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Fluid Flux and Clearance in Acute Lung Injury

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Abstract

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), were presciently described nearly two centuries ago by René Laennec, later to be described clinically in the 1950s and 1960s. Substantial advances have been made in understanding the pathogenesis of these forms of permeability pulmonary edema, including Starling forces and cellular transport mechanisms involved in the generation and resolution of this form of lung injury. Functional animal models and clinically applicable case definitions for ALI and ARDS were instrumental in gaining these new insights. Although no specific pharmacological therapies for ALI and ARDS yet exist, outcomes have improved with advancements in respiratory and fluid‐based supportive therapies, and methods to prevent the development or exacerbation of lung injury. Newer targeted therapies continue to be tested for efficacy in this condition where mortality rates frequently exceed 30%. In this article, we review the history of the pathophysiology of lung fluid and solute movement and the seminal clinical observations that brought that history to clinical relevance. We review the relevant lung structure and function and the dynamics of edema formation and resolution, and we describe the related clinical syndromes and the current treatment modalities. © 2012 American Physiological Society. Compr Physiol 2:2471‐2480, 2012.

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Figure 1. Figure 1.

The physiology of microvascular fluid exchange in the normal lung (Panel A) and the edematous lung (hydrostatic edema in Panel B, permeability edema in Panel C). The Starling equation for filtration of fluid across a semipermeable membrane describes the factors that determine the amount of fluid leaving the vascular space. In the normal lung (Panel A), fluid moves continuously from the vasculature to the interstitial space according to the net difference between hydrostatic and protein osmotic pressures, as well as to the permeability of the capillary membrane. When vascular hydrostatic pressure increases, the rate of transvascular fluid filtration rises and hydrostatic pulmonary edema develops first in the interstitium and later in the alveolus (Panel B). Permeability pulmonary edema (Panel C) occurs when the microvascular membrane permeability increases because of direct or indirect injury, resulting in a net increase in fluid and protein leaving the vascular space and reaching the alveolus. Reproduced with permission from reference .

Figure 2. Figure 2.

Illustration of Starling's equation, depicting the balance of forces affecting fluid flux across a semipermeable membrane, as with the alveolocapillary membrane. Pc = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, πc = capillary colloid osmotic pressure, πi = interstitial oncotic pressure, Kf = capillary filtration coefficient, QLYMPH = lymphatic flow, and δ = capillary reflection coefficient. Reproduced with permission from reference .



Figure 1.

The physiology of microvascular fluid exchange in the normal lung (Panel A) and the edematous lung (hydrostatic edema in Panel B, permeability edema in Panel C). The Starling equation for filtration of fluid across a semipermeable membrane describes the factors that determine the amount of fluid leaving the vascular space. In the normal lung (Panel A), fluid moves continuously from the vasculature to the interstitial space according to the net difference between hydrostatic and protein osmotic pressures, as well as to the permeability of the capillary membrane. When vascular hydrostatic pressure increases, the rate of transvascular fluid filtration rises and hydrostatic pulmonary edema develops first in the interstitium and later in the alveolus (Panel B). Permeability pulmonary edema (Panel C) occurs when the microvascular membrane permeability increases because of direct or indirect injury, resulting in a net increase in fluid and protein leaving the vascular space and reaching the alveolus. Reproduced with permission from reference .



Figure 2.

Illustration of Starling's equation, depicting the balance of forces affecting fluid flux across a semipermeable membrane, as with the alveolocapillary membrane. Pc = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, πc = capillary colloid osmotic pressure, πi = interstitial oncotic pressure, Kf = capillary filtration coefficient, QLYMPH = lymphatic flow, and δ = capillary reflection coefficient. Reproduced with permission from reference .

