Hydrostatic Edema Research Articles

CEREBRAL EDEMA DUE TO TRAUMATIC BRAIN INJURY: PATHOPHYSIOLOGY AND ROLE OF NOVEL TARGETED THERAPIES

Cerebral edema is the accumulation of water in intracellular and interstitial brain tissue due to some neurological pathology. There are three principle mechanisms for cerebral edema: Cytotoxic edema, Vasogenic edema, Hydrostatic edema. There are multiple options available for treating cerebral edema including: medical management and surgical management. But none of the current treatment modalities address the underlying pathogenetic mechanism. So, targeted therapies are need of the hour. It may include NKCC1 antagonists, aquaporin inhibitors, Sur1-Trpm4 channel inhibitors, NHE inhibitors and VEGF inhibitors; which are in different stages of development. But, there are very few human trials that are conducted to assess the role of these pharmacologic agents in cerebral edema due to traumatic brain injury

Pulmonary Edema II: Noncardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome [ARDS]). This review focuses on noncardiogenic pulmonary edema and describes the general approach to patients with suspected pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of noncardiogenic pulmonary edema are reviewed. Miscellaneous causes of pulmonary edema are discussed, including neurologic insults, exposure to high altitude, reexpansion of a collapsed lung, lung transplantation, upper airway obstruction, drugs, and lung resection. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with noncardiogenic pulmonary edema, the definition of ARDS, causes of ARDS, and treatments for ARDS that do not involve ventilation. This review contains 3 figures, 9 tables, and 55 references. Key words: acute respiratory distress syndrome, diffuse alveolar damage, noncardiogenic pulmonary edema, pulmonary edema

Pulmonary Edema II: Noncardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome [ARDS]). This review focuses on noncardiogenic pulmonary edema and describes the general approach to patients with suspected pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of noncardiogenic pulmonary edema are reviewed. Miscellaneous causes of pulmonary edema are discussed, including neurologic insults, exposure to high altitude, reexpansion of a collapsed lung, lung transplantation, upper airway obstruction, drugs, and lung resection. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with noncardiogenic pulmonary edema, the definition of ARDS, causes of ARDS, and treatments for ARDS that do not involve ventilation. This review contains 3 figures, 9 tables, and 55 references. Key words: acute respiratory distress syndrome, diffuse alveolar damage, noncardiogenic pulmonary edema, pulmonary edema

Pulmonary Edema I: Cardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 24 references. Key words: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

Pulmonary Edema I: Cardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 29 references Keywords: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

Pulmonary Edema I: Cardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 24 references. Key words: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

Restricted, optimized or liberal fluid strategy in thoracic surgery: A narrative review.

Perioperative fluid balance has a major impact on clinical and functional outcome, regardless of the type of interventions. In thoracic surgery, patients are more vulnerable to intravenous fluid overload and to develop acute respiratory distress syndrome and other complications. New insight has been gained on the mechanisms causing pulmonary complications and the role of the endothelial glycocalix layer to control fluid transfer from the intravascular to the interstitial spaces and to promote tissue blood flow. With the implementation of standardized processes of care, the preoperative fasting period has become shorter, surgical approaches are less invasive and patients are allowed to resume oral intake shortly after surgery. Intraoperatively, body fluid homeostasis and adequate tissue oxygen delivery can be achieved using a normovolemic therapy targeting a “near-zero fluid balance” or a goal-directed hemodynamic therapy to maximize stroke volume and oxygen delivery according to the Franck–Starling relationship. In both fluid strategies, the use of cardiovascular drugs is advocated to counteract the anesthetic-induced vasorelaxation and maintain arterial pressure whereas fluid intake is limited to avoid cumulative fluid balance exceeding 1 liter and body weight gain (~1-1.5 kg). Modern hemodynamic monitors provide valuable physiological parameters to assess patient volume responsiveness and circulatory flow while guiding fluid administration and cardiovascular drug therapy. Given the lack of randomized clinical trials, controversial debate still surrounds the issues of the optimal fluid strategy and the type of fluids (crystalloids versus colloids). To avoid the risk of lung hydrostatic or inflammatory edema and to enhance the postoperative recovery process, fluid administration should be prescribed as any drug, adapted to the patient's requirement and the context of thoracic intervention.

