia admitted to the intensive care unit, the PaO2/FiO2 ratio is typically <26.7 kPa (200 mmHg), whereas lung volume appears relatively unchanged. This hypoxaemia is likely determined by a heterogeneous mismatch of pulmonary ventilation and perfusion, mainly associated with immunothrombosis, endothelialitis and neovascularisation. During the disease, lung weight, elastance and dead space can increase, affecting respiratory drive, effort and dyspnoea. In some severe cases, COVID-19 pneumonia may lead to irreversible pulmonary fibrosis. SUMMARY: This review summarises the fundamental pathophysiological features of COVID-19 in the context of the respiratory system. It provides an overview of the key clinical manifestations of COVID-19 pneumonia, including gas exchange impairment, altered pulmonary mechanics and implications of abnormal chemical and mechanical stimuli. It also critically discusses the clinical implications for mechanical ventilation therapy.

Continuous measurement of arterial oxygenation in mechanically ventilated horses.

BACKGROUND: The possibility of accurately and continuously measuring arterial oxygen partial pressure (PaO2 ) in horses may facilitate the management of hypoxaemia during general anaesthesia. OBJECTIVES: The aim of this study was to evaluate the ability of a novel fibreoptic sensor to measure PaO2 (PaO2Sensor ) continuously and in real time in horses undergoing ventilatory manoeuvres during general anaesthesia. STUDY DESIGN: In vivo experimental study. METHODS: Six adult healthy horses were anaesthetised and mechanically ventilated in dorsal recumbency. A fibreoptic sensor was placed in one of the facial arteries through a catheter to continuously measure and record PaO2Sensor . After an alveolar recruitment manoeuvre, a decremental positive end-expiratory pressure (PEEP) titration using 20-minute steps of 5 cm H2 O from 20 to 0 cm H2 O was performed. An arterial blood sample was collected at 15 minutes of ventilation at each PEEP level for PaO2 measurement using an automated blood gas machine (PaO2Ref ). The agreement between PaO2Sensor and PaO2Ref was assessed by Pearson's correlation, Bland-Altman plot and four-quadrant plot analysis. In the last minute of ventilation at each PEEP level, a slow tidal inflation/deflation manoeuvre was performed. RESULTS: The mean relative bias between PaO2Sensor and PaO2Ref was 4% with limits of agreement between -17% and 29%. The correlation coefficient between PaO2Sensor and PaO2Ref was 0.98 (P < .001). The PaO2Sensor and PaO2Ref concordance rate for changes was 95%. Measurements of PaO2Sensor during the slow inflation/deflation manoeuvre at PEEP 15 and 10 cm H2 O were not possible because of significant noise on the PaO2 signal generated by a small blood clot. MAIN LIMITATIONS: Small sample size. CONCLUSION: The tested fibreoptic probe was able to accurately and continuously measure PaO2Sensor in anaesthetised horses undergoing ventilatory manoeuvres. A heparinised system in the catheter used by the fibreoptic sensor should be used to avoid blood clots and artefacts in the PaO2 measurements.

Bedside monitoring of lung volume available for gas exchange.

BACKGROUND: Bedside measurement of lung volume may provide guidance in the personalised setting of respiratory support, especially in patients with the acute respiratory distress syndrome at risk of ventilator-induced lung injury. We propose here a novel operator-independent technique, enabled by a fibre optic oxygen sensor, to quantify the lung volume available for gas exchange. We hypothesised that the continuous measurement of arterial partial pressure of oxygen (PaO2) decline during a breath-holding manoeuvre could be used to estimate lung volume in a single-compartment physiological model of the respiratory system. METHODS: Thirteen pigs with a saline lavage lung injury model and six control pigs were studied under general anaesthesia during mechanical ventilation. Lung volumes were measured by simultaneous PaO2 rate of decline (VPaO2) and whole-lung computed tomography scan (VCT) during apnoea at different positive end-expiratory and end-inspiratory pressures. RESULTS: A total of 146 volume measurements was completed (range 134 to 1869 mL). A linear correlation between VCT and VPaO2 was found both in control (slope = 0.9, R2 = 0.88) and in saline-lavaged pigs (slope = 0.64, R2 = 0.70). The bias from Bland-Altman analysis for the agreement between the VCT and VPaO2 was - 84 mL (limits of agreement ± 301 mL) in control and + 2 mL (LoA ± 406 mL) in saline-lavaged pigs. The concordance for changes in lung volume, quantified with polar plot analysis, was - 4º (LoA ± 19°) in control and - 9° (LoA ± 33°) in saline-lavaged pigs. CONCLUSION: Bedside measurement of PaO2 rate of decline during apnoea is a potential approach for estimation of lung volume changes associated with different levels of airway pressure.

Real-time effects of PEEP and tidal volume on regional ventilation and perfusion in experimental lung injury.

