Mechanisms Of Alveolar Protein Clearance In The Intact Lung
acute respiratory distress syndrome; air-blood barrier; apoprotein sp-a; bronchoalveolar lavage fluid; diffusion; endocytosis; epithelial-cell monolayers; ii cells; instillation; intratracheal; junctions; opens tight; perfused rabbit lungs; Physiology; protein; rat lung; Respiratory System; respiratory-distress syndrome; transport pulmonary edema
Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lung. Various mechanisms have been proposed for clearing alveolar protein, including transport by the mucociliary escalator, intra-alveolar degradation, or phagocytosis by macrophages. However, the most likely processes are endocytosis across the alveolar epithelium, known as transcytosis, or paracellular diffusion through the epithelial barrier. This article focuses on protein transport studies that evaluate these two potential mechanisms in whole lung or animal preparations. When protein concentrations in the air spaces are low, e. g., albumin concentrations <0.5 g/100 ml, protein transport demonstrates saturation kinetics, temperature dependence indicating high energy requirements, and sensitivity to pharmacological agents that affect endocytosis. At higher concentrations, the protein clearance rate is proportional to protein concentration without signs of saturation, inversely related to protein size, and insensitive to endocytosis inhibition. Temperature dependence suggests a passive process. Based on these findings, alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations. Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs by paracellular pathways in the setting of pulmonary edema. Transcytosis may be important in regulating the alveolar milieu under nonpathological circumstances. Alveolar degradation may become important in long-term protein clearance, clearance of insoluble proteins, or under pathological conditions such as immune reactions or acute lung injury.
Hastings R H; Folkesson H G; Matthay M A
American Journal of Physiology-Lung Cellular and Molecular Physiology
2004
2004-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajplung.00205.2003" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00205.2003</a>
Dopexamine Hydrochloride In Septic Shock
consumption; dobutamine; dopexamine hydrochloride; endotoxic dogs; General & Internal Medicine; heart failure; infusion; inotropic support; lactate; muscle; O-2 transport; O-2 uptake; optimal values; oxygen delivery; Respiratory System; respiratory-distress syndrome; sepsis; septic shock; tissue oxygenation; volume support
Objective: To test whether dopexamine hydrochloride, by its beta(2)-adrenoceptor and dopaminergic 1 (DA(1)) and dopaminergic 2 (DA(2)) agonistic properties, can improve oxygen consumption (V over dot O-2) in hyperdynamic patients with septic shock. Design: Prospective, single-cohort study. Setting: ICU, university hospital. Patients: Twenty-nine postoperative, hemodynamically stabilized, hyperdynamic patients with septic shock. Interventions: Short-term application (30 min) of dopexamine hydrochloride at a dose of 2 mu g/kg/min. Measurements: Complete hemodynamic profile with O-2 transport-related variables at baseline, 30 min after starting the dopexamine infusion, and 30 min after stopping the infusion. Main results: The dopexamine infusion resulted in significant increases in cardiac index (17%) (p<0.001) and O-2 delivery (DO2) (16%) (p<0.001), V over dot O-2 increased slightly but significantly about 4% (p<0.01) by respiratory gas exchange measurements and 9% (p<0.01) by cardiovascular Fick calculations. The O-2 extraction ratio decreased about 8% (0.001). Conclusions: The addition of dopexamine hydrochloride at a dose of 2 mu g/kg/min resulted in significant increases of DO2 and to a lesser extent V over dot O-2. Much of the global DO2 increase was not utilized, because O-2 extraction ratio decreased. Direct calorigenic effects of dopexamine and an increase in myocardial V over dot O-2 likely account for a large portion of the increase in global V over dot O-2. Whether any of the V over dot O-2 increase reflects improvement in regions of jeopardized tissue oxygenation remains to be clarified before the definite value of this lug in septic shock can be established.
