Late Adult Respiratory Distress Syndrome Research Articles

Is there a role for insulin-like growth factor inhibition in the treatment of COVID-19-related adult respiratory distress syndrome?

Adult respiratory distress syndrome (ARDS) is the leading cause of death associated with SARS-CoV-2 infection and COVID-19. IGF-1 has been implicated in ARDS, yet its role in relation to COVID-19-related lung injury has not been investigated. We hypothesize that blockage of the IGF-1 receptor (IGF-1R) mitigates lung injury and decreases the risk of death in patients COVID-19-related ARDS. Patients with fibroproliferative ARDS have been shown to have increased IGF-1 and IGF-1R staining in lung tissue specimens. Rising levels of IGF-1 in bronchioalveolar fluid (BAL) and increased IGF-1 mRNA expression in lung tissues (but declining serum IGF-1 levels) have been found in late stage ARDS compared with early lung injury. Blockage of IGF-1R decreases lung tissue damage and increases survival in bleomycin-induced as well as H1N1 influenza-related lung injury in animal models. Teprotumumab is a monoclonal antibody directed against the IGF-1R that was FDA-approved in 2020 for the treatment of Graves’ orbitopathy. In order to determine if teprotumumab may reduce lung injury and death related to ARDS in the setting of COVID-19, preliminary clinical data is needed. IGF-1 levels in serum and BAL fluid must be measured in patients with COVID-19-related ARDS. Histopathology from lung samples from patients with COVID-19-related ARDS must be examined for increased expression of the IGF-1R. Once these are ascertained, and if the data support IGF-1 involvement, a randomized, placebo-controlled phase 2A trial of teprotumumab therapy in the setting of COVID-19-related ARDS and non-COVID-19-related ARDS designed to generate initial data on short-term efficacy, safety, dosing and administration should be performed.

Ventilator-associated pneumonia in patients with adult respiratory distress syndrome: CT evaluation.

To determine the diagnostic accuracy of computed tomography (CT) for pneumonia in patients with adult respiratory distress syndrome (ARDS). CT scans were obtained within 1 week of bronchoscopic sampling in 31 patients receiving mechanical ventilation for ARDS for more than 48 hours. Of 11 patients with pneumonia, five developed symptoms less than 11 days after the onset of ARDS (early ARDS). CT scans were rated for pneumonia independently by four radiologists who were unaware of the clinical diagnosis. Diagnostic accuracy was defined by means of the area under the receiver operating characteristic curve, or A2. Diagnostic accuracy for pneumonia was fair (A2 = 0.69 +/- 0.04 [standard error]) owing to 70% true-negative ratings (vs 59% true-positive ratings). The generalizability coefficient was good (0.79). No single CT finding was significantly different for the presence of pneumonia. Nondependent opacities predominated in 10 (91%) of 11 patients with pneumonia and 12 (60%) of 20 without pneumonia. Nondependent opacities predominated in nine (56%) of 16 patients with early ARDS and 13 (87%) of 15 with late ARDS. CT has fair diagnostic accuracy for ventilator-associated pneumonia in patients with ARDS owing primarily to identification of patients without pneumonia. No single CT sign was significantly different for pneumonia, but dependent atelectasis was more common in patients with early ARDS without pneumonia.

Computed tomography in adult respiratory distress syndrome: what has it taught us?

Computed tomography (CT) has played an important role in improving our knowledge of the pathophysiology of the adult respiratory distress syndrome (ARDS), and in determining the morphological and functional relationships of different manoeuvres commonly used in the therapeutic management of this syndrome (changes in body position, application of positive end-expiratory pressure (PEEP) and mechanical ventilation). During the early phase of the disease, the ARDS lung is characterized by a homogenous alteration of the vascular permeability. Thus, oedema accumulates evenly in all lung regions with a nongravitational distribution (homogenous lung). The increased lung weight, due to increased oedema, causes a collapse of the lung regions along the vertical axis, through the transmission of hydrostatic forces (compression atelectasis). Thus, the lesions appear mainly in the dependent lung regions (dishomogeneous lung). During inspiration, at plateau pressure, the pulmonary units reopen and, if the PEEP applied is adequate, they stay open during the following expiration. Adequate PEEP is equal to or higher than the hydrostatic forces compressing that unit. Prone position is another manoeuvre which allows previously collapsed lung regions to reopen and, conversely, compresses previously aerated regions, reversing the distribution of gravitational forces. During late ARDS, there is less compression atelectasis and the lung undergoes structural changes, due to the reduced amount of oedema. This is usually associated with CO2 retention and the development of emphysema-like lesions. In conclusion, computed tomography is not only a research tool, but a useful technique which allows a better understanding of the progressive change in strategy needed to ventilate the adult respiratory distress syndrome lung at different stages of the disease.

The role of gallium-67 scintigraphy in diagnosing sources of fever in ventilated patients.