References
 1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 2: 319‐323, 1967.
 2. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. The American‐European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149: 818‐824, 1994.
 3. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM, Sibbald WJ, Kariman K, Higgins S, Bradley R, Metz CA. High‐dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 317: 1565‐1570, 1987.
 4. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, Wright PE. A trial of antioxidants N‐acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 112: 164‐172, 1997.
 5. Berthiaume Y, Folkesson HG, Matthay MA. Lung edema clearance: 20 years of progress: Invited review: Alveolar edema fluid clearance in the injured lung. J Appl Physiol 93: 2207‐2213, 2002.
 6. Bhattacharya J, Gropper MA, Shepard JM. Lung expansion and the perialveolar interstitial pressure gradient. J Appl Physiol 66: 2600‐2605, 1989.
 7. Bhattacharya J, Gropper MA, Staub NC. Interstitial fluid pressure gradient measured by micropuncture in excised dog lung. J Appl Physiol 56: 271‐277, 1984.
 8. Boitano S, Safdar Z, Welsh DG, Bhattacharya J, Koval M. Cell‐cell interactions in regulating lung function. Am J Physiol Lung Cell Mol Physiol 287: L455‐L459, 2004.
 9. Bone RC. Treatment of adult respiratory distress syndrome with diuretics, dialysis, and positive end‐expiratory pressure. Crit Care Med 6: 136‐139, 1978.
 10. Boyd JE, Newman JH, Brigham KL. Permeability pulmonary edema. Diagnosis and management. Arch Intern Med 144: 143‐147, 1984.
 11. Brigham KL, Bowers R, Haynes J. Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. Circ Res 45: 292‐297, 1979.
 12. Brigham KL, Harris TR, Bowers RE, Roselli RJ. Lung vascular permeability: Inferences from measurements of plasma to lung lymph protein transport. Lymphology 12: 177‐190, 1979.
 13. Brigham KL, Ramsey LH, Snell JD, Merritt CR, III. On defining the pulmonary extravascular water volume. Circ Res 29: 385‐397, 1971.
 14. Brigham KL, Staub NC. Pulmonary edema and acute lung injury research. Am J Respir Crit Care Med 157: S109‐S113, 1998.
 15. Brigham KL, Woolverton WC, Blake LH, Staub NC. Increased sheep lung vascular permeability caused by Pseudomonas bacteremia. J Clin Invest 54: 792‐804, 1974.
 16. Brower RG, Fessler HE. Mechanical ventilation in acute lung injury and acute respiratory distress syndrome. Clin Chest Med 21: 491‐510, viii, 2000.
 17. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. Higher versus lower positive end‐expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351: 327‐336, 2004.
 18. Conhaim RL, Lai‐Fook SJ, Staub NC. Sequence of perivascular liquid accumulation in liquid‐inflated dog lung lobes. J Appl Physiol 60: 513‐520, 1986.
 19. Cribbs SK, Martin GS. Fluid balance and colloid osmotic pressure in acute respiratory failure: Optimizing therapy. Expert Rev Respir Med 3: 651‐662, 2009.
 20. Davidson TA, Caldwell ES, Curtis JR, Hudson LD, Steinberg KP. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 281: 354‐360, 1999.
 21. Diaz JV, Brower R, Calfee CS, Matthay MA. Therapeutic strategies for severe acute lung injury. Crit Care Med 38: 1644‐1650, 2010.
 22. Drinker CK. The Lymphatic System: Its Part in Regulating Composition and Volume of Tissue Fluid. Stanford, California: Stanford University Press, 1942,
 23. Eaton DC, Helms MN, Koval M, Bao HF, Jain L. The contribution of epithelial sodium channels to alveolar function in health and disease. Annu Rev Physiol 71: 403‐423, 2009.
 24. Effros RM, Parker JC. Pulmonary vascular heterogeneity and the Starling hypothesis. Microvasc Res 78: 71‐77, 2009.