Standardization of methods for sampling the distal airspace in mechanically ventilated patients using heat moisture exchange filter fluid.

Noninvasive sampling of the distal airspace in patients with acute respiratory distress syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from heat moisture exchange (HME) filters closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to determine fluid yield from different HME types, optimal HME circuit dwell time, and reliability of HME fluid in reflecting the distal airspace. We studied fluid yield from four different filter types by loading increasing volumes of saline and measuring volumes of fluid recovered. We collected filters after 1, 2, and 4 h of dwell time for measurement of fluid volume and total protein from 13 subjects. After identifying 4 h as the optimal dwell time, we measured total protein and IgM in HME fluid from 42 subjects with ARDS and nine with hydrostatic pulmonary edema (HYDRO). We found that the fluid yield varies greatly by filter type. With timed sample collection, fluid recovery increased with increasing circuit dwell time with a median volume of 2.0 mL [interquartile range (IQR) 1.2-2.7] after 4 h. Total protein was higher in the 42 subjects with ARDS compared with nine with HYDRO [median 708 µg/mL (IQR 244-2017) vs. 364 µg/mL (IQR 136-578), P = 0.047], confirming that total protein concentration in HME is higher in ARDS compared with hydrostatic edema. These studies establish a standardized HME fluid collection protocol and confirm that HME fluid analysis is a novel noninvasive tool for the study of the distal airspace in ARDS.

A TACO PRESENTATION MIMICKING NEW DIAGNOSIS OF ACUTE MYELOID LEUKEMIA WITH TUMOR LYSIS

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Transfusion-associated circulatory overload (TACO) should be suspected in patients who progress into acute respiratory distress and decompensate within several hours of a blood transfusion. TACO is separated from transfusion-related acute lung injury (TRALI) physiologically in development of hydrostatic cardiogenic edema rather than permeability edema. According to the NHSN (National Healthcare Safety Network) 2016-TACO clinical definition, the criteria consists of new onset dyspnea and cough, positive fluid balance, elevation in brain natriuretic peptide (BNP), and radiographic findings of pulmonary edema with evidence of left heart failure. Unfortunately, patients with leukemia, previous stem cell transplants, and other hematologic disorders can be more predisposed to TRALI; the risk factors are unclear although HLA incompatibility is theorized to be associated. Although TRALI has been mentioned in a few case reports for leukemia patients, interestingly TACO has not been described at all. CASE PRESENTATION: A 58-year-old male, otherwise healthy, initially presented with fatigue and shortness of breath. He was hemodynamically stable, and labs showed hemoglobin of 4.2 (normal 13.5—17.5), white blood cell count 20.1 (4.5—11.0), and platelet count 43 (160—420), BNP 617 (0—900 pg/ml). He received one unit of packed red blood cells and in several hours became hypoxic and tachypneic, hypertensive to 233/160, and required intubation. Repeat BNP was 1,676. Chest CT (Figure 1) showed bilateral pleural effusions and concern for ARDS. An echocardiogram showed new severely reduced systolic function with ejection fraction (EF) of 29% along with grade 2 diastolic dysfunction (Figure 2). Given flash pulmonary edema and a rising WBC count, he was given aggressive diuresis and broad spectrum antibiotics. WBC trended as high as 71.7, creatinine worsened to 2.0 (0.8—1.4 mg/dl), uric acid increased to 11.1 (3.7—7.0 mg/dl) and LDH worsened to 2,907 (87-241 units/L). Bone marrow biopsy showed hypercellular marrow with 21% blasts, trilineage dyspoiesis, consistent with acute myeloid leukemia with myelodysplasia related changes (AML-MRC) with positive CD117 stain. Patient was treated with rasburicase and allopurinol for tumor lysis. Repeat echo showed recovered EF to 55%, and patient was started on daunorubicin and cytarabine for chemotherapy. DISCUSSION: Signs of volume overload such as shortness of breath can occasionally be the clinical presentation of AML. Transfusion of packed RBCs was thought to contribute to acute cardiogenic pulmonary edema. This patient fulfilled all criteria of TACO surveillance diagnosis including acute respiratory distress within 6 hours of transfusion, pulmonary edema, volume overload, and BNP elevation. CONCLUSIONS: This case aims to remind the clinician to be cognizant of underlying etiologies that can "tip over” the threshold for TACO, such as leukemia. Reference #1: Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusion-related acute lung injury. Blood. 2019 Apr 25;133(17):1840-1853. doi:10.1182/blood-2018-10-860809. Epub 2019 Feb 26. Review. Reference #2: Ido, K., Aoyama, Y., Nagasaki, J., Koh, S., Ichihara, H., Harada, H., … Mugitani, A. (2017). Pulmonary Involvement of Acute Myeloid Leukemia Mimicking Transfusion-related Acute Lung Injury. Internal medicine (Tokyo, Japan), 56(18), 2493–2496. doi:10.2169/internalmedicine.8505-16 Reference #3: Kuriyan M. Commentary on TRALI in leukemia. J Pediatr Hematol Oncol. 2006 Jun;28(6):328-30. DISCLOSURES: No relevant relationships by Jonathan Chang, source=Web Response No relevant relationships by JENNIFER CHIURCO, source=Web Response No relevant relationships by Hanyuan Shi, source=Web Response No relevant relationships by Justin Spraglin, source=Web Response

