Diagnostic importance of lung perfusion/ventilation scans in the evaluation of pulmonary embolism in COVID-19 patients: systematic review of the literature.

OBJECTIVE: To investigate the outcomes of ventilation/perfusion scintigraphy on the diagnosis of pulmonary embolism in coronavirus disease 2019 (COVID-19) patients, we performed a systematic review of the available literature. MATERIALS AND METHODS: PubMed and Scopus were systematically searched up to 4 June 2022, for relevant studies. We included studies on patients with COVID-19 who have performed ventilation/perfusion scintigraphy for diagnosis of pulmonary embolism to describe any diagnosis outcome. Irrelevant and non-English articles were excluded. RESULTS: Overall, 27 articles were included in our review. The database search yielded studies from PubMed, Scopus, and studies identified through reviewing the reference list of included studies. Extracted information from the included studies could be categorized into several aspects: Diagnosis of pulmonary embolism with Q single-photon emission computed tomography (SPECT) CT, Tracheobronchial uptake, Diagnostic value of V/Q rather than Q at diagnosis pulmonary embolism, Different characteristics (morphological alterations) of COVID-19 in ventilation orperfusion scan, the prevalence of pulmonary embolism with Q or V/Q criteria, and Design of radiotherapy planning in lung cancer patients with COVID-19. CONCLUSION: Different perfusion patterns in COVID-19 are challenging but can be alleviated by adding SPECT/computed tomography (CT) to lung perfusion scans. Although perfusion only SPECT/CT can rule out or rule in others in considerable number of patients, ventilation scan is still needed in certain patients.

Lung Ventilation-Perfusion Scan in COVID-19: Various Patterns of Perfusion Defects.

ABSTRACT: Although COVID-19 infection is associated with the increased risk of pulmonary thromboembolism (PTE), COVID-19 pulmonary lesions cause ventilation-perfusion (V/Q) patterns other than PTE. Although extensive research has been done to address different anatomical patterns of COVID-19, there is a knowledge gap in terms of V/Q lung scintigraphy in these patients. The purpose of this study is to demonstrate these patterns and to show how important it is to use SPECT/CT in addition to planar images to differentiate between these patterns from PTE. In the current collection, we presented various patterns of V/Q SPECT/CT abnormalities in COVID-19 patients.

Ventilation Scintigraphy With Radiolabeled Carbon Nanoparticulate Aerosol (Technegas): State-of-the-Art Review and Diagnostic Applications to Pulmonary Embolism During COVID-19 Pandemic.

ABSTRACT: Invented and first approved for clinical use in Australia 36 years ago, Technegas is the technology that enabled ventilation scintigraphy with 99m Tc-labeled carbon nanoparticles ( 99m Tc-CNP). The US Food and Drug Administration (FDA) has considered this technology for more than 30 years but only now is getting close to approving it. Meanwhile, more than 4.4 million patients benefited from this technology in 64 countries worldwide. The primary application of 99m Tc-CNP ventilation imaging is the diagnostic evaluation for suspicion of pulmonary embolism using ventilation-perfusion quotient (V/Q) imaging. Because of 99m Tc-CNP's long pulmonary residence, tomographic imaging emerged as the preferred V/Q methodology. The FDA-approved ventilation imaging agents are primarily suitable for planar imaging, which is less sensitive. After the FDA approval of Technegas, the US practice will likely shift to tomographic V/Q. The 99m Tc-CNP use is of particular interest in the COVID-19 pandemic because it offers an option of a dry radioaerosol that takes approximately only 3 to 5 tidal breaths, allowing the shortest exposure to and contact with possibly infected patients. Indeed, countries where 99m Tc-CNP was approved for clinical use continued using it throughout the COVID-19 pandemic without known negative viral transmission consequences. Conversely, the ventilation imaging was halted in most US facilities from the beginning of the pandemic. This review is intended to familiarize the US clinical nuclear medicine community with the basic science of 99m Tc-CNP ventilation imaging and its clinical applications, including common artifacts and interpretation criteria for tomographic V/Q imaging for pulmonary embolism.

Intrapulmonary shunting is a key contributor to hypoxia in COVID-19: An update on the pathophysiology.

BACKGROUND: The pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical model to construct oxygen-haemoglobin dissociation curves (ODCs). METHODS: ODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network. RESULTS: Overall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8-24.5); VA/Q was 0.61 (IQR 0.52-0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9-29) compared to survivors (16%, 8-21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01-1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87-0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50-0.73) and survivors (0.61; IQR 0.52-0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18-2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12). INTERPRETATION: Shunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.

