Modulation of pulmonary blood flow in patients with acute respiratory failure.

BACKGROUND: Impairment of ventilation and perfusion (V/Q) matching is a common mechanism leading to hypoxemia in patients with acute respiratory failure requiring intensive care unit (ICU) admission. While ventilation has been thoroughly investigated, little progress has been made to monitor pulmonary perfusion at the bedside and treat impaired blood distribution. The study aimed to assess real-time changes in regional pulmonary perfusion in response to a therapeutic intervention. METHODS: Single-center prospective study that enrolled adult patients with ARDS caused by SARS-Cov-2 who were sedated, paralyzed, and mechanically ventilated. The distribution of pulmonary perfusion was assessed through electrical impedance tomography (EIT) after the injection of a 10-ml bolus of hypertonic saline. The therapeutic intervention consisted in the administration of inhaled nitric oxide (iNO), as rescue therapy for refractory hypoxemia. Each patient underwent two 15-min steps at 0 and 20 ppm iNO, respectively. At each step, respiratory, gas exchange, and hemodynamic parameters were recorded, and V/Q distribution was measured, with unchanged ventilatory settings. RESULTS: Ten 65 [56-75] years old patients with moderate (40%) and severe (60%) ARDS were studied 10 [4-20] days after intubation. Gas exchange improved at 20 ppm iNO (PaO2/FiO2 from 86 ± 16 to 110 ± 30 mmHg, p = 0.001; venous admixture from 51 ± 8 to 45 ± 7%, p = 0.0045; dead space from 29 ± 8 to 25 ± 6%, p = 0.008). The respiratory system's elastic properties and ventilation distribution were unaltered by iNO. Hemodynamics did not change after gas initiation (cardiac output 7.6 ± 1.9 vs. 7.7 ± 1.9 L/min, p = 0.66). The EIT pixel perfusion maps showed a variety of patterns of changes in pulmonary blood flow, whose increase positively correlated with PaO2/FiO2 increase (R2 = 0.50, p = 0.049). CONCLUSIONS: The assessment of lung perfusion is feasible at the bedside and blood distribution can be modulated with effects that are visualized in vivo. These findings might lay the foundations for testing new therapies aimed at optimizing the regional perfusion in the lungs.

Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients.

OBJECTIVES: To evaluate the frequency and pattern of pulmonary vascular abnormalities in the year following COVID-19. METHODS: The study population included 79 patients remaining symptomatic more than 6 months after hospitalization for SARS-CoV-2 pneumonia who had been evaluated with dual-energy CT angiography. RESULTS: Morphologic images showed CT features of (a) acute (2/79; 2.5%) and focal chronic (4/79; 5%) PE; and (b) residual post COVID-19 lung infiltration (67/79; 85%). Lung perfusion was abnormal in 69 patients (87.4%). Perfusion abnormalities included (a) perfusion defects of 3 types: patchy defects (n = 60; 76%); areas of non-systematized hypoperfusion (n = 27; 34.2%); and/or PE-type defects (n = 14; 17.7%) seen with (2/14) and without (12/14) endoluminal filling defects; and (b) areas of increased perfusion in 59 patients (74.9%), superimposed on ground-glass opacities (58/59) and vascular tree-in-bud (5/59). PFTs were available in 10 patients with normal perfusion and in 55 patients with abnormal perfusion. The mean values of functional variables did not differ between the two subgroups with a trend toward lower DLCO in patients with abnormal perfusion (74.8 ± 16.7% vs 85.0 ± 8.1). CONCLUSION: Delayed follow-up showed CT features of acute and chronic PE but also two types of perfusion abnormalities suggestive of persistent hypercoagulability as well as unresolved/sequelae of microangiopathy. CLINICAL RELEVANCE STATEMENT: Despite dramatic resolution of lung abnormalities seen during the acute phase of the disease, acute pulmonary embolism and alterations at the level of lung microcirculation can be identified in patients remaining symptomatic in the year following COVID-19. KEY POINTS: • This study demonstrates newly developed proximal acute PE/thrombosis in the year following SARS-CoV-2 pneumonia. • Dual-energy CT lung perfusion identified perfusion defects and areas of increased iodine uptake abnormalities, suggestive of unresolved damage to lung microcirculation. • This study suggests a complementarity between HRCT and spectral imaging for proper understanding of post COVID-19 lung sequelae.

Clinical characteristics and computed tomographical features of pulmonary thromboembolic disease associated with COVID-19 infection: A tertiary hospital analysis.

