Long-term dyspnea, regional ventilation distribution and peripheral lung function in COVID-19 survivors: a 1 year follow up study.

BACKGROUND: Dyspnea is common after COVID-19 pneumonia and can be characterized by a defective CO2 diffusion (DLCO) despite normal pulmonary function tests (PFT). Nevertheless, DLCO impairment tends to normalize at 1 year, with no dyspnea regression. The altered regional distribution of ventilation and a dysfunction of the peripheral lung may characterize dyspnea at 1 year after COVID-19 pneumonia. We aimed at assessing the pattern of airway resistance and inflammation and the regional ventilation inhomogeneity in COVID-19 pneumonia survivors at 12-months after hospital discharge. METHODS: We followed up at 1-year patients previously admitted to the respiratory units (intensive care or sub-intensive care unit) for COVID-19 acute respiratory failure at 1-year after hospital discharge. PFT (spirometry, DLCO), impulse oscillometry (IOS), measurements of the exhaled nitric oxide (FENO) and Electrical Impedance Tomography (EIT) were used to evaluate lung volumes, CO2 diffusion capacity, peripheral lung inflammation/resistances and the regional inhomogeneity of ventilation distribution. A full medical examination was conducted, and symptoms of new onset (not present before COVID-19) were recorded. Patients were therefore divided into two groups based on the presence/absence of dyspnea (defined as mMRC ≥1) compared to evaluate differences in the respiratory function derived parameters. RESULTS: Sixty-seven patients were admitted between October and December 2020. Of them, 42/67 (63%) patients were discharged alive and 33 were evaluated during the follow up. Their mean age was 64 ± 11 years and 24/33 (73%) were males. Their maximum respiratory support was in 7/33 (21%) oxygen, in 4/33 (12%) HFNC, in 14/33 (42%) NIV/CPAP and in 8/33 (24%) invasive mechanical ventilation. During the clinical examination, 15/33 (45%) reported dyspnea. When comparing the two groups, no significant differences were found in PFT, in the peripheral airway inflammation (FENO) or mechanical properties (IOS). However, EIT showed a significantly higher regional inhomogeneity in patients with dyspnea both during resting breathing (0.98[0.96-1] vs 1.1[1-1.1], p = 0.012) and during forced expiration (0.96[0.94-1] vs 1 [0.98-1.1], p = 0.045). CONCLUSIONS: New onset dyspnea characterizes 45% of patients 1 year after COVID-19 pneumonia. In these patients, despite pulmonary function test may be normal, EIT shows a higher regional inhomogeneity both during quiet and forced breathing which may contribute to dyspnea. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04343053, registration date 13/04/2020.

Variation of poorly ventilated lung units (silent spaces) measured by electrical impedance tomography to dynamically assess recruitment.

BACKGROUND: Assessing alveolar recruitment at different positive end-expiratory pressure (PEEP) levels is a major clinical and research interest because protective ventilation implies opening the lung without inducing overdistention. The pressure-volume (P-V) curve is a validated method of assessing recruitment but reflects global characteristics, and changes at the regional level may remain undetected. The aim of the present study was to compare, in intubated patients with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS), lung recruitment measured by P-V curve analysis, with dynamic changes in poorly ventilated units of the dorsal lung (dependent silent spaces [DSSs]) assessed by electrical impedance tomography (EIT). We hypothesized that DSSs might represent a dynamic bedside measure of recruitment. METHODS: We carried out a prospective interventional study of 14 patients with AHRF and ARDS admitted to the intensive care unit undergoing mechanical ventilation. Each patient underwent an incremental/decremental PEEP trial that included five consecutive phases: PEEP 5 and 10 cmH2O, recruitment maneuver + PEEP 15 cmH2O, then PEEP 10 and 5 cmH2O again. We measured, at the end of each phase, recruitment from previous PEEP using the P-V curve method, and changes in DSS were continuously monitored by EIT. RESULTS: PEEP changes induced alveolar recruitment as assessed by the P-V curve method and changes in the amount of DSS (p < 0.001). Recruited volume measured by the P-V curves significantly correlated with the change in DSS (rs = 0.734, p < 0.001). Regional compliance of the dependent lung increased significantly with rising PEEP (median PEEP 5 cmH2O = 11.9 [IQR 10.4-16.7] ml/cmH2O, PEEP 15 cmH2O = 19.1 [14.2-21.3] ml/cmH2O; p < 0.001), whereas regional compliance of the nondependent lung decreased from PEEP 5 cmH2O to PEEP 15 cmH2O (PEEP 5 cmH2O = 25.3 [21.3-30.4] ml/cmH2O, PEEP 15 cmH2O = 20.0 [16.6-22.8] ml/cmH2O; p <0.001). By increasing the PEEP level, the center of ventilation moved toward the dependent lung, returning to the nondependent lung during the decremental PEEP steps. CONCLUSIONS: The variation of DSSs dynamically measured by EIT correlates well with lung recruitment measured using the P-V curve technique. EIT might provide useful information to titrate personalized PEEP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02907840 . Registered on 20 September 2016.