"Mosaic Perfusion Pattern" on Dual-Energy CT in COVID-19 Pneumonia: Pulmonary Vasoplegia or Vasoconstriction?

HomeRadiology: Cardiothoracic ImagingVol. 2, No. 5 PreviousNext Letters to the EditorFree Access“Mosaic Perfusion Pattern” on Dual-Energy CT in COVID-19 Pneumonia: Pulmonary Vasoplegia or Vasoconstriction?Amit Jain* , D. John Doyle*, Ramesh Mangal†Amit Jain* , D. John Doyle*, Ramesh Mangal†Author AffiliationsAnesthesiology Institute, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates*Radiology Institute, Mednext, Ahmedabad, India†e-mail: [email protected]Amit Jain* D. John Doyle*Ramesh Mangal†Published Online:Sep 10 2020https://doi.org/10.1148/ryct.2020200433MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack Citations ShareShare onFacebookTwitterLinked In Editor:Finding dilated subsegmental vessels at dual-energy CT (DECT), Dr Lang and colleagues (1) proposed inflammatory-mediated impaired hypoxic pulmonary vasoconstriction (HPV) with overactive regional vasodilation to explain coronavirus disease 2019 (COVID-19) hypoxemia in their article in the June issue of Radiology: Cardiothoracic Imaging. However, this was not associated with increased pulmonary blood volume (PBV) in consolidated areas; instead, most (96%) patients had decreased peripheral perfusion corresponding to peripheral lung opacities, and only one-third demonstrated a halo of increased perfusion surrounding peripheral opacities. If HPV loss occurs in consolidated regions, PBV should have increased, producing hyperemia rather than oligemia. We instead propose an angiotensin II–mediated, nonimmune, noninflammatory mechanism to explain the mosaic perfusion pattern.Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection of alveolar epithelium results in downregulation of angiotensin-converting enzyme 2 (ACE-2) and ACE-angiotensin II-angiotensin II type 1 receptor pathway overactivity, producing heterogeneous small vessel vasoconstriction (2) and recruitment of segmental/subsegmental vessels with relatively less vasoconstriction, causing regional overperfusion, reduced diffusion capacity, increased shunt and hypoxia, even in the absence of radiologically evident lesions. Where precapillary constriction is intense (due to high local concentration of angiotensin II), PBV would decrease, reducing perfusion even in normal lung or may produce wedge-shaped areas of pulmonary deficit on DECT (3). In areas of ineffective constriction due to lower concentrations of angiotensin II, capillary filtration pressure would increase, resulting in capillary stress failure and hydrostatic interstitial edema with patchy ground-glass opacities (GGOs) on CT. Disruption of the alveolocapillary membrane develops, with SARS-CoV-2 directly infecting endothelial cells. Endothelialitis with intracapillary fibrin-microthrombi blocks alveolar capillaries and further decreases perfusion within the areas of GGOs and consolidation but, with dilatation of proximal subsegmental arterioles, along with a halo of increased perfusion surrounding regions of consolidation. Thus, in COVID-19 pneumonia as the GGOs worsens to consolidation, oligemia or hyperemia in the area of consolidation is largely determined by the balance between the endothelialitis-mediated capillary obstruction (in consolidation regions) versus angiotensin II-mediated regional vasoconstriction (in healthy lung regions) (3,4).Our theory is supported by high incidence of raised PVR and right ventricular dysfunction in early COVID-19 disease (5) and reports of lung perfusion deficits that do not overlap with GGOs or consolidation and are not associated with major vessel occlusion (3). We believe determining the predominant pathophysiology—heterogeneous pulmonary vasoconstriction versus pulmonary vasoplegia—has treatment implications: pulmonary vasoconstrictors versus vasodilators.Disclosures of Conflicts of Interest: A.J. disclosed no relevant relationships. D.J.D. disclosed no relevant relationships. R.M. disclosed no relevant relationships.