Identifying putative ventilation-perfusion distributions in COVID-19 pneumonia.

Busana et al. (doi.org/10.1152/japplphysiol.00871.2020) published 5 patients with COVID-19 in whom the fraction of non-aerated lung tissue had been quantified by computed tomography. They assumed that shunt flow fraction was proportional to the non-aerated lung fraction, and, by randomly generating 106 different bimodal distributions for the ventilation-perfusion ([Formula: see text]) ratios in the lung, specified as sets of paired values {[Formula: see text]}, sought to identify as solutions those that generated the observed arterial partial pressures of CO2 and O2 (PaCO2 and PaO2). Our study sought to develop a direct method of calculation to replace the approach of randomly generating different distributions, and so provide more accurate solutions that were within the measurement error of the blood-gas data. For the one patient in whom Busana et al. did not find solutions, we demonstrated that the assumed shunt flow fraction led to a non-shunt blood flow that was too low to support the required gas exchange. For the other four patients, we found precise solutions (prediction error < 1x10-3 mmHg for both PaCO2 and PaO2), with distributions qualitatively similar to those of Busana et al. These distributions were extremely wide and unlikely to be physically realisable, because they predict the maintenance of very large concentration gradients in regions of the lung where convection is slow. We consider that these wide distributions arise because the assumed value for shunt flow is too low in these patients, and we discuss possible reasons why the assumption relating to shunt flow fraction may break down in COVID-19 pneumonia.

Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial.

BACKGROUND: SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA. METHODS: Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis. RESULTS: Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41-68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7-12 days vs. 12 IQR 9-21 days, p = 0.04). CONCLUSIONS: No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results. TRIAL REGISTRATION: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446 .

Lung Scintigraphy for Pulmonary Embolism Diagnosis in COVID-19 Patients: A Multicenter Study.

In patients with novel coronavirus disease 2019 (COVID-19) referred for lung scintigraphy because of suspected pulmonary embolism (PE), there has been an ongoing debate within the nuclear medicine community as to whether and when the ventilation imaging should be performed. Indeed, whereas PE diagnosis typically relies on the recognition of ventilation-perfusion (V/P) mismatched defects, the ventilation procedure potentially increases the risk of contamination to health-care workers. The primary aim of this study was to assess the role of ventilation imaging when lung scintigraphy is performed because of suspected PE in COVID-19 patients. The secondary aim was to describe practices and imaging findings in this specific population. Methods: A national registry was created in collaboration with the French Society of Nuclear Medicine to collect lung scans performed on COVID-19 patients for suspected PE. The practices of departments were assessed regarding imaging protocols and aerosol precautions. A retrospective review of V/P SPECT/CT scans was then conducted. Two physicians masked to clinical information reviewed each case by sequentially viewing perfusion SPECT, perfusion SPECT/CT, and V/P SPECT/CT images. The scans were classified into 1 of the 4 following categories: patients for whom PE could reasonably be excluded on the basis of perfusion SPECT only, perfusion SPECT/CT, or V/P SPECT/CT and patients with mismatched defects suggestive of PE according to the European Association of Nuclear Medicine criteria. Results: Data from 12 French nuclear medicine departments were collected. Lung scans were performed between March 2020 and April 2021. Personal protective equipment and dedicated cleaning procedures were used in all departments. Of the 145 V/Q SPECT/CT scans included in the central review, PE could be excluded using only perfusion SPECT, perfusion SPECT/CT, or V/P SPECT/CT in 27 (19%), 55 (38%), and 45 (31%) patients, respectively. V/P SPECT/CT was positive for PE in 18 (12%) patients, including 12 (67%) with a low burden of PE (≤10%). Conclusion: In this population of COVID-19 patients assessed with lung scintigraphy, PE could confidently be excluded without the ventilation imaging in only 57% of patients. Ventilation imaging was required to confidently rule out PE in 31% of patients. Overall, the prevalence of PE was low (12%).

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

BACKGROUND: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. METHODS: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. RESULTS: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). CONCLUSIONS: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

Experience with a Perfusion-Only Screening Protocol for Evaluation of Pulmonary Embolism During the COVID-19 Pandemic Surge.