Physiologic Effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure.

RATIONALE: High-flow nasal cannula (HFNC) improves the clinical outcomes of nonintubated patients with acute hypoxemic respiratory failure (AHRF). OBJECTIVES: To assess the effects of HFNC on gas exchange, inspiratory effort, minute ventilation, end-expiratory lung volume, dynamic compliance, and ventilation homogeneity in patients with AHRF. METHODS: This was a prospective randomized crossover study in nonintubated patients with AHRF with PaO2/setFiO2 less than or equal to 300 mm Hg admitted to the intensive care unit. We randomly applied HFNC set at 40 L/min compared with a standard nonocclusive facial mask at the same clinically set FiO2 (20 min/step). MEASUREMENTS AND MAIN RESULTS: Toward the end of each phase, we measured arterial blood gases, inspiratory effort, and work of breathing by esophageal pressure swings (ΔPes) and pressure time product, and we estimated changes in lung volumes and ventilation homogeneity by electrical impedance tomography. We enrolled 15 patients aged 60 ± 14 years old with PaO2/setFiO2 130 ± 35 mm Hg. Seven (47%) had bilateral lung infiltrates. Compared with the facial mask, HFNC significantly improved oxygenation (P < 0.001) and lowered respiratory rate (P < 0.01), ΔPes (P < 0.01), and pressure time product (P < 0.001). During HFNC, minute ventilation was reduced (P < 0.001) at constant arterial CO2 tension and pH (P = 0.27 and P = 0.23, respectively); end-expiratory lung volume increased (P < 0.001), and tidal volume did not change (P = 0.44); the ratio of tidal volume to ΔPes (an estimate of dynamic lung compliance) increased (P < 0.05); finally, ventilation distribution was more homogeneous (P < 0.01). CONCLUSIONS: In patients with AHRF, HFNC exerts multiple physiologic effects including less inspiratory effort and improved lung volume and compliance. These benefits might underlie the clinical efficacy of HFNC.

Control of Respiratory Drive and Effort in Extracorporeal Membrane Oxygenation Patients Recovering from Severe Acute Respiratory Distress Syndrome.

BACKGROUND: The amount of extracorporeal carbon dioxide removal may influence respiratory drive in acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). The authors evaluated the effects of different levels of extracorporeal carbon dioxide removal in patients recovering from severe ARDS undergoing pressure support ventilation (PSV) and neurally adjusted ventilatory assist (NAVA). METHODS: The authors conducted a prospective, randomized, crossover study on eight spontaneously breathing ARDS patients undergoing venovenous ECMO since 28 ± 20 days. To modulate carbon dioxide extraction, ECMO gas flow (GF) was decreased from baseline resting protective conditions (i.e., GF100%, set to obtain pressure generated in the first 100 ms of inspiration against an occluded airway less than 2 cm H2O, respiratory rate less than or equal to 25 bpm, tidal volume less than 6 ml/kg, and peak airway pressure less than 25 cm H2O) to GF50%-GF25%-GF0% during both PSV and NAVA (random order for ventilation mode). Continuous recordings of airway pressure and flow and esophageal pressure were obtained and analyzed during all study phases. RESULTS: At higher levels of extracorporeal carbon dioxide extraction, pressure generated in the first 100 ms of inspiration against an occluded airway decreased from 2.8 ± 2.7 cm H2O (PSV, GF0%) and 3.0 ± 2.1 cm H2O (NAVA, GF0%) to 0.9 ± 0.5 cm H2O (PSV, GF100%) and 1.0 ± 0.8 cm H2O (NAVA, GF100%; P < 0.001) and patients' inspiratory muscle pressure passed from 8.5 ± 6.3 and 6.5 ± 5.5 cm H2O to 4.5 ± 3.1 and 4.2 ± 3.7 cm H2O (P < 0.001). In time, decreased inspiratory drive and effort determined by higher carbon dioxide extraction led to reduction of tidal volume from 6.6 ± 0.9 and 7.5 ± 1.2 ml/kg to 4.9 ± 0.8 and 5.3 ± 1.3 ml/kg (P < 0.001) and of peak airway pressure from 21 ± 3 and 25 ± 4 cm H2O to 21 ± 3 and 21 ± 5 cm H2O (P < 0.001). Finally, transpulmonary pressure linearly decreased when the amount of carbon dioxide extracted by ECMO increased (R = 0.823, P < 0.001). CONCLUSIONS: In patients recovering from ARDS undergoing ECMO, the amount of carbon dioxide removed by the artificial lung may influence spontaneous breathing. The effects of carbon dioxide removal on spontaneous breathing during the earlier acute phases of ARDS remain to be elucidated.