Hannemann L; Reinhart K; Meierhellmann A; Wallenfang G; Bredle D L
Chest
1996
1996-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1378/chest.109.3.756" target="_blank" rel="noreferrer noopener">10.1378/chest.109.3.756</a>
Prostacyclin In Septic Shock
critically; delivery; failure; General & Internal Medicine; ill patients; increases oxygen-consumption; infusion; lactate; norepinephrine therapy; Respiratory System; respiratory-distress syndrome; sepsis; tissue oxygenation
Objective: Investigation of the hypothesis that the infusion of 10 ng/kg/min prostacyclin (epoprostenol) (PGI(2)) improves O-2 uptake in patients with hyperdynamic septic shock. Design: Prospective, single cohort design. Setting: ICU, university hospital. Patients: Fifteen postoperative patients with septic shock. Interventions: Infusion of 10 ng/kg/min of PGI(2) for 60 min. Measurements: Complete hemodynamic profile with O-2 transport-related variables (simultaneous measurements of Vo(2) from the respiratory gases and by cardiovascular Fick) and blood lactate levels before start of the PGI(2)-infusion and 60 min thereafter. Main results: Oxygen delivery increased significantly (14 percent) from its already high value, 750+/-238 to 852+/-214 ml/min/m(2). The O-2 extraction ratio remained unchanged. When Vo(2) was measured from the respiratory gases, it was unchanged. When Vo(2) was measured by cardiovascular Fick, it increased slightly (p<0.05). Conclusions: We conclude that in this O-2 challenge test with PGI(2) in patients with septic shock, an increase in O-2 delivery was not matched by an increase in Vo(2). We believe that the adequate conventional support of these patients may have prevented the PGI(2) from revealing a ''covert'' O-2 debt. The PGI(2) test did not predict mortality by O-2 supply dependency. The small increase in Vo(2) as calculated indirectly suggests a degree of mathematical coupling of O-2 delivery and uptake.
Hannemann L; Reinhart K; Meierhellmann A; Bredle D L
Chest
1994
1994-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1378/chest.105.5.1504" target="_blank" rel="noreferrer noopener">10.1378/chest.105.5.1504</a>
Hypertonic Saline In Stabilized Hyperdynamic Sepsis
& Cardiology; cardiac-output; Cardiovascular System; delivery; dogs; fluid resuscitation; General & Internal Medicine; Hematology; hyperosmotic nacl; osmolality; oxygen consumption; respiratory-distress syndrome; septic shock; severe hemorrhagic-shock; Surgery
Hypertonic saline with or without colloidal solution has been successfully used for treating hemorrhagic shock in animal experiments and clinical studies. Due to its various effects at systemic, organ, and microcirculatory levels, the substance appears to be a promising candidate for improving tissue oxygenation in sepsis. We therefore investigated the hypothesis that infusion of hypertonic saline would further improve O-2 delivery, O-2 extraction, and O-2 uptake in hyperdynamic septic shock patients already stabilized by adequate volume and catecholamine infusion. Twenty-one patients received 2-4 mL/kg body weight of hypertonic saline in hydroxyethyl starch within 15 min. This hypertonic saline infusion caused a rapid significant increase in O-2 delivery by 14% but only a marginal increase in O-2 consumption (7% by cardiovascular Fick [p < .05], 4% by respiratory gases [n.s.]). Hypertonic saline increased the already elevated cardiac output by 24%. The pulmonary capillary wedge pressure increased from 14 +/- 3 to 23 +/- 3 mmHg and pulmonary shunt fraction increased 15%, but arterial PO2 did not fall. Except for the increase in pulmonary capillary wedge pressure, none of the cardiovascular changes lasted longer than 60 min. Plasma sodium levels increased from 138 +/- 25 to 163 +/- 38 mmol/L and normalized within 24 h. In these hyperdynamic septic patients, hypertonic saline infusion produced a transient increase in circulation, but no evidence of a substantial increase in O-2 consumption. Either there was no significant O-2 debt due to the already elevated O-2 delivery levels at baseline (700 mL/min/m(2)) or the global O-2 measurements we used were not able to detect discrete regional hypoxia.
Hannemann L; Reinhart K; Korell R; Spies C; Bredle D L
Shock
1996
1996-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/00024382-199602000-00008" target="_blank" rel="noreferrer noopener">10.1097/00024382-199602000-00008</a>
Neuromuscular Blocking Agents Use And Controversy In The Hospital Setting
Anesthesia; blockade; cardiac-arrest; intubation; management; meperidine; metaanalysis; paralysis; Pharmacology & Pharmacy; respiratory-distress syndrome; vecuronium
Neuromuscular blocking agents (NMBAs) play an important role in the management of a large number of hospital patients. The pharmacology of NMBAs is well understood, but the use of these agents can be controversial. NMBAs are common in surgical situations and rapid sequence intubation, but other indications, such as acute respiratory distress syndrome, therapeutic hypothermia, and elevated intracranial pressure, are somewhat divisive. It is essential for pharmacists to be familiar with clinical implications and outcomes associated with the use of NMBAs. In addition, it is important to understand concurrent considerations such as sedation, monitoring, and reversal. Pharmacists in the hospital setting should be familiar with the recently approved novel direct-reversal agent sugammadex (Bridion).