BACKGROUND: Real-time bedside information on regional ventilation and perfusion during mechanical ventilation (MV) may help to elucidate the physiological and pathophysiological effects of MV settings in healthy and injured lungs. We aimed to study the effects of positive end-expiratory pressure (PEEP) and tidal volume (VT) on the distributions of regional ventilation and perfusion by electrical impedance tomography (EIT) in healthy and injured lungs. METHODS: One-hit acute lung injury model was established in 6 piglets by repeated lung lavages (injured group). Four ventilated piglets served as the control group. A randomized sequence of any possible combination of three VT (7, 10, and 15 ml/kg) and four levels of PEEP (5, 8, 10, and 12 cmH2O) was performed in all animals. Ventilation and perfusion distributions were computed by EIT within three regions-of-interest (ROIs): nondependent, middle, dependent. A mixed design with one between-subjects factor (group: intervention or control), and two within-subjects factors (PEEP and VT) was used, with a three-way mixed analysis of variance (ANOVA). RESULTS: Two-way interactions between PEEP and group, and VT and group, were observed for the dependent ROI (p = 0.035 and 0.012, respectively), indicating that the increase in the dependent ROI ventilation was greater at higher PEEP and VT in the injured group than in the control group. A two-way interaction between PEEP and VT was observed for perfusion distribution in each ROI: nondependent (p = 0.030), middle (p = 0.006), and dependent (p = 0.001); no interaction was observed between injured and control groups. CONCLUSIONS: Large PEEP and VT levels were associated with greater pulmonary ventilation of the dependent lung region in experimental lung injury, whereas they affected pulmonary perfusion of all lung regions both in the control and in the experimental lung injury groups.

Validating the inspired sinewave technique to measure the volume of the 'baby lung' in a porcine lung-injury model.

BACKGROUND: Bedside lung volume measurement could personalise ventilation and reduce driving pressure in patients with acute respiratory distress syndrome (ARDS). We investigated a modified gas-dilution method, the inspired sinewave technique (IST), to measure the effective lung volume (ELV) in pigs with uninjured lungs and in an ARDS model. METHODS: Anaesthetised mechanically ventilated pigs were studied before and after surfactant depletion by saline lavage. Changes in PEEP were used to change ELV. Paired measurements of absolute ELV were taken with IST (ELVIST) and compared with gold-standard measures (sulphur hexafluoride wash in/washout [ELVSF6] and computed tomography (CT) [ELVCT]). Measured volumes were used to calculate changes in ELV (ΔELV) between PEEP levels for each method (ΔELVIST, ΔELVSF6, and ΔELVCT). RESULTS: The coefficient of variation was <5% for repeated ELVIST measurements (n=13 pigs). There was a strong linear relationship between ELVIST and ELVSF6 in uninjured lungs (r2=0.97), and with both ELVSF6 and ELVCT in the ARDS model (r2=0.87 and 0.92, respectively). ELVIST had a mean bias of -12 to 13% (95% limits=±17 - 25%) compared with ELVSF6 and ELVCT. ΔELVIST was concordant with ΔELVSF6 and ΔELVCT in 98-100% of measurements, and had a mean bias of -73 to -77 ml (95% limits=±128 - 186 ml) compared with ΔELVSF6 and -1 ml (95% limits ±333 ml) compared with ΔELVCT. CONCLUSIONS: IST provides a repeatable measure of absolute ELV and shows minimal bias when tracking PEEP-induced changes in lung volume compared with CT in a saline-lavage model of ARDS.

Mechanical Ventilation Redistributes Blood to Poorly Ventilated Areas in Experimental Lung Injury.

OBJECTIVES: Determine the intra-tidal regional gas and blood volume distributions at different levels of atelectasis in experimental lung injury. Test the hypotheses that pulmonary aeration and blood volume matching is reduced during inspiration in the setting of minimal tidal recruitment/derecruitment and that this mismatching is an important determinant of hypoxemia. DESIGN: Preclinical study. SETTING: Research laboratory. SUBJECTS: Seven anesthetized pigs 28.7 kg (SD, 2.1 kg). INTERVENTIONS: All animals received a saline-lavage surfactant depletion lung injury model. Positive end-expiratory pressure was varied between 0 and 20 cm H2O to induce different levels of atelectasis. MEASUREMENTS AND MAIN RESULTS: Dynamic dual-energy CT images of a juxtadiaphragmatic slice were obtained, gas and blood volume fractions within three gravitational regions calculated and normalized to lung tissue mass (normalized gas volume and normalized blood volume, respectively). Ventilatory conditions were grouped based upon the fractional atelectatic mass in expiration (< 20%, 20-40%, and ≥ 40%). Tidal recruitment/derecruitment with fractional atelectatic mass in expiration greater than or equal to 40% was less than 7% of lung mass. In this group, inspiration-related increase in normalized gas volume was greater in the nondependent (818 µL/g [95% CI, 729-908 µL/g]) than the dependent region (149 µL/g [120-178 µL/g]). Normalized blood volume decreased in inspiration in the nondependent region (29 µL/g [12-46 µL/g]) and increased in the dependent region (39 µL/g [30-48 µL/g]). Inspiration-related changes in normalized gas volume and normalized blood volume were negatively correlated in fractional atelectatic mass in expiration greater than or equal to 40% and 20-40% groups (r = 0.56 and 0.40), but not in fractional atelectatic mass in expiration less than 20% group (r = 0.01). Both the increase in normalized blood volume in the dependent region and fractional atelectatic mass in expiration negatively correlated with PaO2/FIO2 ratio (ρ = -0.77 and -0.93, respectively). CONCLUSIONS: In experimental atelectasis with minimal tidal recruitment/derecruitment, mechanical inspiratory breaths redistributed blood volume away from well-ventilated areas, worsening PaO2/FIO2.