Heterogeneity of Ventilation/Perfusion Mismatch at Different Levels of PEEP and in Mechanical Phenotypes of COVID-19 ARDS.

BACKGROUND: COVID-19-related ARDS is characterized by severe hypoxemia with initially preserved lung compliance and impaired ventilation/perfusion (V̇/Q̇) matching. PEEP can increase end-expiratory lung volume, but its effect on V̇/Q̇ mismatch in COVID-19-related ARDS is not clear. METHODS: We enrolled intubated and mechanically ventilated subjects with COVID-19 ARDS and used the automatic lung parameter estimator (ALPE) to measure V̇/Q̇. Respiratory mechanics measurements, shunt, and V̇/Q̇ mismatch (low V̇/Q̇ and high V̇/Q̇) were collected at 3 PEEP levels (clinical PEEP = intermediate PEEP, low PEEP [clinical - 50%], and high PEEP [clinical + 50%]). A mixed-effect model was used to evaluate the impact of PEEP on V̇/Q̇. We also investigated if PEEP might have a different effect on V̇/Q̇ mismatch in 2 different respiratory mechanics phenotypes, that is, high elastance/low compliance (phenotype H) and low elastance/high compliance (phenotype L). RESULTS: Seventeen subjects with COVID-related ARDS age 66 [60-71] y with a PaO2 /FIO2 of 141 ± 74 mm Hg were studied at low PEEP = 5.6 ± 2.2 cm H2O, intermediate PEEP = 10.6 ± 3.8 cm H2O, and high PEEP = 15 ± 5 cm H2O. Shunt, low V̇/Q̇, high V̇/Q̇, and alveolar dead space were not significantly influenced, on average, by PEEP. Respiratory system compliance decreased significantly when increasing PEEP without significant variation of PaO2 /FIO2 (P = .26). In the 2 phenotypes, PEEP had opposite effects on shunt, with a decrease in the phenotype L and an increase in phenotype H (P = .048). CONCLUSIONS: In subjects with COVID-related ARDS placed on invasive mechanical ventilation for > 48 h, PEEP had a heterogeneous effect on V̇/Q̇ mismatch and, on average, higher levels were not able to reduce shunt. The subject's compliance could influence the effect of PEEP on V̇/Q̇ mismatch since an increased shunt was observed in subjects with lower compliance, whereas the opposite occurred in those with higher compliance.

Management of Intraoperative Mechanical Ventilation to Prevent Postoperative Complications after General Anesthesia: A Narrative Review.

Mechanical ventilation (MV) is still necessary in many surgical procedures; nonetheless, intraoperative MV is not free from harmful effects. Protective ventilation strategies, which include the combination of low tidal volume and adequate positive end expiratory pressure (PEEP) levels, are usually adopted to minimize the ventilation-induced lung injury and to avoid post-operative pulmonary complications (PPCs). Even so, volutrauma and atelectrauma may co-exist at different levels of tidal volume and PEEP, and therefore, the physiological response to the MV settings should be monitored in each patient. A personalized perioperative approach is gaining relevance in the field of intraoperative MV; in particular, many efforts have been made to individualize PEEP, giving more emphasis on physiological and functional status to the whole body. In this review, we summarized the latest findings about the optimization of PEEP and intraoperative MV in different surgical settings. Starting from a physiological point of view, we described how to approach the individualized MV and monitor the effects of MV on lung function.