Gustafson K A; Brown A S
Us Pharmacist
2017
2017-01
Journal Article or Conference Abstract Publication
n/a
Therapeutic Strategies To Hasten The Resolution Of Pulmonary Edema
acute respirator distress syndrome; adult; aldosterone; alveolar fluid clearance; catecholamines; clearance; dexamethasone; epithelial fluid clearance; General & Internal Medicine; guinea-pigs; liquid; lung; lung fluid balance; pulmonary edema; rats; respiratory-distress syndrome
Folkesson H G; Matthay M A
Critical Care Medicine
2003
2003-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/01.ccm.0000059641.03915.75" target="_blank" rel="noreferrer noopener">10.1097/01.ccm.0000059641.03915.75</a>
Lung epithelial fluid transport and the resolution of pulmonary edema
Physiology; sodium transport; tumor-necrosis-factor; alveolar liquid clearance; respiratory-distress syndrome; adenovirus-mediated transfer; active; aquaporin water channels; beta-adrenergic receptors; pseudomonas-aeruginosa pneumonia; sensitive na+ channel; surface fluorescence method
The discovery of mechanisms that regulate salt and water transport by the alveolar and distal airway epithelium of the lung has generated new insights into the regulation of lung fluid balance under both normal and pathological conditions. There is convincing evidence that active sodium and chloride transporters are expressed in the distal lung epithelium and are responsible for the ability of the lung to remove alveolar fluid at the time of birth as well as in the mature lung when pathological conditions lead to the development of pulmonary edema. Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels. Both catecholamine-dependent and -independent mechanisms can upregulate isosmolar fluid transport across the distal lung epithelium. Experimental and clinical studies have made it possible to examine the role of these transporters in the resolution of pulmonary edema.
Matthay M A; Folkesson H G; Clerici C
Physiological Reviews
2002
2002-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/physrev.00003.2002" target="_blank" rel="noreferrer noopener">10.1152/physrev.00003.2002</a>
THROMBOCYTOPENIA IN INTENSIVE-CARE PATIENTS - A COMPREHENSIVE ANALYSIS OF RISK-FACTORS IN 314 PATIENTS
vancomycin; Pharmacology & Pharmacy; antibodies; respiratory-distress syndrome; septicemia; heparin-associated thrombocytopenia; intravascular coagulation
OBJECTIVE: To define the incidence and severity of thrombocytopenia in a mixed medical-surgical population of critically ill patients and to examine factors that may be related to the development of thrombocytopenia. DESIGN: Retrospective chart review of 314 critically ill patients requiring at least 3 days of critical care. SETTING: A 17-bed combined medical-surgical intensive care unit (ICU) in a 560-bed tertiary care community hospital. PATIENTS: Medical and surgical patients admitted to the ICU. INTERVENTIONS: All medical records over the duration of the ICU stay were reviewed, All scheduled medications, including dosage and start/stop dates, were recorded. All platelet counts, placement of pulmonary artery catheters, liver function test results, and admission serum creatinine concentrations were collected. MEASUREMENT AND MAIN RESULTS: Thrombocytopenia (platelet count less than 200 x 10(9)/L) was observed frequently, but rarely reached a severe stage (7 patients). No single diagnostic category was significantly associated with thrombocytopenia alone, although the combination of sepsis syndrome/septic shock and respiratory failure was strongly correlated (p < 0.0001) with thrombocytopenia. Liver function abnormalities were correlated strongly with thrombocytopenia, and the majority of patients (5 of 7) with severe thrombocytopenia (less than 20 x 10(9)/L) were found to have concurrent severe alterations in liver function test results. Pulmonary artery catheter placement and heparin exposure were associated strongly with thrombocytopenia (p < 0.0001). Drug therapies that were correlated with thrombocytopenia included heparin and vancomycin (p < 0.05). Hemodynamic instability was correlated strongly with the presence and severity of thrombocytopenia. In a stepwise linear regression model, the admission platelet count accounted for the largest proportion of the variance (43%), followed by hemodynamic instability (8%) and the requirement for inotropic agents (2%). CONCLUSIONS: Thrombocytopenia in the critically ill occurs frequently, rarely reaches severely depressed concentrations, and primarily represents a manifestation of disease processes initiated prior to admission. Hemodynamic instability and/or heparin exposure appear to be the strongest identifiable correlates with thrombocytopenia. Although these may cause infrequent isolated cases, other specific drug causes of thrombocytopenia are not responsible for the majority of cases of thrombocytopenia in the critically ill.