INTRODUCTION: The co-existence of coronavirus disease 2019 (COVID-19) and pulmonary thromboembolic (PTE) disease poses a great clinical challenge. To date, few researches have addressed this important clinical issue among the South-East Asian populations. The objectives of this study were as follow: (1) to describe the clinical characteristics and computed tomographical (CT) features of patients with PTE disease associated with COVID-19 infection and (2) to compare these parameters with those COVID-19 patients without PTE disease. MATERIALS AND METHODS: This cross-sectional study with retrospective record review was conducted in Hospital Tengku Ampuan Rahimah, Selangor, Malaysia. We included all hospitalised patients with confirmed COVID-19 infection who had undergone CT pulmonary angiogram (CTPA) examinations for suspected PTE disease between April 2021 and May 2021. Clinical data and laboratory data were extracted by trained data collectors, whilst CT images retrieved were analysed by a senior radiologist. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 20. RESULTS: We studied 184 COVID-19 patients who were suspected to have PTE disease. CTPA examinations revealed a total of 150 patients (81.5%) suffered from concomitant PTE disease. Among the PTE cohort, the commonest comorbidities were diabetes mellitus (n=78, 52.0%), hypertension (n=66, 44.0%) and dyslipidaemia (n=25, 16.7%). They were generally more ill than the non-PTE cohort as they reported a significantly higher COVID-19 disease category during CTPA examination with p=0.042. Expectedly, their length of both intensive care unit stays (median number of days 8 vs. 3; p=0.021) and hospital stays (median number of days 14.5 vs. 12; p=0.006) were significantly longer. Intriguingly, almost all the subjects had received either therapeutic anticoagulation or thromboprophylactic therapy prior to CTPA examination (n=173, 94.0%). Besides, laboratory data analysis identified a significantly higher peak C-reactive protein (median 124.1 vs. 82.1; p=0.027) and ferritin levels (median 1469 vs. 1229; p=0.024) among them. Evaluation of CT features showed that COVID-19 pneumonia pattern (p<0.001) and pulmonary angiopathy (p<0.001) were significantly more profound among the PTE cohort. To note, the most proximal pulmonary thrombosis was located in the segmental (n=3, 2.0%) and subsegmental pulmonary arteries (n=147, 98.0%). Also, the thrombosis predominantly occurred in bilateral lungs with multilobar involvement (n=95, 63.3%). CONCLUSION: Overall, PTE disease remains prevalent among COVID-19 patients despite timely administration of thromboprophylactic therapy. The presence of hyperinflammatory activities, unique thrombotic locations as well as concurrent pulmonary parenchyma and vasculature aberrations in our PTE cohort implicate immunothrombosis as the principal mechanism of this novel phenomenon. We strongly recommend future researchers to elucidate this important clinical disease among our post- COVID vaccination populations.

An expert opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation on screening for chronic thromboembolic pulmonary hypertension patients after acute pulmonary embolism: Update.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism (APE). Both pharmacological and invasive treatments for CTEPH are available in Poland, and awareness of the disease among physicians is growing. It has been suggested that the COVID-19 pandemic may increase the incidence of CTEPH and facilitate disease detection during more advanced stages of the illness. Thus, the Polish Cardiac Society's Working Group on Pulmonary Circulation, in cooperation with independent experts in this field, launched the updated statement on the algorithm to guide a CTEPH diagnosis in patients with previous APE. CTEPH should be suspected in individuals after APE with dyspnea, despite at least 3 months of effective anticoagulation, particularly when specific risk factors are present. Echocardiography is the main screening tool for CTEPH. A diagnostic workup of patients with significant clinical suspicion of CTEPH and right ventricular overload evident on echocardiography should be performed in reference centers. Pulmonary scintigraphy is a safe and highly sensitive screening test for CTEPH. Computed tomography pulmonary angiography with precise detection of thromboembolic residues in the pulmonary circulation is important for the planning of a pulmonary thromboendarterectomy. Right heart catheterization definitively confirms the presence of pulmonary hypertension and direct pulmonary angiography allows for the identification of lesions suitable for thromboendarterectomy or balloon pulmonary angioplasty. In this document, we propose a diagnostic algorithm for patients with suspected CTEPH. With an individualized and sequential diagnostic strategy, each patient can be provided with suitable and tailored therapy provided by a dedicated CTEPH Heart Team.

Impact of Right Ventricular-Pulmonary Circulation Coupling on Mortality in SARS-CoV-2 Infection.