Pulmonary Edema: A Pictorial Review of Imaging Manifestations and Current Understanding of Mechanisms of Disease

Pulmonary edema is a common clinical entity caused by the extravascular movement of fluid into the pulmonary interstitium and alveoli. The four physiologic categories of edema include hydrostatic pressure edema, permeability edema with and without diffuse alveolar damage (DAD), and mixed edema where there is both an increase in hydrostatic pressure and membrane permeability. As radiographic manifestations and etiologies are varied, an appreciation for both the common and uncommon manifestations and causes of pulmonary edema is essential for accurate diagnosis.

PULMONARY EDEMA AND HEMOPTYSIS AFTER AN ORTHOPEDIC SURGERY

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Negative pressure pulmonary edema(NPPE) is an acute respiratory failure usually caused after a strong inspiratory effort generated against an obstructed upper airway[1]. CASE PRESENTATION: A 29-year-old man was admitted to the hospital for an elective open reduction with internal fixation of left bimalleolar ankle fracture. The surgery was uneventful. After extubation, he became hypoxic and started coughing up bloody phlegm without evidence of vomiting. He was afebrile, HR 96, RR 22 and BP 146/96. Chest x-ray showed bilateral alveolar consolidations in the upper and mid zones(Fig1). He was given Lasix 40 mg IV once and was transferred to the ICU. He was hemodynamically stable on high-flow oxygen. Arterial blood gas was showing pH of 7.41, PO2 98, pCO2 46 and HCO3 28.4. There was no evidence of swelling in the posterior pharynx. Lung exam showed good air entry on both sides, bilateral crepitations without wheezes. Laboratory work was unremarkable. Echocardiogram revealed normal ejection fraction, no significant valvular heart disease. He made a strong inspiratory effort after extubation due to upper airway laryngospasm and developed NPPE with alveolar hemorrhage. He was started on steroids. CT chest with contrast showed bilateral ground-glass opacities with alveolar infiltration in parenchymal hemorrhagic pattern(Fig2). He was continued on supportive treatment. Hemoptysis resolved in a day. He was transitioned to nasal cannula. Follow up chest x-ray showed significant improvement in alveolar infiltrates(Fig3). He was discharged home after a 48-h stay in the hospital. DISCUSSION: In adults, the most reported causes of airway obstruction leading to NPPE are in the context of laryngospasm following surgery[2]. The incidence of NPPE is as low as 0.1% of laryngospasm cases [3]. The first case of NPPE was reported and published in 1973 by Capitano and Kirkpatrick. There was a question whether NPPE was a result of high vessel permeability or hydrostatic pressure edema formation[1]. The high negative intrathoracic pressure generated to overcome the upper airway obstruction can reach -140 cm H2O[1]. The hydrostatic pressure in the pulmonary capillaries increases, the rate of interstitial fluid accumulation outgrows the capacity of the lymphatic drainage and fluid floods into the alveoli. Stress fracture can develop in the pulmonary capillaries leading to high permeability edema and blood-tinged secretions. Most cases of NPPE resolve