Quantifying heterogeneity in an animal model of acute respiratory distress syndrome, a comparison of inspired sinewave technique to computed tomography.

The inspired sinewave technique (IST) is a non-invasive method to measure lung heterogeneity indices (including both uneven ventilation and perfusion or heterogeneity), which reveal multiple conditions of the lung and lung injury. To evaluate the reproducibility and predicted clinical outcomes of IST heterogeneity values, a comparison with a quantitative lung computed tomography (CT) scan is performed. Six anaesthetised pigs were studied after surfactant depletion by saline-lavage. Paired measurements of lung heterogeneity were then taken with both the IST and CT. Lung heterogeneity measured by the IST was calculated by (a) the ratio of tracer gas outputs measured at oscillation periods of 180 s and 60 s, and (b) by the standard deviation of the modelled log-normal distribution of ventilations and perfusions in the simulation lung. In the CT images, lungs were manually segmented and divided into different regions according to voxel density. A quantitative CT method to calculate the heterogeneity (the Cressoni method) was applied. The IST and CT show good Pearson correlation coefficients in lung heterogeneity measurements (ventilation: 0.71, and perfusion, 0.60, p < 0.001). Within individual animals, the coefficients of determination average ventilation (R2 = 0.53) and perfusion (R2 = 0.68) heterogeneity. Strong concordance rates of 98% in ventilation and 89% when the heterogeneity changes were reported in pairs measured by CT scanning and IST methods. This quantitative method to identify heterogeneity has the potential to replicate CT lung heterogeneity, and to aid individualised care in ARDS.

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.

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.

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.

Lung simulation to support non-invasive pulmonary blood flow measurement in Acute Respiratory Distress Syndrome in animals.

Patients undergoing mechanical lung ventilation are at risk of lung injury. A noninvasive bedside lung monitor may benefit these patients. The Inspired Sinewave Test (IST) can measure cardio-pulmonary parameters noninvasively. We propose a lung simulation to improve the measurement of pulmonary blood flow using IST. The new method was applied to 12 pigs' data before lung injury (control) and after lung injury (ARDS model). Results using the lung simulation shown improvements in correlation in both simulated data (R2 increased from 0.98 to 1) and pigs' data (R2 increased from <0.001 to 0.26). Paired blood flow measurements were performed by both the IST (noninvasive) and thermodilution (invasive). In the control group, the bias of the two methods was negligible (0.02L/min), and the limit of agreement was from -1.20 to 1.18 L/min. The bias was -0.68 L/min in the ARDS group and with a broader limit of agreement (-2.49 to 1.13 L/min).Clinical Relevance- the inspired sinewave test can be used to measure cardiac output noninvasively in mechanically ventilated subjects with and without acute respiratory distress syndrome.

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.

A tidal lung simulation to quantify lung heterogeneity with the Inspired Sinewave Test.

We have created a lung simulation to quantify lung heterogeneity from the results of the inspired sinewave test (IST). The IST is a lung function test that is non-invasive, non-ionising and does not require patients' cooperation. A tidal lung simulation is developed to assess this test and also a method is proposed to calculate lung heterogeneity from IST results. A sensitivity analysis based on the Morris method and linear regression were applied to verify and to validate the simulation. Additionally, simulated emphysema and pulmonary embolism conditions were created using the simulation to assess the ability of the IST to identify these conditions. Experimental data from five pigs (pre-injured vs injured) were used for validation. This paper contributes to the development of the IST. Firstly, our sensitivity analysis reveals that the IST is highly accurate with an underestimation of about 5% of the simulated values. Sensitivity analysis suggested that both instability in tidal volume and extreme expiratory flow coefficients during the test cause random errors in the IST results. Secondly, the ratios of IST results obtained at two tracer gas oscillation frequencies can identify lung heterogeneity (ELV60/ELV180 and Qp60/Qp180). There was dissimilarity between simulated emphysema and pulmonary embolism (p < 0.0001). In the animal model, the control group had ELV60/ELV180 = 0.58 compared with 0.39 in injured animals (p < 0.0001).

Lung heterogeneity and deadspace volume in animals with acute respiratory distress syndrome using the inspired sinewave test.