To evaluate the diagnostic value of gallium-67 scintigraphy in febrile ventilated patients by correlating the findings of 67Ga scintigraphy to sources of fever and pulmonary density, as determined by a comprehensive protocolized diagnostic evaluation. Prospective observational study. Thirty-two intubated patients on mechanical ventilation for > or = 3 days with fever (> or = 38.3 degrees C) and a new or progressive density on chest radiograph. Twenty patients (21 tests) had adult respiratory distress syndrome (ARDS). Diagnostic evaluation for fever included bronchoscopy with protected specimen brushing and (protected) bronchoalveolar lavage (BAL); computed tomography (CT) of sinuses; cultures of blood, urine, and central lines; and CT of the abdomen in high-risk patients. Uptake of 67Ga was reported as either focal or diffuse pulmonary uptake and extrapulmonary uptake. The combined causes of fever were pneumonia (9), fibroproliferation of late ARDS (7), abdominal process (4), sinusitis (4), urinary tract infection (3), and others (6). Causes of the pulmonary densities were pneumonia (9), ARDS (13), atelectasis (7), congestive heart failure (3), and empyema (1). Marked and diffuse pulmonary uptake was found only in patients with ARDS; however, it was not useful in discriminating those patients with pulmonary fibroproliferation as the sole cause of fever (p = 0.167) from those with infection. 67Ga scintigraphy was inadequate for detecting pneumonia but valuable in identifying extrapulmonary sites of infection in patients with ARDS (p = 0.021). 67Ga scintigraphy should be considered only as an adjunct diagnostic test in the febrile, ventilated patient who has no obvious source of fever, despite a negative evaluation that includes testing for pneumonia, sinusitis, and urinary tract infection, conditions that are rarely detected by 67Ga scintigraphy.

Fever in Late Adult Respiratory Distress Syndrome: Etiology, Pathophysiology, and Diagnostic Evaluation

Fever in Late Adult Respiratory Distress Syndrome: Etiology, Pathophysiology, and Diagnostic Evaluation

Lung structure and function in different stages of severe adult respiratory distress syndrome

To assess the clinical consequences of duration of adult respiratory distress syndrome (ARDS) on lung structure and function. Retrospective analysis. A university hospital referral center for extracorporeal support. A total of 84 patients with severe ARDS (Murray score > 2.5) recruited from 48 intensive care units (1979 to 1992), who suffered ARDS and underwent mechanical ventilation for up to 1 week (37 patients with early ARDS), between 1 and 2 weeks (24 patients with intermediate ARDS), or more than 2 weeks (23 patients with late ARDS) and subsequently underwent extracorporeal support. Before beginning extracorporeal support, we measured gas exchange, pulmonary mechanics, hemodynamics, oxygen transport and delivery, incidence of barotrauma (presence of one or more thoracic tubes for pneumothorax drainage), and organ dysfunctions. In a subgroup of 16 patients, we studied lung structure by computed tomographic scan, scoring the densities and quantifying the emphysemalike lesions (bullae). Late ARDS showed lower respiratory compliance, higher dead space, higher PaCO2, lower venous admixture, and lower positive end-expiratory pressure requirement compared with early ARDS (P < .01). The incidence of pneumothorax (48.8% of the entire population) was significantly (P < .01) higher in late ARDS (87%) vs intermediate ARDS (46%) and early ARDS (30%). The mortality of patients with pneumothorax (66%) was significantly (P < .01) higher compared with patients without pneumothorax (46%). The number of bullae per lung was significantly higher in late ARDS vs intermediate and early ARDS (mean [SD], 8 [4], 4.3 [5], and 1.9 [3.9], respectively; P < .01), and they were preferentially distributed in the dependent lung regions. The number of bullae per lung was significantly higher in patients with pneumothorax vs those without pneumothorax (mean [SD], 13.6 [9.8] vs 1.4 [2.1]; P = .007). The mean (SD) duration of ARDS in patients with pneumothorax was 15.3 (10.0) days vs 7.0 (6.6) days in those without pneumothorax (P = .0001). No differences within the three groups were found in computed tomographic scan densities, hemodynamics, and number of organ system dysfunctions. The lung structure and function changes markedly with ARDS duration, and the late stages may be described as restrictive lung disease with superimposed emphysemalike lesions. Presence of pneumothorax affects survival and appears to be related to the lung structural changes occurring with time.

Fibroproliferation in Late Adult Respiratory Distress Syndrome: Pathophysiology, Clinical and Laboratory Manifestations, and Response to Corticosteroid Rescue Treatment