in 24-48h. Diuretics have been used to hasten the resolution of the pulmonary edema. Beta agonist improves the clearance of the fluid by increasing active cation transport. In case of severe obstruction, cricothyroidotomy or tracheostomy can been used. Sedating and paralyzing the patient prevent more laryngospasm or biting of the endotracheal tube. CONCLUSIONS: NPPE is an entity not frequent encountered, but life threatening if not recognized or managed appropriately. Reference #1: M. Bhattacharya, R. H. Kallet, L. B. Ware, and M. A. Matthay, “Negative-Pressure Pulmonary Edema,” Chest, vol. 150, no. 4, pp. 927–933, Oct. 2016. Reference #2: A. Udeshi, S. M. Cantie, and E. Pierre, “Postobstructive pulmonary edema,” J. Crit. Care, vol. 25, no. 3, p. 538.e1-538.e5, 2010. Reference #3: B. Bhaskar and J. F. Fraser, “Negative pressure pulmonary edema revisited: Pathophysiology and review of management,” Saudi J. Anaesth., vol. 5, no. 3, pp. 308–313, 2011. DISCLOSURES: No relevant relationships by Arul Chandran, source=Web Response No relevant relationships by Michele Obeid, source=Web Response

Preliminary evidence that hydrostatic edema may contribute to the formation of diffuse alveolar damage in a Holstein calf model

Background: Two notable findings of clinically healthy feedlot cattle suggest they may have pulmonary hydrostatic edema during the finishing phase of production: increased pulmonary arterial wedge pressures and pulmonary venous hypertrophy. The goal of this study was to determine if increased pulmonary arterial wedge pressure (PAWP) in a Holstein calf could lead to diffuse alveolar damage consistent with the early, exudative phase of acute interstitial pneumonia of feedlot cattle. Methods: Six male Holstein dairy calves were given daily subcutaneous injections of the nonspecific ß-adrenergic agonist isoprenaline (10 mg/kg/d), to induce left ventricular diastolic dysfunction, or sterile water for 14 days. On Day 14, pulmonary arterial pressures and wedge pressures were measured, echocardiography performed, and the ratio of mitral valve flow velocity (E) to septal lengthening velocity (e’) calculated. Calves were euthanized on Day 15 and lung lesions semi-quantitatively scored. Results: Mean PAWP was 12 ± 1 mm Hg in calves that received isoprenaline and 7 ± 1 mm Hg in controls ( P = 0.01). Calves that received isoprenaline tended to have greater relative wall thickness than control calves ( P = 0.15) and greater E/e’ ratios ( P = 0.16), suggestive of concentric hypertrophy and diastolic dysfunction, respectively. Calves that received isoprenaline also tended to have a left ventricle and interventricular septum that was 29 ± 10 g heavier than control calves ( P = 0.10) when controlling for body mass. Hyaline membranes, the hallmark feature of diffuse alveolar damage, were evident in lung sections from all calves that received isoprenaline but none of the controls. Conclusions: Consistent with prior pathological and physiological studies of feedlot cattle, this study provides preliminary evidence that cattle presenting with clinical signs and pathology consistent with early stage acute interstitial pneumonia could be attributable to hydrostatic edema associated with left ventricular failure.