 25. Erickson SE, Martin GS, Davis JL, Matthay MA, Eisner MD. Recent trends in acute lung injury mortality: 1996‐2005. Crit Care Med 37: 1574‐1579, 2009.
 26. Fernandez ME, Vazquez MG, Cardenas A, Mansilla A, Cantalejo F, Rivera R. Ventilation with positive end‐expiratory pressure reduces extravascular lung water and increases lymphatic flow in hydrostatic pulmonary edema. Crit Care Med 24: 1562‐1567, 1996.
 27. Fung YC, Sobin SS. Elasticity of the pulmonary alveolar sheet. Circ Res 30: 451‐469, 1972.
 28. Glucksberg MR, Bhattacharya J. Effect of vascular pressure on interstitial pressures in the isolated dog lung. J Appl Physiol 75: 268‐272, 1993.
 29. Gorin AB, Stewart PA. Differential permeability of endothelial and epithelial barriers to albumin flux. J Appl Physiol 47: 1315‐1324, 1979.
 30. Guidot DM, Folkesson HG, Jain L, Sznajder JI, Pittet JF, Matthay MA. Integrating acute lung injury and regulation of alveolar fluid clearance. Am J Physiol Lung Cell Mol Physiol 291: L301‐L306, 2006.
 31. Guyton A, Lindsey A. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 7: 649‐657, 1959.
 32. Hansen‐Flaschen J. Cardiogenic and noncardiogenic pulmonary edema. In: Grippi M, editor. Pulmonary Pathophysiology, Philadelphia: J.B. Lippincott, 1995.
 33. Herridge MS, Cheung AM, Tansey CM, Matte‐Martyn A, Diaz‐Granados N, Al‐Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS. One‐year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348: 683‐693, 2003.
 34. Humphrey H, Hall J, Sznajder I, Silverstein M, Wood L. Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest 97: 1176‐1180, 1990.
 35. Jayr C, Matthay MA. Alveolar and lung liquid clearance in the absence of pulmonary blood flow in sheep. J Appl Physiol 71: 1679‐1687, 1991.
 36. Laennec RTH. A Treatise on Diseases of the Chest. London: 1821, pp. 98‐99.
 37. Landis EM, Pappenheimer JR. Exchange of substances through capillary walls. In: Hamilton WF, Dow P, editors. Handbook of Physiology, Washington, DC: American Physiological Society, 1963, pp. 961‐1034.
 38. Lewis CA, Martin GS. Understanding and managing fluid balance in patients with acute lung injury. Curr Opin Crit Care 10: 13‐17, 2004.
 39. Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, Christman BW, Dupont WD, Higgins SB, Swindell BB. Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 28: 3137‐3145, 2000.
 40. Martin GS, Bernard GR. Airway and lung dysfunction in sepsis. Intensive Care Med 27(Suppl 1): S63‐S79, 2001.
 41. Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, Morris JA, Bernard GR. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med 30: 2175‐2182, 2002.
 42. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 33: 1681‐1687, 2005.
 43. Matthay MA, Berthiaume Y, Jayr C, Hastings R. Alveolar liquid and protein clearance: In vivo studies. In: Effros R, Chang H, editors. Fluid and Solute Transport in the Airspaces of the Lungs, New York: Marcel Dekker, 1994.
 44. McClintock D, Zhuo H, Wickersham N, Matthay MA, Ware LB. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 12: R41, 2008.
 45. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: A randomized controlled trial. JAMA 280: 159‐165, 1998.
 46. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 145: 990‐998, 1992.
 47. Mutlu GM, Sznajder JI. Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol 289: L685‐L695, 2005.
 48. NHLBI ARDS Network. Albuterol for the treatment of ALI (ALTA) [Online]. http://www.ardsnet.org/studies/alta. Accessed on: February 14, 2011.
 49. Pappenheimer JR. Osmotic reflection coefficients in capillary membranes. In: Crone C, Lassen N, editors. Capillary Permeability. New York: Academic Press, 1970.