Dynamic single-slice CT estimates whole-lung dual-energy CT variables in pigs with and without experimental lung injury.

BACKGROUND: Dynamic single-slice CT (dCT) is increasingly used to examine the intra-tidal, physiological variation in aeration and lung density in experimental lung injury. The ability of dCT to predict whole-lung values is unclear, especially for dual-energy CT (DECT) variables. Additionally, the effect of inspiration-related lung movement on CT variables has not yet been quantified. METHODS: Eight domestic pigs were studied under general anaesthesia, including four following saline-lavage surfactant depletion (lung injury model). DECT, dCT and whole-lung images were collected at 12 ventilatory settings. Whole-lung single energy scans images were collected during expiratory and inspiratory apnoeas at positive end-expiratory pressures from 0 to 20 cmH2O. Means and distributions of CT variables were calculated for both dCT and whole-lung images. The cranio-caudal displacement of the anatomical slice was measured from whole-lung images. RESULTS: Mean CT density and volume fractions of soft tissue, gas, iodinated blood, atelectasis, poor aeration, normal aeration and overdistension correlated between dCT and the whole lung (r2 0.75-0.94) with agreement between CT density distributions (r 0.89-0.97). Inspiration increased the matching between dCT and whole-lung values and was associated with a movement of 32% (SD 15%) of the imaged slice out of the scanner field-of-view. This effect introduced an artefactual increase in dCT mean CT density during inspiration, opposite to that caused by the underlying physiology. CONCLUSIONS: Overall, dCT closely approximates whole-lung aeration and density. This approximation is improved by inspiration where a decrease in CT density and atelectasis can be interpreted as physiological rather than artefactual.

Respiratory oscillations in alveolar oxygen tension measured in arterial blood.

Arterial oxygen partial pressure can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. We measured arterial oxygen partial pressure continuously with a fast intra-vascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that arterial oxygen partial pressure shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (as determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the conditions of mechanical ventilation. These arterial oxygen partial pressure respiratory oscillations can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in the acute respiratory distress syndrome.

Laminar distribution of GABAA- and glycine-receptor mediated tonic inhibition in the dorsal horn of the rat lumbar spinal cord: effects of picrotoxin and strychnine on expression of Fos-like immunoreactivity.

Inhibitory mechanisms are essential in suppressing the development of allodynia and hyperalgesia in the normal animal and there is evidence that loss of inhibition can lead to the development of neuropathic pain. We used Fos expression to map the distribution of tonically inhibited cells in the healthy rat lumbar spinal cord. In a control group, Fos-like immunoreactive (Fos-LI) cells were rare, averaging 7.5+/-2.2 cells (mean+/-SEM; N=13 sections) per 20 microm thick section of dorsal horn. This rose to 103+/-11 (mean+/-SEM; N=20) in picrotoxin-treated rats and to 88+/-11 (mean+/-SEM; N=18) in strychnine-treated rats. These changes were significant (ANOVA; P<0.001). There were marked regional variations in the distribution of Fos-LI cells between picrotoxin- and strychnine-treated animals. Picrotoxin induced a significant increase in the number of Fos-LI cells throughout the dorsal horn (lamina I-VI) while strychnine significantly elevated Fos-like immunoreactivity only in deep laminae (III-VI). For both picrotoxin and strychnine, the increase in Fos-like immunoreactivity peaked in lamina V (at 3579+/-319 and 3649+/-375% of control, respectively; mean+/-SEM) but for picrotoxin an additional peak was observed in the outer part of lamina II (1959+/-196%). Intrathecal administration of both GABAA and glycine receptor antagonists has been shown elsewhere to induce tactile allodynia. The present data suggest that this allodynia could arise due to blockade of tonic GABAA and glycine-receptor mediated inhibition in the deep dorsal horn. GABAA antagonists also induce hypersensitivity to noxious inputs. The blockade of tonic inhibition in the superficial dorsal horn shown here may underlie this hyperalgesia.