A dult respiratory distress syndrome (ARDS) is a dynamic disease that rapidly progresses into phases with different clinicopathophysiologic characteristics and different therapeutic needs. Late ARDS refers to the clinical stage of ARDS when the lung attempts to repair the initial or persistent injury to the endothelial and epithelial lining of the respiratory units. Its histologic correspondent is termed fibroproliferative phase which, if unhalted, leads to extensive fibrosis. Pulmonary fibroproliferation is a stereotypic reparative reaction to tissue injury characterized by the replacement of damaged epithelial cells and the striking accumulation of mesenchymal cells and their connective tissue products in the airspaces and walls of the intra-acinar microvessels. 1 Meduri GU Late ARDS New Horizons. 1993; 1: 563-577 PubMed Google Scholar Its evolution is determined by the extent of initial inflammatory reaction in the lung (alveolar denudation, basement membrane destruction, and quantity of intraalveolar exudate) and by the presence of a protracted inflammatory response (with or without control of the cause of ARDS). 2 Headley S Meduri GU Stentz F et al. Unfavorable outcome in patients with ARDS is related to persistent release of inflammatory cytokines [abstract]. Chest. 1993; 104: 154S Google Scholar , 3 Burkhardt A Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis. 1989; 140: 513-524 Crossref PubMed Scopus (143) Google Scholar Fibroproliferation is a diffuse process, as indicated by the findings of computed tomography, gross inspection at surgery, and microscopic analysis of biopsy specimens from different lobes. 1 Meduri GU Late ARDS New Horizons. 1993; 1: 563-577 PubMed Google Scholar Regional heterogeneity, however, exists, 1 Meduri GU Late ARDS New Horizons. 1993; 1: 563-577 PubMed Google Scholar and at histologic examination, focal areas of normal parenchyma are occasionally found. 1 Meduri GU Late ARDS New Horizons. 1993; 1: 563-577 PubMed Google Scholar

Alveolar surfactant and adult respiratory distress syndrome

SummaryThe adult respiratory distress syndrome (ARDS) is characterized by extended inflammatory processes in the lung microvascular, interstitial, and alveolar compartments, resulting in vasomotor disturbances, plasma leakage, cell injury, and complex gas exchange disturbances. Abnormalities in the alveolar surfactant system have long been implicated in the pathogenetic sequelae of this life-threatening syndrome. This hypothesis is supported by similarities in pulmonary failure between patients with ARDS and preterm babies with infant respiratory distress syndrome, known to be triggered primarily by lack of surfactant material. Mechanisms of surfactant alterations in ARDS include: (a) lack of surface-active compounds (phospholipids, apoproteins) due to reduced generation/release by diseased pneumocytes or to increased loss of material (this feature includes changes in the relative composition of the surfactant phospholipid and/or apoprotein profiles); (b) inhibition of surfactant function by plasma protein leakage (inhibitory potencies of different plasma proteins have been defined); (c) “incorporation” of surfactant phospholipids and apoproteins into polymerizing fibrin upon hyaline membrane formation; and (d) damage/inhibition of surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids). Alterations in alveolar surfactant function may well contribute to a variety of pathophysiological key events encountered in ARDS. These include decrease in compliance, ventilation-perfusion mismatch including shunt flow due to altered gas flow distribution (atelectasis, partial alveolar collapse, small airway collapse), and lung edema formation. Moreover, more speculative at the present time, surfactant abnormalities may add to a reduction in alveolar host defense competence and an upregulation of inflammatory events under conditions of ARDS. Persistent atelectasis of surfactant-deficient and in particular fibrin-loaded alveoli may represent a key event to trigger fibroblast proliferation and fibrosis in late ARDS (“collapse induration”). Overall, the presently available data on surfactant abnormalities in ARDS lend credit to therapeutic trials with transbronchial surfactant administration. In addition to the classical goals of replacement therapy defined for preterm infants (rapid improvement in lung compliance and gas exchange), this approach will have to consider its impact on host defense competence and inflammatory and proliferative processes when applied in adults with respiratory failure.

Fibroproliferative Phase of ARDS: Clinical Findings and Effects of Corticosteroids

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p less than 0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.

Pulmonary vascular permeability during the adult respiratory distress syndrome: a positron emission tomographic study.

The natural history of change in pulmonary vascular permeability (PVP) during the adult respiratory distress syndrome (ARDS) is unknown. Therefore, we evaluated PVP by measuring the pulmonary transcapillary escape rate (PTCER) for transferrin with positron emission tomography (PET) in 15 ARDS patients, including 5 patients studied within 4 days of onset and 13 patients studied at least 7 days after onset. In 3 patients, studies were performed at both early and late stages. These results were compared to 12 non-smoking adult volunteers. Regional PTCER and extravascular lung density (EVD) were determined from a 1-h PET scan after intravenous injection of gallium-68 citrate, which binds rapidly to native transferrin. Oxygenation, radiologic score, as well as outcome were recorded for each patient. Mean PTCER was highest during the early phase of ARDS (560 +/- 275 x 10(-4) min-1) although PTCER in the late ARDS patients was also significantly higher than in normals (319 +/- 187 vs 58 +/- 33 x 10(-4) min-1; p less than .01). EVD was similar in both early and late ARDS groups (.39 +/- .08 and .37 +/- .13 g/ml lung, respectively) and markedly higher than in normals (.22 +/- .05 g/ml lung, p less than 0.01). PTCER decreased in each of the 3 serial studies. The correlation between PTCER and EVD was poor, as were correlations for either PTCER or EVD versus changes in oxygenation, radiologic score, survival, or duration of ventilator dependency. In the late ARDS patients, PTCER was usually elevated even if EVD had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)