Dynamic bedside assessment of the physiologic effects of prone position in acute respiratory distress syndrome patients by electrical impedance tomography.

BACKGROUND: Prone position (PP) improves acute respiratory distress syndrome (ARDS) survival by reducing the risk of ventilation-induced lung injury. However, inter-individual variability is a hallmark of ARDS and lung protection by PP might not be optimal in all patients. In the present study, we dynamically assessed physiologic effects of PP by electrical impedance tomography (EIT) and identified predictors of improved lung protection by PP in ARDS patients. METHODS: Prospective physiologic study on 16 intubated, sedated and paralyzed patients with ARDS undergoing PP as per clinical decision. EIT data were recorded during two consecutive steps: 1) baseline supine position before and after a recruitment maneuver (RM); 2) prone position before and after a RM. "Improved lung protection" by PP was defined in the presence of simultaneous improvement of ventilation homogeneity (Hom), alveolar overdistension and collapse (ODCL) and amount of recruitable lung volume by RM in comparison to supine. RESULTS: PP versus supine increased the tidal volume distending the dependent regions (Vtdep), resulting in improved Hom (1.1±0.9 vs. 1.7±0.9, P=0.021). PP also reduced ODCL (19±9% vs. 28±8%, P=0.005) and increased the recruitable lung volume (80 [71-157] vs. 59 [1-110] mL, P=0.025). "Improved lung protection" by PP was predicted by lower Vtdep, higher Vtndep and poorer Hom measured during baseline supine position (P<0.05). CONCLUSIONS: EIT enables dynamic bedside assessment of the physiologic effects of PP and might support early recognition of ARDS patients more likely to benefit from PP.

Noninvasive assessment of airflows by electrical impedance tomography in intubated hypoxemic patients: an exploratory study.

BACKGROUND: Noninvasive monitoring of maximal inspiratory and expiratory flows (MIF and MEF, respectively) by electrical impedance tomography (EIT) might enable early recognition of changes in the mechanical properties of the respiratory system due to new conditions or in response to treatments. We aimed to validate EIT-based measures of MIF and MEF against spirometry in intubated hypoxemic patients during controlled ventilation and spontaneous breathing. Moreover, regional distribution of maximal airflows might interact with lung pathology and increase the risk of additional ventilation injury. Thus, we also aimed to describe the effects of mechanical ventilation settings on regional MIF and MEF. METHODS: We performed a new analysis of data from two prospective, randomized, crossover studies. We included intubated patients admitted to the intensive care unit with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) undergoing pressure support ventilation (PSV, n = 10) and volume-controlled ventilation (VCV, n = 20). We measured MIF and MEF by spirometry and EIT during six different combinations of ventilation settings: higher vs. lower support during PSV and higher vs. lower positive end-expiratory pressure (PEEP) during both PSV and VCV. Regional airflows were assessed by EIT in dependent and non-dependent lung regions, too. RESULTS: MIF and MEF measured by EIT were tightly correlated with those measured by spirometry during all conditions (range of R2 0.629-0.776 and R2 0.606-0.772, respectively, p < 0.05 for all), with clinically acceptable limits of agreement. Higher PEEP significantly improved homogeneity in the regional distribution of MIF and MEF during volume-controlled ventilation, by increasing airflows in the dependent lung regions and lowering them in the non-dependent ones. CONCLUSIONS: EIT provides accurate noninvasive monitoring of MIF and MEF. The present study also generates the hypothesis that EIT could guide PSV and PEEP settings aimed to increase homogeneity of distending and deflating regional airflows.

Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine.

Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611--620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for "lumping and splitting" are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147--155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939). Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS. Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of ß2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).

Increasing support by nasal high flow acutely modifies the ROX index in hypoxemic patients: A physiologic study.