The purpose of this study was to evaluate a pulmonary embolism (PE) perfusion-only screening (POS) protocol introduced during the coronavirus disease 2019 (COVID-19) pandemic surge. Subjects without dense parenchymal lung opacities were studied; those with less than 1 segmental perfusion defect were considered to have no PE, whereas those exhibiting 1 or more defects were indeterminate, mandating additional examinations to determine the final diagnosis. Methods: We analyzed demographic information, clinical data, imaging findings, and follow-up data from the electronic records of COVID-19 patients who underwent lung scintigraphy during the 60-d study period. Results: In total, 53 studies were performed on 17 COVID-19-positive and 36 COVID-19-negative patients. The POS protocol efficiently excluded PE in 79% of cases; the remaining 21%, indeterminate for PE, were generally referred for alternative testing or were directly anticoagulated. In patients with negative POS results, there was a very low mortality before hospital discharge (1/42) and normal results on follow-up studies (6/6). Conclusion: The POS protocol, implemented during the COVID-19 surge, efficiently and safely excluded PE in 79% of patients.

Evaluation of the efficacy and safety of inhaled magnesium sulphate in combination with standard treatment in patients with moderate or severe COVID-19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Basic and clinical studies have shown that magnesium sulphate ameliorates lung injury and controls asthma attacks by anti-inflammatory and bronchodilatory effects. Both intravenous and inhaled magnesium sulphate have a clinical impact on acute severe asthma by inhibition of airway smooth muscle contraction. Besides, magnesium sulphate can dilate constricted pulmonary arteries and reduce pulmonary artery resistance. However, it may affect systemic arteries when administered intravenously. A large number of patients with covid-19 admitted to the hospital suffer from pulmonary involvement. COVID-19 can cause hypoxia due to the involvement of the respiratory airways and parenchyma along with circulatory impairment, which induce ventilation-perfusion mismatch. This condition may result in hypoxemia and low arterial blood oxygen pressure and saturation presented with some degree of dyspnoea and shortness of breath. Inhaled magnesium sulphate as a smooth muscle relaxant (natural calcium antagonist) can cause both bronchodilator and consequently vasodilator effects (via a direct effect on alveolar arterioles in well-ventilated areas) in the respiratory tract. We aim to investigate if inhaled magnesium sulphate as adjuvant therapy to standard treatment can reduce ventilation-perfusion mismatch in the respiratory tract and subsequently improve arterial oxygen saturation in hospitalized patients with COVID-19. TRIAL DESIGN: A multi-centre, open-label, randomised controlled trial (RCT) with two parallel arms design (1:1 ratio) PARTICIPANTS: Patients aged 18-80 years hospitalized at Masih Daneshvari Hospital and Shahid Dr. Labbafinejad hospital in Tehran and Shahid Sadoughi Hospital in Yazd will be included if they meet the inclusion criteria of the study. Inclusion criteria are defined as 1. Confirmed diagnosis of SARS-CoV-2 infection based on polymerase chain reaction (PCR) of nasopharyngeal secretions or clinical manifestations along with chest computed tomography (chest CT) scan 2. Presenting with moderate or severe COVID-19 lung involvement confirmed with chest CT scan and arterial oxygen saturation below 93% 3. Length of hospital stay ≤48 hours. Patients with underlying cardiovascular diseases including congestive heart failure, bradyarrhythmia, heart block, the myocardial injury will be excluded from the study. INTERVENTION AND COMPARATOR: Participants will be randomly divided into two arms. Patients in the intervention arm will be given both standard treatment for COVID-19 (according to the national guideline) and magnesium sulphate (5 cc of a 20% injectable vial or 2 cc of a 50% injectable vial will be diluted by 50 cc distilled water and nebulized via a mask) every eight hours for five days. Patients in the control (comparator) arm will only receive standard treatment for COVID-19. MAIN OUTCOMES: Improvement of respiratory function and symptoms including arterial blood oxygen saturation, dyspnoea (according to NYHA functional classification), and cough within the first five days of randomization. RANDOMISATION: Block randomisation will be used to allocate eligible patients to the study arms (in a 1:1 ratio). Computer software will be applied to randomly select the blocks. BLINDING (MASKING): The study is an open-label RCT without blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The trial will be performed on 100 patients who will be randomly divided into two arms of control (50) and intervention (50). TRIAL STATUS: The protocol is Version 5.0, January 05, 2021. Recruitment of the participants started on July 30, 2020, and it is anticipated to be completed by February 28, 2021. TRIAL REGISTRATION: The trial was registered in the Iranian Registry of Clinical Trials (IRCT) on July 28, 2020. It is available on https://en.irct.ir/trial/49879 . The registration number is IRCT20191211045691N1. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The impact of ventilation-perfusion inequality in COVID-19: a computational model.