Preliminary evidence that hydrostatic edema may contribute to the formation of diffuse alveolar damage in a Holstein calf model.

Background: Two notable findings of clinically healthy feedlot cattle suggest they may have pulmonary hydrostatic edema during the finishing phase of production: increased pulmonary arterial wedge pressures and pulmonary venous hypertrophy. The goal of this study was to determine if increased pulmonary arterial wedge pressure (PAWP) in a Holstein calf could lead to diffuse alveolar damage consistent with the early, exudative phase of acute interstitial pneumonia of feedlot cattle. Methods: Six male Holstein dairy calves were given daily subcutaneous injections of the nonspecific ß-adrenergic agonist isoprenaline (10 mg/kg/d), to induce left ventricular diastolic dysfunction, or sterile water for 14 days. On Day 14, pulmonary arterial pressures and wedge pressures were measured, echocardiography performed, and the ratio of mitral valve flow velocity (E) to septal lengthening velocity (e') calculated. Calves were euthanized on Day 15 and lung lesions semi-quantitatively scored. Results: Mean PAWP was 12 ± 1 mm Hg in calves that received isoprenaline and 7 ± 1 mm Hg in controls ( P = 0.01). Calves that received isoprenaline tended to have greater relative wall thickness than control calves ( P = 0.15) and greater E/e' ratios ( P = 0.16), suggestive of concentric hypertrophy and diastolic dysfunction, respectively. Calves that received isoprenaline also tended to have a left ventricle and interventricular septum that was 29 ± 10 g heavier than control calves ( P = 0.10) when controlling for body mass. Hyaline membranes, the hallmark feature of diffuse alveolar damage, were evident in lung sections from all calves that received isoprenaline but none of the controls. Conclusions: Consistent with prior pathological and physiological studies of feedlot cattle, this study provides preliminary evidence that cattle presenting with clinical signs and pathology consistent with early stage acute interstitial pneumonia could be attributable to hydrostatic edema associated with left ventricular failure.

Pulmonary vascular dysfunction secondary to pulmonary arterial hypertension: insights gained through retrograde perfusion.

Here, we tested the hypothesis that severe pulmonary arterial hypertension impairs retrograde perfusion. To test this hypothesis, pulmonary arterial hypertension was induced in Fischer rats using a single injection of Sugen 5416 followed by 3 wk of exposure to 10% hypoxia and then 2 wk of normoxia. This Sugen 5416 and hypoxia regimen caused severe pulmonary arterial hypertension, with a Fulton index of 0.73 ± 0.07, reductions in both the pulmonary arterial acceleration time and pulmonary arterial acceleration to pulmonary arterial ejection times ratio, and extensive medial hypertrophy and occlusive neointimal lesions. Whereas the normotensive circulation accommodated large increases in forward and retrograde flow, the hypertensive circulation did not. During forward flow, pulmonary artery and double occlusion pressures rose sharply at low perfusion rates, resulting in hydrostatic edema. Pulmonary arterial hypertensive lungs possessed an absolute intolerance to retrograde perfusion, and they rapidly developed edema. Retrograde perfusion was not rescued by maximal vasodilation. Retrograde perfusion was preserved in lungs from animals treated with Sugen 5416 and hypoxia for 1 and 3 wk, in lungs from animals with a milder form of hypoxic hypertension, and in normotensive lungs subjected to high outflow pressures. Thus impaired retrograde perfusion coincides with development of severe pulmonary arterial hypertension, with advanced structural defects in the microcirculation.