Bonfiglio M F; Traeger S M; Kier K L; Martin B R; Hulisz D T; Verbeck S R
Annals of Pharmacotherapy
1995
1995-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1177/106002809502900901" target="_blank" rel="noreferrer noopener">10.1177/106002809502900901</a>
Lung edema clearance: 20 years of progress - Invited review: Alveolar edema fluid clearance in the injured lung
therapy; liquid clearance; Physiology; pulmonary-edema; Sport Sciences; sodium transport; agonist; epithelial; active sodium-transport; alveolar fluid clearance; barrier function; agonists; respiratory-distress syndrome; na-k-atpase; adenovirus-mediated transfer; beta-adrenergic; beta(1) subunit gene; lung injury; rat lungs
Resolution of pulmonary edema involved active transepithelial sodium transport. Although several of the cellular and molecular mechanisms involved are relatively well understood, it is only recently that the regulation of these mechanisms in injured lung are being evaluated. Interestingly, in mild-to-moderate lung injury, alveolar edema fluid clearance is often preserved. This preserved or enhanced alveolar fluid clearance is mediated by catecholamine-dependent or -independent mechanisms. This stimulation of alveolar liquid clearance is related to activation or increased expression of sodium transport molecules such as the epithelial sodium channel or the Na+-K+-ATPase pump and may also involve the cystic fibrosis transmembrane conductance regulator. When severe lung injury occurs, the decrease in alveolar liquid clearance may be related to changes in alveolar permeability or to changes in activity or expression of sodium or chloride transport molecules. Multiple pharmacological tools such as beta-adrenergic agonists, vasoactive drugs, or gene therapy may prove effective in stimulating the resolution of alveolar edema in the injured lung.
Berthiaume Y; Folkesson H G; Matthay M A
Journal of Applied Physiology
2002
2002-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/japplphysiol.01201.2001" target="_blank" rel="noreferrer noopener">10.1152/japplphysiol.01201.2001</a>
Protective effect of endogenous beta-adrenergic tone on lung fluid balance in acute bacterial pneumonia in mice
active sodium-transport; alveolar fluid clearance; alveolar liquid clearance; barrier function; beta-adrenoceptor inhibition; dependent; Escherichia coli; hemorrhagic-shock; ion-transport; Physiology; protein-kinase; pulmonary edema; pulmonary edema; Respiratory System; respiratory-distress syndrome; septic; shock; sodium channel; up-regulation
Some investigators have reported that endogenous beta-adrenoceptor tone can provide protection against acute lung injury. Therefore, we tested the effects of beta-adrenoceptor inhibition in mice with acute Escherichia coli pneumonia. Mice were pretreated with propranolol or saline and then intratracheally instilled with live E. coli (10(7) colony-forming units). Hemodynamics, arterial blood gases, plasma catecholamines, extravascular lung water, lung permeability to protein, bacterial counts, and alveolar fluid clearance were measured. Acute E. coli pneumonia was established after 4 h with histological evidence of acute pulmonary inflammation, arterial hypoxemia, a threefold increase in lung vascular permeability, and a 30% increase in extravascular lung water as an increase in plasma catecholamine levels. beta-Adrenoceptor inhibition resulted in a marked increase in extravascular lung water that was explained by both an increase in lung vascular permeability and a reduction in net alveolar fluid clearance. The increase in extravascular lung water with propranolol pretreatment was not explained by an increase in systemic or vascular pressures. The increase in lung vascular permeability was explained in part by anti-inflammatory effects of beta-adrenoceptor stimulation because plasma macrophage inflammatory protein-2 levels were higher in the propranolol pretreatment group compared with controls. The decrease in alveolar fluid clearance with propranolol was explained by a decrease in catecholamine-stimulated fluid clearance. Together, these results indicate that endogenous beta-adrenoceptor tone has a protective effect in limiting accumulation of extravascular lung water in acute severe E. coli pneumonia in mice by two mechanisms: 1) reducing lung vascular injury and 2) upregulating the resolution of alveolar edema.
Su X; Robriquet L; Folkesson H G; Matthay M A
American Journal of Physiology-Lung Cellular and Molecular Physiology
2006
2006-04
Journal Article
<a href="http://doi.org/10.1152/ajplung.00334.2005" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00334.2005</a>