COVID-19 infection may lead to acute respiratory distress syndrome (CARDS) where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This may suggest that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (VentriQlar), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation-perfusion (VA/Q) compartments and, after calculating their blood composition (PO2, PCO2, and pH), we randomly chose 106 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO2 and PaCO2 were within 10% of the patient's values. We assumed that the shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO2/FiO2 was 91.1 ± 18.6 mmHg and PaCO2 69.0 ± 16.1 mmHg. Cardiac output was 9.58 ± 0.99 L/min. The fraction of non-aerated tissue was 0.33 ± 0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low VA/Q (Qmean = 0.06 ± 0.02) and a smaller fraction in regions with moderately high VA/Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high VA/Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant VA/Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue.NEW & NOTEWORTHY Hypothesizing that the non-aerated lung fraction as evaluated by the quantitative analysis of the lung computed tomography (CT) equals shunt (VA/Q = 0), we used a computational approach to estimate the magnitude of the ventilation-perfusion inequality in severe COVID-19. The results show that a severe hyperperfusion of poorly ventilated lung region is likely the cause of the observed hypoxemia. The extensive microthrombosis or abnormal vasodilation of the pulmonary circulation may represent the pathophysiological mechanism of such VA/Q distribution.

Pulmonary Embolism in an Asymptomatic COVID-19 Patient Detected on Ventilation/Perfusion SPECT/CT.

ABSTRACT: Severe COVID-19 infection is associated with significant coagulopathy. We would like share a case of an asymptomatic 26-year-old man who tested positive for COVID-19 and had elevated d-dimer levels. Because of inconclusive CTPA findings, V/Q (ventilation/perfusion) SPECT/CT was performed, which confirmed the presence of pulmonary embolism. This case highlights the fact that pulmonary embolism should not be overlooked in a COVID-19 patient who has raised d-dimer levels, even in the absence of symptoms. It also highlights the importance of performing a V/Q study when CTPA results are inconclusive or when there are contraindications for iodinated contrast media.

Haemodynamic characteristics of COVID-19 patients with acute respiratory distress syndrome requiring mechanical ventilation. An invasive assessment using right heart catheterization.

AIMS: Interstitial pneumonia due to coronavirus disease 2019 (COVID-19) is often complicated by severe respiratory failure. In addition to reduced lung compliance and ventilation/perfusion mismatch, a blunted hypoxic pulmonary vasoconstriction has been hypothesized, that could explain part of the peculiar pathophysiology of the COVID-19 cardiorespiratory syndrome. However, no invasive haemodynamic characterization of COVID-19 patients has been reported so far. METHODS AND RESULTS: Twenty-one mechanically-ventilated COVID-19 patients underwent right heart catheterization. Their data were compared both with those obtained from non-mechanically ventilated paired control subjects matched for age, sex and body mass index, and with pooled data of 1937 patients with 'typical' acute respiratory distress syndrome (ARDS) from a systematic literature review. Cardiac index was higher in COVID-19 patients than in controls [3.8 (2.7-4.5) vs. 2.4 (2.1-2.8) L/min/m2 , P < 0.001], but slightly lower than in ARDS patients (P = 0.024). Intrapulmonary shunt and lung compliance were inversely related in COVID-19 patients (r = -0.57, P = 0.011) and did not differ from ARDS patients. Despite this, pulmonary vascular resistance of COVID-19 patients was normal, similar to that of control subjects [1.6 (1.1-2.5) vs. 1.6 (0.9-2.0) WU, P = 0.343], and lower than reported in ARDS patients (P < 0.01). Pulmonary hypertension was present in 76% of COVID-19 patients and in 19% of control subjects (P < 0.001), and it was always post-capillary. Pulmonary artery wedge pressure was higher in COVID-19 than in ARDS patients, and inversely related to lung compliance (r = -0.46, P = 0.038). CONCLUSIONS: The haemodynamic profile of COVID-19 patients needing mechanical ventilation is characterized by combined cardiopulmonary alterations. Low pulmonary vascular resistance, coherent with a blunted hypoxic vasoconstriction, is associated with high cardiac output and post-capillary pulmonary hypertension, that could eventually contribute to lung stiffness and promote a vicious circle between the lung and the heart.

Modeling lung perfusion abnormalities to explain early COVID-19 hypoxemia.

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.