Acute respiratory distress syndrome (ARDS) is associated with a high rate of morbidity and mortality, as patients undergoing mechanical ventilation are at risk of ventilator-induced lung injuries.Objective: To measure the lung heterogeneity and deadspace volume to find safer ventilator strategies. The ventilator settings could then offer homogeneous ventilation and theoretically equalize and reduce tidal strain/stress in the lung parenchyma.Approach: The inspired sinewave test (IST) is a non-invasive lung measurement tool which does not require cooperation from the patient. The IST can measure the effective lung volume, pulmonary blood flow and deadspace volume. We developed a computational simulation of the cardiopulmonary system to allow lung heterogeneity to be quantified using data solely derived from the IST. Then, the method to quantify lung heterogeneity using two IST tracer gas frequencies (180 and 60 s) was introduced and used in lung simulations and animal models. Thirteen anaesthetized pigs were studied with the IST both before and after experimental lung injury (saline-lavage ARDS model). The deadspace volume was compared between the IST and the SF6washout method.Main results: The IST could measure lung heterogeneity using two tracer gas frequencies. Furthermore, the value of IST ventilation heterogeneity in ARDS lungs was higher than in control lungs at a positive end-expiratory pressure of 10 cmH2O (area under the curve = 0.85,p<0.001). Values for the deadspace volume measured by the IST have a strong relationship with the measured values of SF6(9 ml bias and limits of agreement from -79 to 57 ml in control animals).Significance: The IST technique has the potential for use in the identification of ventilation and perfusion heterogeneity during ventilator support.

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.

Effect of nitrite on the electroencephalographic activity in the healthy brain.

BACKGROUND: Nitrite is a major intravascular store for nitric oxide. The conversion of nitrite to the active nitric oxide occurs mainly under hypoxic conditions to increase blood flow where it is needed the most. The use of nitrite is, therefore, being evaluated widely to reduce the brain injury in conditions resulting in cerebral hypoxia, such as cardiac arrest, ischaemic stroke or subarachnoid haemorrhage. However, as it is still unknown how exogenous nitrite affects the brain activity of healthy individuals, it is difficult to clearly understand how it affects the ischaemic brain. OBJECTIVE: Here we performed a double-blind placebo-controlled crossover study to investigate the effects of nitrite on neural activity in the healthy brain. METHODS: Twenty-one healthy volunteers were recruited into the study. All participants received a continuous infusion of sodium nitrite (0.6 mg/kg/h) on one occasion and placebo (sodium chloride) on another occasion. Electroencephalogram was recorded before the start and during the infusion. We computed the power spectrum density within the conventional frequency bands (delta, theta, alpha, beta), and the ratio of the power within the alpha and delta bands. We also measured peripheral cardiorespiratory physiology and cerebral blood flow velocities. RESULTS: We found no significant effect of nitrite on the power spectrum density in any frequency band. Similarly, the alpha-delta power ratio did not differ between the two conditions. The peripheral cardiorespiratory physiology and middle cerebral artery velocity and associated indices were also unaffected by the nitrite infusion. However, nitrite infusion decreased the mean blood pressure and increased the methaemoglobin concentration in the blood. CONCLUSION: Our study shows that exogenous sodium nitrite does not alter the electrical activity in the healthy brain. This might be because the sodium nitrite is converted to vasoactive nitric oxide in areas of hypoxia, and in the healthy brain there is no significant amount of conversion due to lack of hypoxia. However, this lack of change in the power spectrum density in healthy people emphasises the specificity of the brain's response to nitrite in disease.

Noninvasive cardiac output monitoring in a porcine model using the inspired sinewave technique: a proof-of-concept study.

BACKGROUND: Cardiac output (Q˙) monitoring can support the management of high-risk surgical patients, but the pulmonary artery catheterisation required by the current 'gold standard'-bolus thermodilution (Q˙T)-has the potential to cause life-threatening complications. We present a novel noninvasive and fully automated method that uses the inspired sinewave technique to continuously monitor cardiac output (Q˙IST). METHODS: Over successive breaths the inspired nitrous oxide (N2O) concentration was forced to oscillate sinusoidally with a fixed mean (4%), amplitude (3%), and period (60 s). Q˙IST was determined in a single-compartment tidal ventilation lung model that used the resulting amplitude/phase of the expired N2O sinewave. The agreement and trending ability of Q˙IST were compared with Q˙T during pharmacologically induced haemodynamic changes, before and after repeated lung lavages, in eight anaesthetised pigs. RESULTS: Before lung lavage, changes in Q˙IST and Q˙T from baseline had a mean bias of -0.52 L min-1 (95% confidence interval [CI], -0.41 to -0.63). The concordance between Q˙IST and Q˙T was 92.5% as assessed by four-quadrant analysis, and polar plot analysis revealed a mean angular bias of 5.98° (95% CI, -24.4°-36.3°). After lung lavage, concordance was slightly reduced (89.4%), and the mean angular bias widened to 21.8° (-4.2°, 47.6°). Impaired trending ability correlated with shunt fraction (r=0.79, P<0.05). CONCLUSIONS: The inspired sinewave technique provides continuous and noninvasive monitoring of cardiac output, with a 'marginal-good' trending ability compared with cardiac output based on thermodilution. However, the trending ability can be reduced with increasing shunt fraction, such as in acute lung injury.