Cytokine–Ion Channel Interactions in Pulmonary Inflammation

The lungs conceptually represent a sponge that is interposed in series in the bodies’ systemic circulation to take up oxygen and eliminate carbon dioxide. As such, it matches the huge surface areas of the alveolar epithelium to the pulmonary blood capillaries. The lung’s constant exposure to the exterior necessitates a competent immune system, as evidenced by the association of clinical immunodeficiencies with pulmonary infections. From the in utero to the postnatal and adult situation, there is an inherent vital need to manage alveolar fluid reabsorption, be it postnatally, or in case of hydrostatic or permeability edema. Whereas a wealth of literature exists on the physiological basis of fluid and solute reabsorption by ion channels and water pores, only sparse knowledge is available so far on pathological situations, such as in microbial infection, acute lung injury or acute respiratory distress syndrome, and in the pulmonary reimplantation response in transplanted lungs. The aim of this review is to discuss alveolar liquid clearance in a selection of lung injury models, thereby especially focusing on cytokines and mediators that modulate ion channels. Inflammation is characterized by complex and probably time-dependent co-signaling, interactions between the involved cell types, as well as by cell demise and barrier dysfunction, which may not uniquely determine a clinical picture. This review, therefore, aims to give integrative thoughts and wants to foster the unraveling of unmet needs in future research.

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Prospective laboratory animal investigation. Animal research laboratory. Newborn and 3 days to 1 week old pigs. Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset.

There is considerable biological and physiological heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a subgroup of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Nontargeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were conducted to find discriminant metabolites. Seven-hundred and sixty unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared with edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This "high metabolite" endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biological heterogeneity among ARDS patients who meet standard clinical and physiological criteria for ARDS.

Accelerated deflation promotes homogeneous airspace liquid distribution in the edematous lung.

Edematous lungs contain regions with heterogeneous alveolar flooding. Liquid is trapped in flooded alveoli by a pressure barrier-higher liquid pressure at the border than in the center of flooded alveoli-that is proportional to surface tension, T Stress is concentrated between aerated and flooded alveoli, to a degree proportional to T Mechanical ventilation, by cyclically increasing T, injuriously exacerbates stress concentrations. Overcoming the pressure barrier to redistribute liquid more homogeneously between alveoli should reduce stress concentration prevalence and ventilation injury. In isolated rat lungs, we test whether accelerated deflation can overcome the pressure barrier and catapult liquid out of flooded alveoli. We generate a local edema model with normal T by microinfusing liquid into surface alveoli. We generate a global edema model with high T by establishing hydrostatic edema, which does not alter T, and then gently ventilating the edematous lungs, which increases T at 15 cmH2O transpulmonary pressure by 52%. Thus ventilation of globally edematous lungs increases T, which should increase stress concentrations and, with positive feedback, cause escalating ventilation injury. In the local model, when the pressure barrier is moderate, accelerated deflation causes liquid to escape from flooded alveoli and redistribute more equitably. Flooding heterogeneity tends to decrease. In the global model, accelerated deflation causes liquid escape, but-because of elevated T-the liquid jumps to nearby, aerated alveoli. Flooding heterogeneity is unaltered. In pulmonary edema with normal T, early ventilation with accelerated deflation might reduce the positive feedback mechanism through which ventilation injury increases over time.NEW & NOTEWORTHY We introduce, in the isolated rat lung, a new model of pulmonary edema with elevated surface tension. We first generate hydrostatic edema and then ventilate gently to increase surface tension. We investigate the mechanical mechanisms through which 1) ventilation injures edematous lungs and 2) ventilation with accelerated deflation might lessen ventilation injury.

HECTD2 one step closer to understand susceptibility for acute respiratory disease syndrome?

Acute respiratory disease syndrome (ARDS) is defined by the Berlin definition as onset of respiratory distress within 1 week of a known clinical insult together with bilateral opacities in the absence of hydrostatic edema (1). Based on PaO 2 /FiO 2 and positive end expiratory pressure (PEEP) level ARDS is categorized in mild, moderate or severe. ARDS occurs at rates between 30 and 80 per 100,000 person-years and is a common cause of respiratory insufficiency and admission to an intensive care unit (ICU) (2). Prospective studies identified risk factors for developing ARDS such as sepsis, and major trauma. Recent outcome studies show that mortality is still high with hospital mortality between 35% and 46% (3).