 50. Pappenheimer JR, Renkin EM, Borrero LM. Filtration, diffusion and molecular sieving through peripheral capillary membranes; a contribution to the pore theory of capillary permeability. Am J Physiol 167: 13‐46, 1951.
 51. Parker RE, Roselli RJ, Brigham KL. Effects of prolonged elevated microvascular pressure on lung fluid balance in sheep. J Appl Physiol 58: 869‐875, 1985.
 52. Parker RE, Roselli RJ, Harris TR, Brigham KL. Effects of graded increases in pulmonary vascular pressures on lung fluid balance in unanesthetized sheep. Circ Res 49: 1164‐1172, 1981.
 53. Perkins GD, McAuley DF, Thickett DR, Gao F. The beta‐agonist lung injury trial (BALTI): A randomized placebo‐controlled clinical trial. Am J Respir Crit Care Med 173: 281‐287, 2006.
 54. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med 141: 460‐470, 2004.
 55. Pitt Ford TR, Sachs JR, Grotberg JB, Glucksberg MR. Perialveolar interstitial resistance and compliance in isolated rat lung. J Appl Physiol 70: 2750‐2756, 1991.
 56. Renkin EM. Filtration, diffusion, and molecular sieving through porous cellulose membranes. J Gen Physiol 38: 225‐243, 1954.
 57. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685‐1693, 2005.
 58. Sakuma T, Pittet JF, Jayr C, Matthay MA. Alveolar liquid and protein clearance in the absence of blood flow or ventilation in sheep. J Appl Physiol 74: 176‐185, 1993.
 59. Schraufnagel DE, Agaram NP, Faruqui A, Jain S, Jain L, Ridge KM, Sznajder JI. Pulmonary lymphatics and edema accumulation after brief lung injury. Am J Physiol Lung Cell Mol Physiol 284: L891‐L897, 2003.
 60. Sibbald WJ, Driedger AA, Wells GA. The synergistic influence of the intravascular starling forces on pulmonary microvascular solute flux in human ARDS. J Surg Res 37: 123‐132, 1984.
 61. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 19: 312‐326, 1896.
 62. Staub NC. Pulmonary edema: Physiologic approaches to management. Chest 74: 559‐564, 1978.
 63. Staub NC, Bland RD, Brigham KL, Demling R, Erdmann AJ, III, Woolverton WC. Preparation of chronic lung lymph fistulas in sheep. J Surg Res 19: 315‐320, 1975.
 64. Staub NC, Nagano H, Pearce ML. The sequence of events during fluid accumulation in acute pulmonary edema. Jpn Heart J 8: 683‐689, 1967.
 65. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354: 1671‐1684, 2006.
 66. Taylor AE, Gaar KA, Jr. Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes. Am J Physiol 218: 1133‐1140, 1970.
 67. The acute respiratory distress syndrome network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301‐1308, 2000.
 68. Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. N Engl J Med 342: 1360‐1361, 2000.
 69. Tomashefski JF, Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med 21: 435‐466, 2000.
 70. Vadasz I, Raviv S, Sznajder JI. Alveolar epithelium and Na,K‐ATPase in acute lung injury. Intensive Care Med 33: 1243‐1251, 2007.
 71. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 342: 1334‐1349, 2000.
 72. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 163: 1376‐1383, 2001.
 73. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med 353: 2788‐2796, 2005.
 74. Weibel ER. The Pathway for Oxygen: Structure and Function in the Mammalian Respiratory System. Cambridge: Harvard University Press, 1984, pp. 211‐230.
 75. West JB. The physiologic basis of high‐altitude diseases. Ann Intern Med 141: 789‐800, 2004.
 76. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF, Jr., Hite RD, Harabin AL. Comparison of two fluid‐management strategies in acute lung injury. N Engl J Med 354: 2564‐2575, 2006.

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How to Cite

Greg S. Martin, Kenneth L. Brigham. Fluid Flux and Clearance in Acute Lung Injury. Compr Physiol 2012, 2: 2471-2480. doi: 10.1002/cphy.c100050