Background The COVID-19-related pulmonary effects may negatively impact pulmonary hemodynamics and right ventricular function. We examined the prognostic relevance of right ventricular function and right ventricular-to-pulmonary circulation coupling assessed by bedside echocardiography in patients hospitalized with COVID-19 pneumonia and a large spectrum of disease independently of indices of pneumonia severity and left ventricular function. Methods and Results Consecutive COVID-19 subjects who underwent full cardiac echocardiographic evaluation along with gas analyses and computed tomography scans were included in the study. Measurements were performed offline, and quantitative analyses were obtained by an operator blinded to the clinical data. We analyzed 133 patients (mean age 69±12 years, 57% men). During a mean hospital stay of 26±16 days, 35 patients (26%) died. The mean tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio was 0.48±0.18 mm/Hg in nonsurvivors and 0.72±0.32 mm/Hg in survivors (P=0.002). For each 0.1 mm/mm Hg increase in TAPSE/PASP, there was a 27% lower risk of in-hospital death (hazard ratio [HR], 0.73 [95% CI, 0.59-0.89]; P=0.003). At multivariable analysis, TAPSE/PASP ratio remained a predictor of in-hospital death after adjustments for age, oxygen partial pressure at arterial gas analysis/fraction of inspired oxygen, left ventricular ejection fraction, and computed tomography lung score. Receiver operating characteristic analysis was used to identify the cutoff value of the TAPSE/PASP ratio, which best specified high-risk from lower-risk patients. The best cutoff for predicting in-hospital mortality was TAPSE/PASP <0.57 mm/mm Hg (75% sensitivity and 70% specificity) and was associated with a >4-fold increased risk of in-hospital death (HR, 4.8 [95% CI, 1.7-13.1]; P=0.007). Conclusions In patients hospitalized with COVID-19 pneumonia, the assessment of right ventricular to pulmonary circulation coupling appears central to disease evolution and prediction of events. TAPSE/PASP ratio plays a mainstay role as prognostic determinant beyond markers of lung injury.

Effects of rescue inhaled nitric oxide on right ventricle and pulmonary circulation in severe COVID-related acute respiratory distress syndrome.

PURPOSES: To assess the effects of inhaled Nitric Oxide (iNO) on right ventricle dimension and function and systolic pulmonary arterial pressures in severe Acute Respiratory Distress (ARDS) due to Sars-Cov2 (COVID) infection. MATERIALS AND METHODS: We assessed the effects of iNO on right ventricle dimension and function and systolic pulmonary arterial pressures in 12 consecutive COVID-related ARDS patients by means of serial echocardiographic exams (baseline, 12 and 24 h since iNO start). RESULTS: Inhaled NO administration did not influence systolic pulmonary arterial pressures nor RV dimension and function. No changes were detectable in ventilatory data with iNO administration. Considering the negligible effect on oxygenation, iNO use was discontinued in all cases. CONCLUSIONS: In COVID-related severe ARDS iNO administrated as rescue therapy is not able to ameliorate oxygenation nor pulmonary hypertension, as assessed by serial echocardiograms. This finding may be explained by the diffuse loss of hypoxic pulmonary vasoconstriction with increased perfusion around alveolar consolidations which characterizes COVID-related severe ARDS.

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

Interleukin-1RA Mitigates SARS-CoV-2-Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice.

[Figure: see text].

Endothelial metabolism in pulmonary vascular homeostasis and acute respiratory distress syndrome.

Capillary endothelial cells possess a specialized metabolism necessary to adapt to the unique alveolar-capillary environment. Here, we highlight how endothelial metabolism preserves the integrity of the pulmonary circulation by controlling vascular permeability, defending against oxidative stress, facilitating rapid migration and angiogenesis in response to injury, and regulating the epigenetic landscape of endothelial cells. Recent reports on single-cell RNA-sequencing reveal subpopulations of pulmonary capillary endothelial cells with distinctive reparative capacities, which potentially offer new insight into their metabolic signature. Lastly, we discuss broad implications of pulmonary vascular metabolism on acute respiratory distress syndrome, touching on emerging findings of endotheliitis in coronavirus disease 2019 (COVID-19) lungs.

The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report.

Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.

At a crossroads: coronavirus disease 2019 recovery and the risk of pulmonary vascular disease.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has led to almost 3,000,000 deaths across 139 million people infected worldwide. Involvement of the pulmonary vasculature is considered a major driving force for morbidity and mortality. We set out to summarize current knowledge on the acute manifestations of pulmonary vascular disease (PVD) resulting from COVID-19 and prioritize long-term complications that may result in pulmonary hypertension (PH). RECENT FINDINGS: Acute COVID-19 infection can result in widespread involvement of the pulmonary vasculature, myocardial injury, evidence of persistent lung disease, and venous thromboembolism. Post COVID-19 survivors frequently report ongoing symptoms and may be at risk for the spectrum of PH, including group 1 pulmonary arterial hypertension, group 2 PH due to left heart disease, group 3 PH due to lung disease and/or hypoxia, and group 4 chronic thromboembolic PH. SUMMARY: The impact of COVID-19 on the pulmonary vasculature is central to determining disease severity. Although the long-term PVD manifestations of COVID-19 are currently uncertain, optimizing the care of risk factors for PH and monitoring for the development of PVD will be critical to reducing long-term morbidity and improving the health of survivors.