The ROX (Respiratory rate-OXygenation) index is an early predictor of failure of nasal high flow (NHF), with lower values indicating higher risk of intubation. We measured the ROX index at set flow rate of 30 and 60 l/min in 57 hypoxemic patients on NHF. Patients with increased ROX index values at higher flow (n = 40) showed worse baseline oxygenation, higher respiratory rate and lower ROX index in comparison to patients with unchanged or decreased ROX index values (n = 17). The ROX index variation between flows was correlated with the change in end expiratory lung volume. Set flow rate during NHF might impact the ROX index value.

Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates.

PURPOSE: Limited data exist on the correlation between higher flow rates of high-flow nasal cannula (HFNC) and its physiologic effects in patients with acute hypoxemic respiratory failure (AHRF). We assessed the effects of HFNC delivered at increasing flow rate on inspiratory effort, work of breathing, minute ventilation, lung volumes, dynamic compliance and oxygenation in AHRF patients. METHODS: A prospective randomized cross-over study was performed in non-intubated patients with patients AHRF and a PaO2/FiO2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio of ≤300 mmHg. A standard non-occlusive facial mask and HFNC at different flow rates (30, 45 and 60 l/min) were randomly applied, while maintaining constant FiO2 (20 min/step). At the end of each phase, we measured arterial blood gases, inspiratory effort, based on swings in esophageal pressure (ΔPes) and on the esophageal pressure-time product (PTPPes), and lung volume, by electrical impedance tomography. RESULTS: Seventeen patients with AHRF were enrolled in the study. At increasing flow rate, HFNC reduced ΔPes (p < 0.001) and PTPPes (p < 0.001), while end-expiratory lung volume (ΔEELV), tidal volume to ΔPes ratio (V T/ΔPes, which corresponds to dynamic lung compliance) and oxygenation improved (p < 0.01 for all factors). Higher HFNC flow rate also progressively reduced minute ventilation (p < 0.05) without any change in arterial CO2 tension (p = 0.909). The decrease in ΔPes, PTPPes and minute ventilation at increasing flow rates was better described by exponential fitting, while ΔEELV, V T/ΔPes and oxygenation improved linearly. CONCLUSIONS: In this cohort of patients with AHRF, an increasing HFNC flow rate progressively decreased inspiratory effort and improved lung aeration, dynamic compliance and oxygenation. Most of the effect on inspiratory workload and CO2 clearance was already obtained at the lowest flow rate.

Bedside assessment of the effects of positive end-expiratory pressure on lung inflation and recruitment by the helium dilution technique and electrical impedance tomography.

PURPOSE: Higher positive end-expiratory pressure might induce lung inflation and recruitment, yielding enhanced regional lung protection. We measured positive end-expiratory pressure-related lung volume changes by electrical impedance tomography and by the helium dilution technique. We also used electrical impedance tomography to assess the effects of positive end-expiratory pressure on regional determinants of ventilator-induced lung injury. METHODS: A prospective randomized crossover study was performed on 20 intubated adult patients: 12 with acute hypoxemic respiratory failure and 8 with acute respiratory distress syndrome. Each patient underwent protective controlled ventilation at lower (7 [7, 8] cmH2O) and higher (12 [12, 13] cmH2O) positive end-expiratory pressures. At the end of each phase, we collected ventilation, helium dilution, and electrical impedance tomography data. RESULTS: Positive end-expiratory pressure-induced changes in lung inflation and recruitment measured by electrical impedance tomography and helium dilution showed close correlations (R (2) = 0.78, p < 0.001 and R (2) = 0.68, p < 0.001, respectively) but with relatively variable limits of agreement. At higher positive end-expiratory pressure, recruitment was evident in all lung regions (p < 0.01) and heterogeneity of tidal ventilation distribution was reduced by increased tidal volume distending the dependent lung (p < 0.001); in the non-dependent lung, on the other hand, compliance decreased (p < 0.001) and tidal hyperinflation significantly increased (p < 0.001). In the subgroup of ARDS patients (but not in the whole study population) tidal hyperinflation in the dependent lung regions decreased at higher positive end-expiratory pressure (p = 0.05), probably indicating higher potential for recruitment. CONCLUSIONS: Close correlations exist between bedside assessment of positive end-expiratory pressure-induced changes in lung inflation and recruitment by the helium dilution and electrical impedance tomography techniques. Higher positive end-expiratory pressure exerts mixed effects on the regional determinants of ventilator-induced lung injury; these merit close monitoring.